holistic qbd to enable product quality - pqri · – rakhi shah, ph.d., us food and drug...
TRANSCRIPT
PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
Moderator Chris Moreton PhD FinnBrit Consulting Presenters Ajit Narang PhD Genentech
Rakhi Shah PhD US FDADivyakant Desai PhD Bristol-Myers SquibbXavier Pepin PharmD PhD AstraZeneca
Holistic QbD to Enable Product Quality
October 2019
PQRI BTC WebinarOctober 2019
bull Welcome and Overview of Webinar ndash Moderator Chris Moreton PhD FinnBrit Consulting
bull Current State of QbD Practice and Growth Areas ndash An update on the PQRIQbD WG Discussions ndash Ajit Narang PhD Genentech
bull Evolving QbD trends in Regulatory Filings ndash Rakhi Shah PhD US Food and Drug Administration
bull Case study 1 Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations ndash Divyakant Desai PhD Bristol-Myers Squibb
bull Case study 2 Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets ndash Xavier Pepin PharmD PhD AstraZeneca
bull Moderated QampA Session with all speaker
2
Agenda
PQRI BTC WebinarOctober 2019
Please respond to the following polls on screen
3
Quick Polls
PQRI BTC WebinarOctober 2019
4
Poll 1
No38
Yes62
HAVE YOU WORKED WITH QBD PROJECTS BEFORE
PQRI BTC WebinarOctober 2019
5
Poll 2
Formulation Design and Development
27
API Process Development
4
Quality ControlQuality
Assurance16
Regualtory Affairs43
Other10
WHAT IS YOUR AREA OF RESPONSIBILITY (PLEASE SELECT THE AREA THAT BEST FITS YOUR JOB)
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6
GoToWebinar Housekeeping
This webinar is being recorded
The recording will be posted on the PQRI website at wwwpqriorg after the webinar
PQRI BTC WebinarOctober 2019
7
GoToWebinar Housekeeping
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
Mission PQRI is a non-profit consortium of organizations working together to generate and share timely relevant and impactful information that advances drug product quality manufacturing and regulation
8
Product Quality Research Institute (PQRI)
PQRI BTC WebinarOctober 2019
What Does PQRI Do bull Unites thought leaders from regulatory agencies standard setting
bodies industry and academia to conduct research and share knowledge on emerging scientific and regulatory quality challenges
bull Provides a unique neutral forum to develop broad consensus among a diverse collection of industry organizations and regulatory bodies
bull Creates opportunities to accomplish mutual goals that cannot be achieved by individual organizations
bull Impacts global regulatory guidance and standards bringing maximum value to members and patients
9
PQRI BTC WebinarOctober 2019
bull PQRI consists of two governing bodies ndash a Board of Directors and Steering Committee and three Technical Committees
bull Technical Committees each have a broad disciplinary focus that collectively spans the drug product regulatory lifecycle They establish and provide scientific guidance direction and oversight to PQRI working groups and research projects
10
PQRI Structure
bull Current PQRI Technical Committeesbull Biopharmaceutics Technical Committee (BTC)bull Development Technical Committee (DTC)bull Manufacturing Technical Committee (MTC)
bull This webinar is sponsored by the BTC bull The mission of the BTC is to identify disseminate
and facilitate scientific and technical projects to address gaps in biopharmaceutical aspects of drug development and global regulatory guidance
Biopharmaceutics Technical Committee
Manufacturing Technical
Committee
Development Technical
Committee
PQRI BTC WebinarOctober 2019
bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
bull Holistic QbD to Enable Product Quality (Today) Moderator Chris Moreton PhD FinnBrit Consulting PresentersAjit Narang PhD Genentech Rakhi Shah PhD US FDA Divyakant Desai PhD Bristol-Myers Squibb Xavier Pepin PharmD PhD AstraZeneca
bull Topic Complex Non-Oral Dosage Forms (eg Topical Inhalation)ndash NovemberDecember ndash Details to come
11
BTC 2019 Webinar Series
PQRI BTC WebinarOctober 2019
2018bull A Science Based Approach to Simplifying the Regulatory Pathway for Topical Drugs
(April 9 2018) Presenters Vinod P Shah PhD FAAPS FFIP and Flavian Radulescu PhD
bull Questions about the Proposed Topical Classification System (TCS) and What To Do With It (June 19 2018) Presenter Sam Raney PhD FDA
bull Performance Testing in Quality Control and Product Development Where are We (October 23 2018) Presenter Raimar Loumlbenberg PhD University of Alberta
bull Biowaiver Approaches for Solid Oral Dosage Forms in New Drug Applications (December 6 2018) Presenter Poonam Delvadia PhD FDA
2019bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical
Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
Recordings are available on the PQRI website at wwwpqriorg
12
Past BTC Webinars
PQRI BTC WebinarOctober 2019
bull See bios posted on PQRI website for more information
13
Todayrsquos Moderator and Presenters
copy2016 Genentech
Ajit Narang PhDOn behalf of the QbD WG Team
10 October 2019
Current State of QbD Practice and Growth Areas -An Update on the PQRI QbD WG Discussions
copy2016 Genentech
PQRI QbD WG Team
Name Organization Function
Chris Moreton Consultant Excipient supplier
Dilbir Bindra Bristol-Myers Squibb Drug Product ndash small amp large molecule
Jackson Pellett Genentech Analytical ndash small molecule
Tapan Das Bristol-Myers Squibb Analytical ndash large molecule
Atul Saluja Sanofi Drug Product ndash biologics
Sanket Patke Sanofi Drug Product ndash biologics
John Lepore Merck Regulatory
copy2016 Genentech
Highlights of Team Discussions
QbD principles commonly applied in certain areas
Statistical design and interpretation of studies around formulation
composition and process parameters
Justification of product specifications and control strategy
2012 concept paper by the PQRI QbD Specification Design and Lifecycle
Management Working Group of the PQRI Manufacturing Technical Committee on
ldquoQuality by Design Specifications for Solid Oral Dosage Forms Multivariate
Product and Process Monitoring for Managing Drug Quality Attributesrdquo
Justification of scope and ranges of variations within product components
analytical testing and operating parameters
copy2016 Genentech
Highlights of Team Discussions
Industry application of QbD principles is phase appropriate
Regulatory focus on commercial products
Quotient MHRA case of clinical formulation flexibility (Rapid FACT studies)
Provides prospective grounds and boundaries for justification of changes
Applied in clinical Phase 23 stages after process selectionfinalization
Applying QbD when not necessary might make it detrimental to the concept of
QbD
copy2016 Genentech
Highlights of Team Discussions
Common industry application of QbD principles is significantly
different between SM and LM (small amp large molecules)
More well established and widely practiced in the SM than LM
Earlier selection of formulation and process in LM (ie phase 1 in LM
compared to phase 23 in SM)
A likely driving factor limited material availability
Application of high throughput and material conserving workflows can help shift
this balance
Opportunities exist for application throughout LM processes
2015 book by Feroz Jameel Susan Hershenson Mansoor Khan and Sheryl
Martin-Moe on QbD for Biopharmaceutical DP Development AAPS Press
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
PQRI BTC WebinarOctober 2019
bull Welcome and Overview of Webinar ndash Moderator Chris Moreton PhD FinnBrit Consulting
bull Current State of QbD Practice and Growth Areas ndash An update on the PQRIQbD WG Discussions ndash Ajit Narang PhD Genentech
bull Evolving QbD trends in Regulatory Filings ndash Rakhi Shah PhD US Food and Drug Administration
bull Case study 1 Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations ndash Divyakant Desai PhD Bristol-Myers Squibb
bull Case study 2 Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets ndash Xavier Pepin PharmD PhD AstraZeneca
bull Moderated QampA Session with all speaker
2
Agenda
PQRI BTC WebinarOctober 2019
Please respond to the following polls on screen
3
Quick Polls
PQRI BTC WebinarOctober 2019
4
Poll 1
No38
Yes62
HAVE YOU WORKED WITH QBD PROJECTS BEFORE
PQRI BTC WebinarOctober 2019
5
Poll 2
Formulation Design and Development
27
API Process Development
4
Quality ControlQuality
Assurance16
Regualtory Affairs43
Other10
WHAT IS YOUR AREA OF RESPONSIBILITY (PLEASE SELECT THE AREA THAT BEST FITS YOUR JOB)
PQRI BTC WebinarOctober 2019
6
GoToWebinar Housekeeping
This webinar is being recorded
The recording will be posted on the PQRI website at wwwpqriorg after the webinar
PQRI BTC WebinarOctober 2019
7
GoToWebinar Housekeeping
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
Mission PQRI is a non-profit consortium of organizations working together to generate and share timely relevant and impactful information that advances drug product quality manufacturing and regulation
8
Product Quality Research Institute (PQRI)
PQRI BTC WebinarOctober 2019
What Does PQRI Do bull Unites thought leaders from regulatory agencies standard setting
bodies industry and academia to conduct research and share knowledge on emerging scientific and regulatory quality challenges
bull Provides a unique neutral forum to develop broad consensus among a diverse collection of industry organizations and regulatory bodies
bull Creates opportunities to accomplish mutual goals that cannot be achieved by individual organizations
bull Impacts global regulatory guidance and standards bringing maximum value to members and patients
9
PQRI BTC WebinarOctober 2019
bull PQRI consists of two governing bodies ndash a Board of Directors and Steering Committee and three Technical Committees
bull Technical Committees each have a broad disciplinary focus that collectively spans the drug product regulatory lifecycle They establish and provide scientific guidance direction and oversight to PQRI working groups and research projects
10
PQRI Structure
bull Current PQRI Technical Committeesbull Biopharmaceutics Technical Committee (BTC)bull Development Technical Committee (DTC)bull Manufacturing Technical Committee (MTC)
bull This webinar is sponsored by the BTC bull The mission of the BTC is to identify disseminate
and facilitate scientific and technical projects to address gaps in biopharmaceutical aspects of drug development and global regulatory guidance
Biopharmaceutics Technical Committee
Manufacturing Technical
Committee
Development Technical
Committee
PQRI BTC WebinarOctober 2019
bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
bull Holistic QbD to Enable Product Quality (Today) Moderator Chris Moreton PhD FinnBrit Consulting PresentersAjit Narang PhD Genentech Rakhi Shah PhD US FDA Divyakant Desai PhD Bristol-Myers Squibb Xavier Pepin PharmD PhD AstraZeneca
bull Topic Complex Non-Oral Dosage Forms (eg Topical Inhalation)ndash NovemberDecember ndash Details to come
11
BTC 2019 Webinar Series
PQRI BTC WebinarOctober 2019
2018bull A Science Based Approach to Simplifying the Regulatory Pathway for Topical Drugs
(April 9 2018) Presenters Vinod P Shah PhD FAAPS FFIP and Flavian Radulescu PhD
bull Questions about the Proposed Topical Classification System (TCS) and What To Do With It (June 19 2018) Presenter Sam Raney PhD FDA
bull Performance Testing in Quality Control and Product Development Where are We (October 23 2018) Presenter Raimar Loumlbenberg PhD University of Alberta
bull Biowaiver Approaches for Solid Oral Dosage Forms in New Drug Applications (December 6 2018) Presenter Poonam Delvadia PhD FDA
2019bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical
Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
Recordings are available on the PQRI website at wwwpqriorg
12
Past BTC Webinars
PQRI BTC WebinarOctober 2019
bull See bios posted on PQRI website for more information
13
Todayrsquos Moderator and Presenters
copy2016 Genentech
Ajit Narang PhDOn behalf of the QbD WG Team
10 October 2019
Current State of QbD Practice and Growth Areas -An Update on the PQRI QbD WG Discussions
copy2016 Genentech
PQRI QbD WG Team
Name Organization Function
Chris Moreton Consultant Excipient supplier
Dilbir Bindra Bristol-Myers Squibb Drug Product ndash small amp large molecule
Jackson Pellett Genentech Analytical ndash small molecule
Tapan Das Bristol-Myers Squibb Analytical ndash large molecule
Atul Saluja Sanofi Drug Product ndash biologics
Sanket Patke Sanofi Drug Product ndash biologics
John Lepore Merck Regulatory
copy2016 Genentech
Highlights of Team Discussions
QbD principles commonly applied in certain areas
Statistical design and interpretation of studies around formulation
composition and process parameters
Justification of product specifications and control strategy
2012 concept paper by the PQRI QbD Specification Design and Lifecycle
Management Working Group of the PQRI Manufacturing Technical Committee on
ldquoQuality by Design Specifications for Solid Oral Dosage Forms Multivariate
Product and Process Monitoring for Managing Drug Quality Attributesrdquo
Justification of scope and ranges of variations within product components
analytical testing and operating parameters
copy2016 Genentech
Highlights of Team Discussions
Industry application of QbD principles is phase appropriate
Regulatory focus on commercial products
Quotient MHRA case of clinical formulation flexibility (Rapid FACT studies)
Provides prospective grounds and boundaries for justification of changes
Applied in clinical Phase 23 stages after process selectionfinalization
Applying QbD when not necessary might make it detrimental to the concept of
QbD
copy2016 Genentech
Highlights of Team Discussions
Common industry application of QbD principles is significantly
different between SM and LM (small amp large molecules)
More well established and widely practiced in the SM than LM
Earlier selection of formulation and process in LM (ie phase 1 in LM
compared to phase 23 in SM)
A likely driving factor limited material availability
Application of high throughput and material conserving workflows can help shift
this balance
Opportunities exist for application throughout LM processes
2015 book by Feroz Jameel Susan Hershenson Mansoor Khan and Sheryl
Martin-Moe on QbD for Biopharmaceutical DP Development AAPS Press
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
PQRI BTC WebinarOctober 2019
Please respond to the following polls on screen
3
Quick Polls
PQRI BTC WebinarOctober 2019
4
Poll 1
No38
Yes62
HAVE YOU WORKED WITH QBD PROJECTS BEFORE
PQRI BTC WebinarOctober 2019
5
Poll 2
Formulation Design and Development
27
API Process Development
4
Quality ControlQuality
Assurance16
Regualtory Affairs43
Other10
WHAT IS YOUR AREA OF RESPONSIBILITY (PLEASE SELECT THE AREA THAT BEST FITS YOUR JOB)
PQRI BTC WebinarOctober 2019
6
GoToWebinar Housekeeping
This webinar is being recorded
The recording will be posted on the PQRI website at wwwpqriorg after the webinar
PQRI BTC WebinarOctober 2019
7
GoToWebinar Housekeeping
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
Mission PQRI is a non-profit consortium of organizations working together to generate and share timely relevant and impactful information that advances drug product quality manufacturing and regulation
8
Product Quality Research Institute (PQRI)
PQRI BTC WebinarOctober 2019
What Does PQRI Do bull Unites thought leaders from regulatory agencies standard setting
bodies industry and academia to conduct research and share knowledge on emerging scientific and regulatory quality challenges
bull Provides a unique neutral forum to develop broad consensus among a diverse collection of industry organizations and regulatory bodies
bull Creates opportunities to accomplish mutual goals that cannot be achieved by individual organizations
bull Impacts global regulatory guidance and standards bringing maximum value to members and patients
9
PQRI BTC WebinarOctober 2019
bull PQRI consists of two governing bodies ndash a Board of Directors and Steering Committee and three Technical Committees
bull Technical Committees each have a broad disciplinary focus that collectively spans the drug product regulatory lifecycle They establish and provide scientific guidance direction and oversight to PQRI working groups and research projects
10
PQRI Structure
bull Current PQRI Technical Committeesbull Biopharmaceutics Technical Committee (BTC)bull Development Technical Committee (DTC)bull Manufacturing Technical Committee (MTC)
bull This webinar is sponsored by the BTC bull The mission of the BTC is to identify disseminate
and facilitate scientific and technical projects to address gaps in biopharmaceutical aspects of drug development and global regulatory guidance
Biopharmaceutics Technical Committee
Manufacturing Technical
Committee
Development Technical
Committee
PQRI BTC WebinarOctober 2019
bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
bull Holistic QbD to Enable Product Quality (Today) Moderator Chris Moreton PhD FinnBrit Consulting PresentersAjit Narang PhD Genentech Rakhi Shah PhD US FDA Divyakant Desai PhD Bristol-Myers Squibb Xavier Pepin PharmD PhD AstraZeneca
bull Topic Complex Non-Oral Dosage Forms (eg Topical Inhalation)ndash NovemberDecember ndash Details to come
11
BTC 2019 Webinar Series
PQRI BTC WebinarOctober 2019
2018bull A Science Based Approach to Simplifying the Regulatory Pathway for Topical Drugs
(April 9 2018) Presenters Vinod P Shah PhD FAAPS FFIP and Flavian Radulescu PhD
bull Questions about the Proposed Topical Classification System (TCS) and What To Do With It (June 19 2018) Presenter Sam Raney PhD FDA
bull Performance Testing in Quality Control and Product Development Where are We (October 23 2018) Presenter Raimar Loumlbenberg PhD University of Alberta
bull Biowaiver Approaches for Solid Oral Dosage Forms in New Drug Applications (December 6 2018) Presenter Poonam Delvadia PhD FDA
2019bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical
Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
Recordings are available on the PQRI website at wwwpqriorg
12
Past BTC Webinars
PQRI BTC WebinarOctober 2019
bull See bios posted on PQRI website for more information
13
Todayrsquos Moderator and Presenters
copy2016 Genentech
Ajit Narang PhDOn behalf of the QbD WG Team
10 October 2019
Current State of QbD Practice and Growth Areas -An Update on the PQRI QbD WG Discussions
copy2016 Genentech
PQRI QbD WG Team
Name Organization Function
Chris Moreton Consultant Excipient supplier
Dilbir Bindra Bristol-Myers Squibb Drug Product ndash small amp large molecule
Jackson Pellett Genentech Analytical ndash small molecule
Tapan Das Bristol-Myers Squibb Analytical ndash large molecule
Atul Saluja Sanofi Drug Product ndash biologics
Sanket Patke Sanofi Drug Product ndash biologics
John Lepore Merck Regulatory
copy2016 Genentech
Highlights of Team Discussions
QbD principles commonly applied in certain areas
Statistical design and interpretation of studies around formulation
composition and process parameters
Justification of product specifications and control strategy
2012 concept paper by the PQRI QbD Specification Design and Lifecycle
Management Working Group of the PQRI Manufacturing Technical Committee on
ldquoQuality by Design Specifications for Solid Oral Dosage Forms Multivariate
Product and Process Monitoring for Managing Drug Quality Attributesrdquo
Justification of scope and ranges of variations within product components
analytical testing and operating parameters
copy2016 Genentech
Highlights of Team Discussions
Industry application of QbD principles is phase appropriate
Regulatory focus on commercial products
Quotient MHRA case of clinical formulation flexibility (Rapid FACT studies)
Provides prospective grounds and boundaries for justification of changes
Applied in clinical Phase 23 stages after process selectionfinalization
Applying QbD when not necessary might make it detrimental to the concept of
QbD
copy2016 Genentech
Highlights of Team Discussions
Common industry application of QbD principles is significantly
different between SM and LM (small amp large molecules)
More well established and widely practiced in the SM than LM
Earlier selection of formulation and process in LM (ie phase 1 in LM
compared to phase 23 in SM)
A likely driving factor limited material availability
Application of high throughput and material conserving workflows can help shift
this balance
Opportunities exist for application throughout LM processes
2015 book by Feroz Jameel Susan Hershenson Mansoor Khan and Sheryl
Martin-Moe on QbD for Biopharmaceutical DP Development AAPS Press
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
PQRI BTC WebinarOctober 2019
4
Poll 1
No38
Yes62
HAVE YOU WORKED WITH QBD PROJECTS BEFORE
PQRI BTC WebinarOctober 2019
5
Poll 2
Formulation Design and Development
27
API Process Development
4
Quality ControlQuality
Assurance16
Regualtory Affairs43
Other10
WHAT IS YOUR AREA OF RESPONSIBILITY (PLEASE SELECT THE AREA THAT BEST FITS YOUR JOB)
PQRI BTC WebinarOctober 2019
6
GoToWebinar Housekeeping
This webinar is being recorded
The recording will be posted on the PQRI website at wwwpqriorg after the webinar
PQRI BTC WebinarOctober 2019
7
GoToWebinar Housekeeping
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
Mission PQRI is a non-profit consortium of organizations working together to generate and share timely relevant and impactful information that advances drug product quality manufacturing and regulation
8
Product Quality Research Institute (PQRI)
PQRI BTC WebinarOctober 2019
What Does PQRI Do bull Unites thought leaders from regulatory agencies standard setting
bodies industry and academia to conduct research and share knowledge on emerging scientific and regulatory quality challenges
bull Provides a unique neutral forum to develop broad consensus among a diverse collection of industry organizations and regulatory bodies
bull Creates opportunities to accomplish mutual goals that cannot be achieved by individual organizations
bull Impacts global regulatory guidance and standards bringing maximum value to members and patients
9
PQRI BTC WebinarOctober 2019
bull PQRI consists of two governing bodies ndash a Board of Directors and Steering Committee and three Technical Committees
bull Technical Committees each have a broad disciplinary focus that collectively spans the drug product regulatory lifecycle They establish and provide scientific guidance direction and oversight to PQRI working groups and research projects
10
PQRI Structure
bull Current PQRI Technical Committeesbull Biopharmaceutics Technical Committee (BTC)bull Development Technical Committee (DTC)bull Manufacturing Technical Committee (MTC)
bull This webinar is sponsored by the BTC bull The mission of the BTC is to identify disseminate
and facilitate scientific and technical projects to address gaps in biopharmaceutical aspects of drug development and global regulatory guidance
Biopharmaceutics Technical Committee
Manufacturing Technical
Committee
Development Technical
Committee
PQRI BTC WebinarOctober 2019
bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
bull Holistic QbD to Enable Product Quality (Today) Moderator Chris Moreton PhD FinnBrit Consulting PresentersAjit Narang PhD Genentech Rakhi Shah PhD US FDA Divyakant Desai PhD Bristol-Myers Squibb Xavier Pepin PharmD PhD AstraZeneca
bull Topic Complex Non-Oral Dosage Forms (eg Topical Inhalation)ndash NovemberDecember ndash Details to come
11
BTC 2019 Webinar Series
PQRI BTC WebinarOctober 2019
2018bull A Science Based Approach to Simplifying the Regulatory Pathway for Topical Drugs
(April 9 2018) Presenters Vinod P Shah PhD FAAPS FFIP and Flavian Radulescu PhD
bull Questions about the Proposed Topical Classification System (TCS) and What To Do With It (June 19 2018) Presenter Sam Raney PhD FDA
bull Performance Testing in Quality Control and Product Development Where are We (October 23 2018) Presenter Raimar Loumlbenberg PhD University of Alberta
bull Biowaiver Approaches for Solid Oral Dosage Forms in New Drug Applications (December 6 2018) Presenter Poonam Delvadia PhD FDA
2019bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical
Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
Recordings are available on the PQRI website at wwwpqriorg
12
Past BTC Webinars
PQRI BTC WebinarOctober 2019
bull See bios posted on PQRI website for more information
13
Todayrsquos Moderator and Presenters
copy2016 Genentech
Ajit Narang PhDOn behalf of the QbD WG Team
10 October 2019
Current State of QbD Practice and Growth Areas -An Update on the PQRI QbD WG Discussions
copy2016 Genentech
PQRI QbD WG Team
Name Organization Function
Chris Moreton Consultant Excipient supplier
Dilbir Bindra Bristol-Myers Squibb Drug Product ndash small amp large molecule
Jackson Pellett Genentech Analytical ndash small molecule
Tapan Das Bristol-Myers Squibb Analytical ndash large molecule
Atul Saluja Sanofi Drug Product ndash biologics
Sanket Patke Sanofi Drug Product ndash biologics
John Lepore Merck Regulatory
copy2016 Genentech
Highlights of Team Discussions
QbD principles commonly applied in certain areas
Statistical design and interpretation of studies around formulation
composition and process parameters
Justification of product specifications and control strategy
2012 concept paper by the PQRI QbD Specification Design and Lifecycle
Management Working Group of the PQRI Manufacturing Technical Committee on
ldquoQuality by Design Specifications for Solid Oral Dosage Forms Multivariate
Product and Process Monitoring for Managing Drug Quality Attributesrdquo
Justification of scope and ranges of variations within product components
analytical testing and operating parameters
copy2016 Genentech
Highlights of Team Discussions
Industry application of QbD principles is phase appropriate
Regulatory focus on commercial products
Quotient MHRA case of clinical formulation flexibility (Rapid FACT studies)
Provides prospective grounds and boundaries for justification of changes
Applied in clinical Phase 23 stages after process selectionfinalization
Applying QbD when not necessary might make it detrimental to the concept of
QbD
copy2016 Genentech
Highlights of Team Discussions
Common industry application of QbD principles is significantly
different between SM and LM (small amp large molecules)
More well established and widely practiced in the SM than LM
Earlier selection of formulation and process in LM (ie phase 1 in LM
compared to phase 23 in SM)
A likely driving factor limited material availability
Application of high throughput and material conserving workflows can help shift
this balance
Opportunities exist for application throughout LM processes
2015 book by Feroz Jameel Susan Hershenson Mansoor Khan and Sheryl
Martin-Moe on QbD for Biopharmaceutical DP Development AAPS Press
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
PQRI BTC WebinarOctober 2019
5
Poll 2
Formulation Design and Development
27
API Process Development
4
Quality ControlQuality
Assurance16
Regualtory Affairs43
Other10
WHAT IS YOUR AREA OF RESPONSIBILITY (PLEASE SELECT THE AREA THAT BEST FITS YOUR JOB)
PQRI BTC WebinarOctober 2019
6
GoToWebinar Housekeeping
This webinar is being recorded
The recording will be posted on the PQRI website at wwwpqriorg after the webinar
PQRI BTC WebinarOctober 2019
7
GoToWebinar Housekeeping
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
Mission PQRI is a non-profit consortium of organizations working together to generate and share timely relevant and impactful information that advances drug product quality manufacturing and regulation
8
Product Quality Research Institute (PQRI)
PQRI BTC WebinarOctober 2019
What Does PQRI Do bull Unites thought leaders from regulatory agencies standard setting
bodies industry and academia to conduct research and share knowledge on emerging scientific and regulatory quality challenges
bull Provides a unique neutral forum to develop broad consensus among a diverse collection of industry organizations and regulatory bodies
bull Creates opportunities to accomplish mutual goals that cannot be achieved by individual organizations
bull Impacts global regulatory guidance and standards bringing maximum value to members and patients
9
PQRI BTC WebinarOctober 2019
bull PQRI consists of two governing bodies ndash a Board of Directors and Steering Committee and three Technical Committees
bull Technical Committees each have a broad disciplinary focus that collectively spans the drug product regulatory lifecycle They establish and provide scientific guidance direction and oversight to PQRI working groups and research projects
10
PQRI Structure
bull Current PQRI Technical Committeesbull Biopharmaceutics Technical Committee (BTC)bull Development Technical Committee (DTC)bull Manufacturing Technical Committee (MTC)
bull This webinar is sponsored by the BTC bull The mission of the BTC is to identify disseminate
and facilitate scientific and technical projects to address gaps in biopharmaceutical aspects of drug development and global regulatory guidance
Biopharmaceutics Technical Committee
Manufacturing Technical
Committee
Development Technical
Committee
PQRI BTC WebinarOctober 2019
bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
bull Holistic QbD to Enable Product Quality (Today) Moderator Chris Moreton PhD FinnBrit Consulting PresentersAjit Narang PhD Genentech Rakhi Shah PhD US FDA Divyakant Desai PhD Bristol-Myers Squibb Xavier Pepin PharmD PhD AstraZeneca
bull Topic Complex Non-Oral Dosage Forms (eg Topical Inhalation)ndash NovemberDecember ndash Details to come
11
BTC 2019 Webinar Series
PQRI BTC WebinarOctober 2019
2018bull A Science Based Approach to Simplifying the Regulatory Pathway for Topical Drugs
(April 9 2018) Presenters Vinod P Shah PhD FAAPS FFIP and Flavian Radulescu PhD
bull Questions about the Proposed Topical Classification System (TCS) and What To Do With It (June 19 2018) Presenter Sam Raney PhD FDA
bull Performance Testing in Quality Control and Product Development Where are We (October 23 2018) Presenter Raimar Loumlbenberg PhD University of Alberta
bull Biowaiver Approaches for Solid Oral Dosage Forms in New Drug Applications (December 6 2018) Presenter Poonam Delvadia PhD FDA
2019bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical
Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
Recordings are available on the PQRI website at wwwpqriorg
12
Past BTC Webinars
PQRI BTC WebinarOctober 2019
bull See bios posted on PQRI website for more information
13
Todayrsquos Moderator and Presenters
copy2016 Genentech
Ajit Narang PhDOn behalf of the QbD WG Team
10 October 2019
Current State of QbD Practice and Growth Areas -An Update on the PQRI QbD WG Discussions
copy2016 Genentech
PQRI QbD WG Team
Name Organization Function
Chris Moreton Consultant Excipient supplier
Dilbir Bindra Bristol-Myers Squibb Drug Product ndash small amp large molecule
Jackson Pellett Genentech Analytical ndash small molecule
Tapan Das Bristol-Myers Squibb Analytical ndash large molecule
Atul Saluja Sanofi Drug Product ndash biologics
Sanket Patke Sanofi Drug Product ndash biologics
John Lepore Merck Regulatory
copy2016 Genentech
Highlights of Team Discussions
QbD principles commonly applied in certain areas
Statistical design and interpretation of studies around formulation
composition and process parameters
Justification of product specifications and control strategy
2012 concept paper by the PQRI QbD Specification Design and Lifecycle
Management Working Group of the PQRI Manufacturing Technical Committee on
ldquoQuality by Design Specifications for Solid Oral Dosage Forms Multivariate
Product and Process Monitoring for Managing Drug Quality Attributesrdquo
Justification of scope and ranges of variations within product components
analytical testing and operating parameters
copy2016 Genentech
Highlights of Team Discussions
Industry application of QbD principles is phase appropriate
Regulatory focus on commercial products
Quotient MHRA case of clinical formulation flexibility (Rapid FACT studies)
Provides prospective grounds and boundaries for justification of changes
Applied in clinical Phase 23 stages after process selectionfinalization
Applying QbD when not necessary might make it detrimental to the concept of
QbD
copy2016 Genentech
Highlights of Team Discussions
Common industry application of QbD principles is significantly
different between SM and LM (small amp large molecules)
More well established and widely practiced in the SM than LM
Earlier selection of formulation and process in LM (ie phase 1 in LM
compared to phase 23 in SM)
A likely driving factor limited material availability
Application of high throughput and material conserving workflows can help shift
this balance
Opportunities exist for application throughout LM processes
2015 book by Feroz Jameel Susan Hershenson Mansoor Khan and Sheryl
Martin-Moe on QbD for Biopharmaceutical DP Development AAPS Press
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
PQRI BTC WebinarOctober 2019
6
GoToWebinar Housekeeping
This webinar is being recorded
The recording will be posted on the PQRI website at wwwpqriorg after the webinar
PQRI BTC WebinarOctober 2019
7
GoToWebinar Housekeeping
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
Mission PQRI is a non-profit consortium of organizations working together to generate and share timely relevant and impactful information that advances drug product quality manufacturing and regulation
8
Product Quality Research Institute (PQRI)
PQRI BTC WebinarOctober 2019
What Does PQRI Do bull Unites thought leaders from regulatory agencies standard setting
bodies industry and academia to conduct research and share knowledge on emerging scientific and regulatory quality challenges
bull Provides a unique neutral forum to develop broad consensus among a diverse collection of industry organizations and regulatory bodies
bull Creates opportunities to accomplish mutual goals that cannot be achieved by individual organizations
bull Impacts global regulatory guidance and standards bringing maximum value to members and patients
9
PQRI BTC WebinarOctober 2019
bull PQRI consists of two governing bodies ndash a Board of Directors and Steering Committee and three Technical Committees
bull Technical Committees each have a broad disciplinary focus that collectively spans the drug product regulatory lifecycle They establish and provide scientific guidance direction and oversight to PQRI working groups and research projects
10
PQRI Structure
bull Current PQRI Technical Committeesbull Biopharmaceutics Technical Committee (BTC)bull Development Technical Committee (DTC)bull Manufacturing Technical Committee (MTC)
bull This webinar is sponsored by the BTC bull The mission of the BTC is to identify disseminate
and facilitate scientific and technical projects to address gaps in biopharmaceutical aspects of drug development and global regulatory guidance
Biopharmaceutics Technical Committee
Manufacturing Technical
Committee
Development Technical
Committee
PQRI BTC WebinarOctober 2019
bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
bull Holistic QbD to Enable Product Quality (Today) Moderator Chris Moreton PhD FinnBrit Consulting PresentersAjit Narang PhD Genentech Rakhi Shah PhD US FDA Divyakant Desai PhD Bristol-Myers Squibb Xavier Pepin PharmD PhD AstraZeneca
bull Topic Complex Non-Oral Dosage Forms (eg Topical Inhalation)ndash NovemberDecember ndash Details to come
11
BTC 2019 Webinar Series
PQRI BTC WebinarOctober 2019
2018bull A Science Based Approach to Simplifying the Regulatory Pathway for Topical Drugs
(April 9 2018) Presenters Vinod P Shah PhD FAAPS FFIP and Flavian Radulescu PhD
bull Questions about the Proposed Topical Classification System (TCS) and What To Do With It (June 19 2018) Presenter Sam Raney PhD FDA
bull Performance Testing in Quality Control and Product Development Where are We (October 23 2018) Presenter Raimar Loumlbenberg PhD University of Alberta
bull Biowaiver Approaches for Solid Oral Dosage Forms in New Drug Applications (December 6 2018) Presenter Poonam Delvadia PhD FDA
2019bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical
Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
Recordings are available on the PQRI website at wwwpqriorg
12
Past BTC Webinars
PQRI BTC WebinarOctober 2019
bull See bios posted on PQRI website for more information
13
Todayrsquos Moderator and Presenters
copy2016 Genentech
Ajit Narang PhDOn behalf of the QbD WG Team
10 October 2019
Current State of QbD Practice and Growth Areas -An Update on the PQRI QbD WG Discussions
copy2016 Genentech
PQRI QbD WG Team
Name Organization Function
Chris Moreton Consultant Excipient supplier
Dilbir Bindra Bristol-Myers Squibb Drug Product ndash small amp large molecule
Jackson Pellett Genentech Analytical ndash small molecule
Tapan Das Bristol-Myers Squibb Analytical ndash large molecule
Atul Saluja Sanofi Drug Product ndash biologics
Sanket Patke Sanofi Drug Product ndash biologics
John Lepore Merck Regulatory
copy2016 Genentech
Highlights of Team Discussions
QbD principles commonly applied in certain areas
Statistical design and interpretation of studies around formulation
composition and process parameters
Justification of product specifications and control strategy
2012 concept paper by the PQRI QbD Specification Design and Lifecycle
Management Working Group of the PQRI Manufacturing Technical Committee on
ldquoQuality by Design Specifications for Solid Oral Dosage Forms Multivariate
Product and Process Monitoring for Managing Drug Quality Attributesrdquo
Justification of scope and ranges of variations within product components
analytical testing and operating parameters
copy2016 Genentech
Highlights of Team Discussions
Industry application of QbD principles is phase appropriate
Regulatory focus on commercial products
Quotient MHRA case of clinical formulation flexibility (Rapid FACT studies)
Provides prospective grounds and boundaries for justification of changes
Applied in clinical Phase 23 stages after process selectionfinalization
Applying QbD when not necessary might make it detrimental to the concept of
QbD
copy2016 Genentech
Highlights of Team Discussions
Common industry application of QbD principles is significantly
different between SM and LM (small amp large molecules)
More well established and widely practiced in the SM than LM
Earlier selection of formulation and process in LM (ie phase 1 in LM
compared to phase 23 in SM)
A likely driving factor limited material availability
Application of high throughput and material conserving workflows can help shift
this balance
Opportunities exist for application throughout LM processes
2015 book by Feroz Jameel Susan Hershenson Mansoor Khan and Sheryl
Martin-Moe on QbD for Biopharmaceutical DP Development AAPS Press
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
PQRI BTC WebinarOctober 2019
7
GoToWebinar Housekeeping
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
Mission PQRI is a non-profit consortium of organizations working together to generate and share timely relevant and impactful information that advances drug product quality manufacturing and regulation
8
Product Quality Research Institute (PQRI)
PQRI BTC WebinarOctober 2019
What Does PQRI Do bull Unites thought leaders from regulatory agencies standard setting
bodies industry and academia to conduct research and share knowledge on emerging scientific and regulatory quality challenges
bull Provides a unique neutral forum to develop broad consensus among a diverse collection of industry organizations and regulatory bodies
bull Creates opportunities to accomplish mutual goals that cannot be achieved by individual organizations
bull Impacts global regulatory guidance and standards bringing maximum value to members and patients
9
PQRI BTC WebinarOctober 2019
bull PQRI consists of two governing bodies ndash a Board of Directors and Steering Committee and three Technical Committees
bull Technical Committees each have a broad disciplinary focus that collectively spans the drug product regulatory lifecycle They establish and provide scientific guidance direction and oversight to PQRI working groups and research projects
10
PQRI Structure
bull Current PQRI Technical Committeesbull Biopharmaceutics Technical Committee (BTC)bull Development Technical Committee (DTC)bull Manufacturing Technical Committee (MTC)
bull This webinar is sponsored by the BTC bull The mission of the BTC is to identify disseminate
and facilitate scientific and technical projects to address gaps in biopharmaceutical aspects of drug development and global regulatory guidance
Biopharmaceutics Technical Committee
Manufacturing Technical
Committee
Development Technical
Committee
PQRI BTC WebinarOctober 2019
bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
bull Holistic QbD to Enable Product Quality (Today) Moderator Chris Moreton PhD FinnBrit Consulting PresentersAjit Narang PhD Genentech Rakhi Shah PhD US FDA Divyakant Desai PhD Bristol-Myers Squibb Xavier Pepin PharmD PhD AstraZeneca
bull Topic Complex Non-Oral Dosage Forms (eg Topical Inhalation)ndash NovemberDecember ndash Details to come
11
BTC 2019 Webinar Series
PQRI BTC WebinarOctober 2019
2018bull A Science Based Approach to Simplifying the Regulatory Pathway for Topical Drugs
(April 9 2018) Presenters Vinod P Shah PhD FAAPS FFIP and Flavian Radulescu PhD
bull Questions about the Proposed Topical Classification System (TCS) and What To Do With It (June 19 2018) Presenter Sam Raney PhD FDA
bull Performance Testing in Quality Control and Product Development Where are We (October 23 2018) Presenter Raimar Loumlbenberg PhD University of Alberta
bull Biowaiver Approaches for Solid Oral Dosage Forms in New Drug Applications (December 6 2018) Presenter Poonam Delvadia PhD FDA
2019bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical
Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
Recordings are available on the PQRI website at wwwpqriorg
12
Past BTC Webinars
PQRI BTC WebinarOctober 2019
bull See bios posted on PQRI website for more information
13
Todayrsquos Moderator and Presenters
copy2016 Genentech
Ajit Narang PhDOn behalf of the QbD WG Team
10 October 2019
Current State of QbD Practice and Growth Areas -An Update on the PQRI QbD WG Discussions
copy2016 Genentech
PQRI QbD WG Team
Name Organization Function
Chris Moreton Consultant Excipient supplier
Dilbir Bindra Bristol-Myers Squibb Drug Product ndash small amp large molecule
Jackson Pellett Genentech Analytical ndash small molecule
Tapan Das Bristol-Myers Squibb Analytical ndash large molecule
Atul Saluja Sanofi Drug Product ndash biologics
Sanket Patke Sanofi Drug Product ndash biologics
John Lepore Merck Regulatory
copy2016 Genentech
Highlights of Team Discussions
QbD principles commonly applied in certain areas
Statistical design and interpretation of studies around formulation
composition and process parameters
Justification of product specifications and control strategy
2012 concept paper by the PQRI QbD Specification Design and Lifecycle
Management Working Group of the PQRI Manufacturing Technical Committee on
ldquoQuality by Design Specifications for Solid Oral Dosage Forms Multivariate
Product and Process Monitoring for Managing Drug Quality Attributesrdquo
Justification of scope and ranges of variations within product components
analytical testing and operating parameters
copy2016 Genentech
Highlights of Team Discussions
Industry application of QbD principles is phase appropriate
Regulatory focus on commercial products
Quotient MHRA case of clinical formulation flexibility (Rapid FACT studies)
Provides prospective grounds and boundaries for justification of changes
Applied in clinical Phase 23 stages after process selectionfinalization
Applying QbD when not necessary might make it detrimental to the concept of
QbD
copy2016 Genentech
Highlights of Team Discussions
Common industry application of QbD principles is significantly
different between SM and LM (small amp large molecules)
More well established and widely practiced in the SM than LM
Earlier selection of formulation and process in LM (ie phase 1 in LM
compared to phase 23 in SM)
A likely driving factor limited material availability
Application of high throughput and material conserving workflows can help shift
this balance
Opportunities exist for application throughout LM processes
2015 book by Feroz Jameel Susan Hershenson Mansoor Khan and Sheryl
Martin-Moe on QbD for Biopharmaceutical DP Development AAPS Press
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
PQRI BTC WebinarOctober 2019
Mission PQRI is a non-profit consortium of organizations working together to generate and share timely relevant and impactful information that advances drug product quality manufacturing and regulation
8
Product Quality Research Institute (PQRI)
PQRI BTC WebinarOctober 2019
What Does PQRI Do bull Unites thought leaders from regulatory agencies standard setting
bodies industry and academia to conduct research and share knowledge on emerging scientific and regulatory quality challenges
bull Provides a unique neutral forum to develop broad consensus among a diverse collection of industry organizations and regulatory bodies
bull Creates opportunities to accomplish mutual goals that cannot be achieved by individual organizations
bull Impacts global regulatory guidance and standards bringing maximum value to members and patients
9
PQRI BTC WebinarOctober 2019
bull PQRI consists of two governing bodies ndash a Board of Directors and Steering Committee and three Technical Committees
bull Technical Committees each have a broad disciplinary focus that collectively spans the drug product regulatory lifecycle They establish and provide scientific guidance direction and oversight to PQRI working groups and research projects
10
PQRI Structure
bull Current PQRI Technical Committeesbull Biopharmaceutics Technical Committee (BTC)bull Development Technical Committee (DTC)bull Manufacturing Technical Committee (MTC)
bull This webinar is sponsored by the BTC bull The mission of the BTC is to identify disseminate
and facilitate scientific and technical projects to address gaps in biopharmaceutical aspects of drug development and global regulatory guidance
Biopharmaceutics Technical Committee
Manufacturing Technical
Committee
Development Technical
Committee
PQRI BTC WebinarOctober 2019
bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
bull Holistic QbD to Enable Product Quality (Today) Moderator Chris Moreton PhD FinnBrit Consulting PresentersAjit Narang PhD Genentech Rakhi Shah PhD US FDA Divyakant Desai PhD Bristol-Myers Squibb Xavier Pepin PharmD PhD AstraZeneca
bull Topic Complex Non-Oral Dosage Forms (eg Topical Inhalation)ndash NovemberDecember ndash Details to come
11
BTC 2019 Webinar Series
PQRI BTC WebinarOctober 2019
2018bull A Science Based Approach to Simplifying the Regulatory Pathway for Topical Drugs
(April 9 2018) Presenters Vinod P Shah PhD FAAPS FFIP and Flavian Radulescu PhD
bull Questions about the Proposed Topical Classification System (TCS) and What To Do With It (June 19 2018) Presenter Sam Raney PhD FDA
bull Performance Testing in Quality Control and Product Development Where are We (October 23 2018) Presenter Raimar Loumlbenberg PhD University of Alberta
bull Biowaiver Approaches for Solid Oral Dosage Forms in New Drug Applications (December 6 2018) Presenter Poonam Delvadia PhD FDA
2019bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical
Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
Recordings are available on the PQRI website at wwwpqriorg
12
Past BTC Webinars
PQRI BTC WebinarOctober 2019
bull See bios posted on PQRI website for more information
13
Todayrsquos Moderator and Presenters
copy2016 Genentech
Ajit Narang PhDOn behalf of the QbD WG Team
10 October 2019
Current State of QbD Practice and Growth Areas -An Update on the PQRI QbD WG Discussions
copy2016 Genentech
PQRI QbD WG Team
Name Organization Function
Chris Moreton Consultant Excipient supplier
Dilbir Bindra Bristol-Myers Squibb Drug Product ndash small amp large molecule
Jackson Pellett Genentech Analytical ndash small molecule
Tapan Das Bristol-Myers Squibb Analytical ndash large molecule
Atul Saluja Sanofi Drug Product ndash biologics
Sanket Patke Sanofi Drug Product ndash biologics
John Lepore Merck Regulatory
copy2016 Genentech
Highlights of Team Discussions
QbD principles commonly applied in certain areas
Statistical design and interpretation of studies around formulation
composition and process parameters
Justification of product specifications and control strategy
2012 concept paper by the PQRI QbD Specification Design and Lifecycle
Management Working Group of the PQRI Manufacturing Technical Committee on
ldquoQuality by Design Specifications for Solid Oral Dosage Forms Multivariate
Product and Process Monitoring for Managing Drug Quality Attributesrdquo
Justification of scope and ranges of variations within product components
analytical testing and operating parameters
copy2016 Genentech
Highlights of Team Discussions
Industry application of QbD principles is phase appropriate
Regulatory focus on commercial products
Quotient MHRA case of clinical formulation flexibility (Rapid FACT studies)
Provides prospective grounds and boundaries for justification of changes
Applied in clinical Phase 23 stages after process selectionfinalization
Applying QbD when not necessary might make it detrimental to the concept of
QbD
copy2016 Genentech
Highlights of Team Discussions
Common industry application of QbD principles is significantly
different between SM and LM (small amp large molecules)
More well established and widely practiced in the SM than LM
Earlier selection of formulation and process in LM (ie phase 1 in LM
compared to phase 23 in SM)
A likely driving factor limited material availability
Application of high throughput and material conserving workflows can help shift
this balance
Opportunities exist for application throughout LM processes
2015 book by Feroz Jameel Susan Hershenson Mansoor Khan and Sheryl
Martin-Moe on QbD for Biopharmaceutical DP Development AAPS Press
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
PQRI BTC WebinarOctober 2019
What Does PQRI Do bull Unites thought leaders from regulatory agencies standard setting
bodies industry and academia to conduct research and share knowledge on emerging scientific and regulatory quality challenges
bull Provides a unique neutral forum to develop broad consensus among a diverse collection of industry organizations and regulatory bodies
bull Creates opportunities to accomplish mutual goals that cannot be achieved by individual organizations
bull Impacts global regulatory guidance and standards bringing maximum value to members and patients
9
PQRI BTC WebinarOctober 2019
bull PQRI consists of two governing bodies ndash a Board of Directors and Steering Committee and three Technical Committees
bull Technical Committees each have a broad disciplinary focus that collectively spans the drug product regulatory lifecycle They establish and provide scientific guidance direction and oversight to PQRI working groups and research projects
10
PQRI Structure
bull Current PQRI Technical Committeesbull Biopharmaceutics Technical Committee (BTC)bull Development Technical Committee (DTC)bull Manufacturing Technical Committee (MTC)
bull This webinar is sponsored by the BTC bull The mission of the BTC is to identify disseminate
and facilitate scientific and technical projects to address gaps in biopharmaceutical aspects of drug development and global regulatory guidance
Biopharmaceutics Technical Committee
Manufacturing Technical
Committee
Development Technical
Committee
PQRI BTC WebinarOctober 2019
bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
bull Holistic QbD to Enable Product Quality (Today) Moderator Chris Moreton PhD FinnBrit Consulting PresentersAjit Narang PhD Genentech Rakhi Shah PhD US FDA Divyakant Desai PhD Bristol-Myers Squibb Xavier Pepin PharmD PhD AstraZeneca
bull Topic Complex Non-Oral Dosage Forms (eg Topical Inhalation)ndash NovemberDecember ndash Details to come
11
BTC 2019 Webinar Series
PQRI BTC WebinarOctober 2019
2018bull A Science Based Approach to Simplifying the Regulatory Pathway for Topical Drugs
(April 9 2018) Presenters Vinod P Shah PhD FAAPS FFIP and Flavian Radulescu PhD
bull Questions about the Proposed Topical Classification System (TCS) and What To Do With It (June 19 2018) Presenter Sam Raney PhD FDA
bull Performance Testing in Quality Control and Product Development Where are We (October 23 2018) Presenter Raimar Loumlbenberg PhD University of Alberta
bull Biowaiver Approaches for Solid Oral Dosage Forms in New Drug Applications (December 6 2018) Presenter Poonam Delvadia PhD FDA
2019bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical
Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
Recordings are available on the PQRI website at wwwpqriorg
12
Past BTC Webinars
PQRI BTC WebinarOctober 2019
bull See bios posted on PQRI website for more information
13
Todayrsquos Moderator and Presenters
copy2016 Genentech
Ajit Narang PhDOn behalf of the QbD WG Team
10 October 2019
Current State of QbD Practice and Growth Areas -An Update on the PQRI QbD WG Discussions
copy2016 Genentech
PQRI QbD WG Team
Name Organization Function
Chris Moreton Consultant Excipient supplier
Dilbir Bindra Bristol-Myers Squibb Drug Product ndash small amp large molecule
Jackson Pellett Genentech Analytical ndash small molecule
Tapan Das Bristol-Myers Squibb Analytical ndash large molecule
Atul Saluja Sanofi Drug Product ndash biologics
Sanket Patke Sanofi Drug Product ndash biologics
John Lepore Merck Regulatory
copy2016 Genentech
Highlights of Team Discussions
QbD principles commonly applied in certain areas
Statistical design and interpretation of studies around formulation
composition and process parameters
Justification of product specifications and control strategy
2012 concept paper by the PQRI QbD Specification Design and Lifecycle
Management Working Group of the PQRI Manufacturing Technical Committee on
ldquoQuality by Design Specifications for Solid Oral Dosage Forms Multivariate
Product and Process Monitoring for Managing Drug Quality Attributesrdquo
Justification of scope and ranges of variations within product components
analytical testing and operating parameters
copy2016 Genentech
Highlights of Team Discussions
Industry application of QbD principles is phase appropriate
Regulatory focus on commercial products
Quotient MHRA case of clinical formulation flexibility (Rapid FACT studies)
Provides prospective grounds and boundaries for justification of changes
Applied in clinical Phase 23 stages after process selectionfinalization
Applying QbD when not necessary might make it detrimental to the concept of
QbD
copy2016 Genentech
Highlights of Team Discussions
Common industry application of QbD principles is significantly
different between SM and LM (small amp large molecules)
More well established and widely practiced in the SM than LM
Earlier selection of formulation and process in LM (ie phase 1 in LM
compared to phase 23 in SM)
A likely driving factor limited material availability
Application of high throughput and material conserving workflows can help shift
this balance
Opportunities exist for application throughout LM processes
2015 book by Feroz Jameel Susan Hershenson Mansoor Khan and Sheryl
Martin-Moe on QbD for Biopharmaceutical DP Development AAPS Press
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
PQRI BTC WebinarOctober 2019
bull PQRI consists of two governing bodies ndash a Board of Directors and Steering Committee and three Technical Committees
bull Technical Committees each have a broad disciplinary focus that collectively spans the drug product regulatory lifecycle They establish and provide scientific guidance direction and oversight to PQRI working groups and research projects
10
PQRI Structure
bull Current PQRI Technical Committeesbull Biopharmaceutics Technical Committee (BTC)bull Development Technical Committee (DTC)bull Manufacturing Technical Committee (MTC)
bull This webinar is sponsored by the BTC bull The mission of the BTC is to identify disseminate
and facilitate scientific and technical projects to address gaps in biopharmaceutical aspects of drug development and global regulatory guidance
Biopharmaceutics Technical Committee
Manufacturing Technical
Committee
Development Technical
Committee
PQRI BTC WebinarOctober 2019
bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
bull Holistic QbD to Enable Product Quality (Today) Moderator Chris Moreton PhD FinnBrit Consulting PresentersAjit Narang PhD Genentech Rakhi Shah PhD US FDA Divyakant Desai PhD Bristol-Myers Squibb Xavier Pepin PharmD PhD AstraZeneca
bull Topic Complex Non-Oral Dosage Forms (eg Topical Inhalation)ndash NovemberDecember ndash Details to come
11
BTC 2019 Webinar Series
PQRI BTC WebinarOctober 2019
2018bull A Science Based Approach to Simplifying the Regulatory Pathway for Topical Drugs
(April 9 2018) Presenters Vinod P Shah PhD FAAPS FFIP and Flavian Radulescu PhD
bull Questions about the Proposed Topical Classification System (TCS) and What To Do With It (June 19 2018) Presenter Sam Raney PhD FDA
bull Performance Testing in Quality Control and Product Development Where are We (October 23 2018) Presenter Raimar Loumlbenberg PhD University of Alberta
bull Biowaiver Approaches for Solid Oral Dosage Forms in New Drug Applications (December 6 2018) Presenter Poonam Delvadia PhD FDA
2019bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical
Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
Recordings are available on the PQRI website at wwwpqriorg
12
Past BTC Webinars
PQRI BTC WebinarOctober 2019
bull See bios posted on PQRI website for more information
13
Todayrsquos Moderator and Presenters
copy2016 Genentech
Ajit Narang PhDOn behalf of the QbD WG Team
10 October 2019
Current State of QbD Practice and Growth Areas -An Update on the PQRI QbD WG Discussions
copy2016 Genentech
PQRI QbD WG Team
Name Organization Function
Chris Moreton Consultant Excipient supplier
Dilbir Bindra Bristol-Myers Squibb Drug Product ndash small amp large molecule
Jackson Pellett Genentech Analytical ndash small molecule
Tapan Das Bristol-Myers Squibb Analytical ndash large molecule
Atul Saluja Sanofi Drug Product ndash biologics
Sanket Patke Sanofi Drug Product ndash biologics
John Lepore Merck Regulatory
copy2016 Genentech
Highlights of Team Discussions
QbD principles commonly applied in certain areas
Statistical design and interpretation of studies around formulation
composition and process parameters
Justification of product specifications and control strategy
2012 concept paper by the PQRI QbD Specification Design and Lifecycle
Management Working Group of the PQRI Manufacturing Technical Committee on
ldquoQuality by Design Specifications for Solid Oral Dosage Forms Multivariate
Product and Process Monitoring for Managing Drug Quality Attributesrdquo
Justification of scope and ranges of variations within product components
analytical testing and operating parameters
copy2016 Genentech
Highlights of Team Discussions
Industry application of QbD principles is phase appropriate
Regulatory focus on commercial products
Quotient MHRA case of clinical formulation flexibility (Rapid FACT studies)
Provides prospective grounds and boundaries for justification of changes
Applied in clinical Phase 23 stages after process selectionfinalization
Applying QbD when not necessary might make it detrimental to the concept of
QbD
copy2016 Genentech
Highlights of Team Discussions
Common industry application of QbD principles is significantly
different between SM and LM (small amp large molecules)
More well established and widely practiced in the SM than LM
Earlier selection of formulation and process in LM (ie phase 1 in LM
compared to phase 23 in SM)
A likely driving factor limited material availability
Application of high throughput and material conserving workflows can help shift
this balance
Opportunities exist for application throughout LM processes
2015 book by Feroz Jameel Susan Hershenson Mansoor Khan and Sheryl
Martin-Moe on QbD for Biopharmaceutical DP Development AAPS Press
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
PQRI BTC WebinarOctober 2019
bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
bull Holistic QbD to Enable Product Quality (Today) Moderator Chris Moreton PhD FinnBrit Consulting PresentersAjit Narang PhD Genentech Rakhi Shah PhD US FDA Divyakant Desai PhD Bristol-Myers Squibb Xavier Pepin PharmD PhD AstraZeneca
bull Topic Complex Non-Oral Dosage Forms (eg Topical Inhalation)ndash NovemberDecember ndash Details to come
11
BTC 2019 Webinar Series
PQRI BTC WebinarOctober 2019
2018bull A Science Based Approach to Simplifying the Regulatory Pathway for Topical Drugs
(April 9 2018) Presenters Vinod P Shah PhD FAAPS FFIP and Flavian Radulescu PhD
bull Questions about the Proposed Topical Classification System (TCS) and What To Do With It (June 19 2018) Presenter Sam Raney PhD FDA
bull Performance Testing in Quality Control and Product Development Where are We (October 23 2018) Presenter Raimar Loumlbenberg PhD University of Alberta
bull Biowaiver Approaches for Solid Oral Dosage Forms in New Drug Applications (December 6 2018) Presenter Poonam Delvadia PhD FDA
2019bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical
Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
Recordings are available on the PQRI website at wwwpqriorg
12
Past BTC Webinars
PQRI BTC WebinarOctober 2019
bull See bios posted on PQRI website for more information
13
Todayrsquos Moderator and Presenters
copy2016 Genentech
Ajit Narang PhDOn behalf of the QbD WG Team
10 October 2019
Current State of QbD Practice and Growth Areas -An Update on the PQRI QbD WG Discussions
copy2016 Genentech
PQRI QbD WG Team
Name Organization Function
Chris Moreton Consultant Excipient supplier
Dilbir Bindra Bristol-Myers Squibb Drug Product ndash small amp large molecule
Jackson Pellett Genentech Analytical ndash small molecule
Tapan Das Bristol-Myers Squibb Analytical ndash large molecule
Atul Saluja Sanofi Drug Product ndash biologics
Sanket Patke Sanofi Drug Product ndash biologics
John Lepore Merck Regulatory
copy2016 Genentech
Highlights of Team Discussions
QbD principles commonly applied in certain areas
Statistical design and interpretation of studies around formulation
composition and process parameters
Justification of product specifications and control strategy
2012 concept paper by the PQRI QbD Specification Design and Lifecycle
Management Working Group of the PQRI Manufacturing Technical Committee on
ldquoQuality by Design Specifications for Solid Oral Dosage Forms Multivariate
Product and Process Monitoring for Managing Drug Quality Attributesrdquo
Justification of scope and ranges of variations within product components
analytical testing and operating parameters
copy2016 Genentech
Highlights of Team Discussions
Industry application of QbD principles is phase appropriate
Regulatory focus on commercial products
Quotient MHRA case of clinical formulation flexibility (Rapid FACT studies)
Provides prospective grounds and boundaries for justification of changes
Applied in clinical Phase 23 stages after process selectionfinalization
Applying QbD when not necessary might make it detrimental to the concept of
QbD
copy2016 Genentech
Highlights of Team Discussions
Common industry application of QbD principles is significantly
different between SM and LM (small amp large molecules)
More well established and widely practiced in the SM than LM
Earlier selection of formulation and process in LM (ie phase 1 in LM
compared to phase 23 in SM)
A likely driving factor limited material availability
Application of high throughput and material conserving workflows can help shift
this balance
Opportunities exist for application throughout LM processes
2015 book by Feroz Jameel Susan Hershenson Mansoor Khan and Sheryl
Martin-Moe on QbD for Biopharmaceutical DP Development AAPS Press
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
PQRI BTC WebinarOctober 2019
2018bull A Science Based Approach to Simplifying the Regulatory Pathway for Topical Drugs
(April 9 2018) Presenters Vinod P Shah PhD FAAPS FFIP and Flavian Radulescu PhD
bull Questions about the Proposed Topical Classification System (TCS) and What To Do With It (June 19 2018) Presenter Sam Raney PhD FDA
bull Performance Testing in Quality Control and Product Development Where are We (October 23 2018) Presenter Raimar Loumlbenberg PhD University of Alberta
bull Biowaiver Approaches for Solid Oral Dosage Forms in New Drug Applications (December 6 2018) Presenter Poonam Delvadia PhD FDA
2019bull The Expanding IVIVC Toolbox to Enable Drug Product Quality and Clinical
Pharmacology ndash Complementary Traditional and PBPK Based Approaches (June 7 2019) Presenters Xianyuan (Susie) Zhang PhD FDA and Filippos Kesisoglou PhD Merck
Recordings are available on the PQRI website at wwwpqriorg
12
Past BTC Webinars
PQRI BTC WebinarOctober 2019
bull See bios posted on PQRI website for more information
13
Todayrsquos Moderator and Presenters
copy2016 Genentech
Ajit Narang PhDOn behalf of the QbD WG Team
10 October 2019
Current State of QbD Practice and Growth Areas -An Update on the PQRI QbD WG Discussions
copy2016 Genentech
PQRI QbD WG Team
Name Organization Function
Chris Moreton Consultant Excipient supplier
Dilbir Bindra Bristol-Myers Squibb Drug Product ndash small amp large molecule
Jackson Pellett Genentech Analytical ndash small molecule
Tapan Das Bristol-Myers Squibb Analytical ndash large molecule
Atul Saluja Sanofi Drug Product ndash biologics
Sanket Patke Sanofi Drug Product ndash biologics
John Lepore Merck Regulatory
copy2016 Genentech
Highlights of Team Discussions
QbD principles commonly applied in certain areas
Statistical design and interpretation of studies around formulation
composition and process parameters
Justification of product specifications and control strategy
2012 concept paper by the PQRI QbD Specification Design and Lifecycle
Management Working Group of the PQRI Manufacturing Technical Committee on
ldquoQuality by Design Specifications for Solid Oral Dosage Forms Multivariate
Product and Process Monitoring for Managing Drug Quality Attributesrdquo
Justification of scope and ranges of variations within product components
analytical testing and operating parameters
copy2016 Genentech
Highlights of Team Discussions
Industry application of QbD principles is phase appropriate
Regulatory focus on commercial products
Quotient MHRA case of clinical formulation flexibility (Rapid FACT studies)
Provides prospective grounds and boundaries for justification of changes
Applied in clinical Phase 23 stages after process selectionfinalization
Applying QbD when not necessary might make it detrimental to the concept of
QbD
copy2016 Genentech
Highlights of Team Discussions
Common industry application of QbD principles is significantly
different between SM and LM (small amp large molecules)
More well established and widely practiced in the SM than LM
Earlier selection of formulation and process in LM (ie phase 1 in LM
compared to phase 23 in SM)
A likely driving factor limited material availability
Application of high throughput and material conserving workflows can help shift
this balance
Opportunities exist for application throughout LM processes
2015 book by Feroz Jameel Susan Hershenson Mansoor Khan and Sheryl
Martin-Moe on QbD for Biopharmaceutical DP Development AAPS Press
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
PQRI BTC WebinarOctober 2019
bull See bios posted on PQRI website for more information
13
Todayrsquos Moderator and Presenters
copy2016 Genentech
Ajit Narang PhDOn behalf of the QbD WG Team
10 October 2019
Current State of QbD Practice and Growth Areas -An Update on the PQRI QbD WG Discussions
copy2016 Genentech
PQRI QbD WG Team
Name Organization Function
Chris Moreton Consultant Excipient supplier
Dilbir Bindra Bristol-Myers Squibb Drug Product ndash small amp large molecule
Jackson Pellett Genentech Analytical ndash small molecule
Tapan Das Bristol-Myers Squibb Analytical ndash large molecule
Atul Saluja Sanofi Drug Product ndash biologics
Sanket Patke Sanofi Drug Product ndash biologics
John Lepore Merck Regulatory
copy2016 Genentech
Highlights of Team Discussions
QbD principles commonly applied in certain areas
Statistical design and interpretation of studies around formulation
composition and process parameters
Justification of product specifications and control strategy
2012 concept paper by the PQRI QbD Specification Design and Lifecycle
Management Working Group of the PQRI Manufacturing Technical Committee on
ldquoQuality by Design Specifications for Solid Oral Dosage Forms Multivariate
Product and Process Monitoring for Managing Drug Quality Attributesrdquo
Justification of scope and ranges of variations within product components
analytical testing and operating parameters
copy2016 Genentech
Highlights of Team Discussions
Industry application of QbD principles is phase appropriate
Regulatory focus on commercial products
Quotient MHRA case of clinical formulation flexibility (Rapid FACT studies)
Provides prospective grounds and boundaries for justification of changes
Applied in clinical Phase 23 stages after process selectionfinalization
Applying QbD when not necessary might make it detrimental to the concept of
QbD
copy2016 Genentech
Highlights of Team Discussions
Common industry application of QbD principles is significantly
different between SM and LM (small amp large molecules)
More well established and widely practiced in the SM than LM
Earlier selection of formulation and process in LM (ie phase 1 in LM
compared to phase 23 in SM)
A likely driving factor limited material availability
Application of high throughput and material conserving workflows can help shift
this balance
Opportunities exist for application throughout LM processes
2015 book by Feroz Jameel Susan Hershenson Mansoor Khan and Sheryl
Martin-Moe on QbD for Biopharmaceutical DP Development AAPS Press
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
copy2016 Genentech
Ajit Narang PhDOn behalf of the QbD WG Team
10 October 2019
Current State of QbD Practice and Growth Areas -An Update on the PQRI QbD WG Discussions
copy2016 Genentech
PQRI QbD WG Team
Name Organization Function
Chris Moreton Consultant Excipient supplier
Dilbir Bindra Bristol-Myers Squibb Drug Product ndash small amp large molecule
Jackson Pellett Genentech Analytical ndash small molecule
Tapan Das Bristol-Myers Squibb Analytical ndash large molecule
Atul Saluja Sanofi Drug Product ndash biologics
Sanket Patke Sanofi Drug Product ndash biologics
John Lepore Merck Regulatory
copy2016 Genentech
Highlights of Team Discussions
QbD principles commonly applied in certain areas
Statistical design and interpretation of studies around formulation
composition and process parameters
Justification of product specifications and control strategy
2012 concept paper by the PQRI QbD Specification Design and Lifecycle
Management Working Group of the PQRI Manufacturing Technical Committee on
ldquoQuality by Design Specifications for Solid Oral Dosage Forms Multivariate
Product and Process Monitoring for Managing Drug Quality Attributesrdquo
Justification of scope and ranges of variations within product components
analytical testing and operating parameters
copy2016 Genentech
Highlights of Team Discussions
Industry application of QbD principles is phase appropriate
Regulatory focus on commercial products
Quotient MHRA case of clinical formulation flexibility (Rapid FACT studies)
Provides prospective grounds and boundaries for justification of changes
Applied in clinical Phase 23 stages after process selectionfinalization
Applying QbD when not necessary might make it detrimental to the concept of
QbD
copy2016 Genentech
Highlights of Team Discussions
Common industry application of QbD principles is significantly
different between SM and LM (small amp large molecules)
More well established and widely practiced in the SM than LM
Earlier selection of formulation and process in LM (ie phase 1 in LM
compared to phase 23 in SM)
A likely driving factor limited material availability
Application of high throughput and material conserving workflows can help shift
this balance
Opportunities exist for application throughout LM processes
2015 book by Feroz Jameel Susan Hershenson Mansoor Khan and Sheryl
Martin-Moe on QbD for Biopharmaceutical DP Development AAPS Press
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
copy2016 Genentech
PQRI QbD WG Team
Name Organization Function
Chris Moreton Consultant Excipient supplier
Dilbir Bindra Bristol-Myers Squibb Drug Product ndash small amp large molecule
Jackson Pellett Genentech Analytical ndash small molecule
Tapan Das Bristol-Myers Squibb Analytical ndash large molecule
Atul Saluja Sanofi Drug Product ndash biologics
Sanket Patke Sanofi Drug Product ndash biologics
John Lepore Merck Regulatory
copy2016 Genentech
Highlights of Team Discussions
QbD principles commonly applied in certain areas
Statistical design and interpretation of studies around formulation
composition and process parameters
Justification of product specifications and control strategy
2012 concept paper by the PQRI QbD Specification Design and Lifecycle
Management Working Group of the PQRI Manufacturing Technical Committee on
ldquoQuality by Design Specifications for Solid Oral Dosage Forms Multivariate
Product and Process Monitoring for Managing Drug Quality Attributesrdquo
Justification of scope and ranges of variations within product components
analytical testing and operating parameters
copy2016 Genentech
Highlights of Team Discussions
Industry application of QbD principles is phase appropriate
Regulatory focus on commercial products
Quotient MHRA case of clinical formulation flexibility (Rapid FACT studies)
Provides prospective grounds and boundaries for justification of changes
Applied in clinical Phase 23 stages after process selectionfinalization
Applying QbD when not necessary might make it detrimental to the concept of
QbD
copy2016 Genentech
Highlights of Team Discussions
Common industry application of QbD principles is significantly
different between SM and LM (small amp large molecules)
More well established and widely practiced in the SM than LM
Earlier selection of formulation and process in LM (ie phase 1 in LM
compared to phase 23 in SM)
A likely driving factor limited material availability
Application of high throughput and material conserving workflows can help shift
this balance
Opportunities exist for application throughout LM processes
2015 book by Feroz Jameel Susan Hershenson Mansoor Khan and Sheryl
Martin-Moe on QbD for Biopharmaceutical DP Development AAPS Press
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
copy2016 Genentech
Highlights of Team Discussions
QbD principles commonly applied in certain areas
Statistical design and interpretation of studies around formulation
composition and process parameters
Justification of product specifications and control strategy
2012 concept paper by the PQRI QbD Specification Design and Lifecycle
Management Working Group of the PQRI Manufacturing Technical Committee on
ldquoQuality by Design Specifications for Solid Oral Dosage Forms Multivariate
Product and Process Monitoring for Managing Drug Quality Attributesrdquo
Justification of scope and ranges of variations within product components
analytical testing and operating parameters
copy2016 Genentech
Highlights of Team Discussions
Industry application of QbD principles is phase appropriate
Regulatory focus on commercial products
Quotient MHRA case of clinical formulation flexibility (Rapid FACT studies)
Provides prospective grounds and boundaries for justification of changes
Applied in clinical Phase 23 stages after process selectionfinalization
Applying QbD when not necessary might make it detrimental to the concept of
QbD
copy2016 Genentech
Highlights of Team Discussions
Common industry application of QbD principles is significantly
different between SM and LM (small amp large molecules)
More well established and widely practiced in the SM than LM
Earlier selection of formulation and process in LM (ie phase 1 in LM
compared to phase 23 in SM)
A likely driving factor limited material availability
Application of high throughput and material conserving workflows can help shift
this balance
Opportunities exist for application throughout LM processes
2015 book by Feroz Jameel Susan Hershenson Mansoor Khan and Sheryl
Martin-Moe on QbD for Biopharmaceutical DP Development AAPS Press
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
copy2016 Genentech
Highlights of Team Discussions
Industry application of QbD principles is phase appropriate
Regulatory focus on commercial products
Quotient MHRA case of clinical formulation flexibility (Rapid FACT studies)
Provides prospective grounds and boundaries for justification of changes
Applied in clinical Phase 23 stages after process selectionfinalization
Applying QbD when not necessary might make it detrimental to the concept of
QbD
copy2016 Genentech
Highlights of Team Discussions
Common industry application of QbD principles is significantly
different between SM and LM (small amp large molecules)
More well established and widely practiced in the SM than LM
Earlier selection of formulation and process in LM (ie phase 1 in LM
compared to phase 23 in SM)
A likely driving factor limited material availability
Application of high throughput and material conserving workflows can help shift
this balance
Opportunities exist for application throughout LM processes
2015 book by Feroz Jameel Susan Hershenson Mansoor Khan and Sheryl
Martin-Moe on QbD for Biopharmaceutical DP Development AAPS Press
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
copy2016 Genentech
Highlights of Team Discussions
Common industry application of QbD principles is significantly
different between SM and LM (small amp large molecules)
More well established and widely practiced in the SM than LM
Earlier selection of formulation and process in LM (ie phase 1 in LM
compared to phase 23 in SM)
A likely driving factor limited material availability
Application of high throughput and material conserving workflows can help shift
this balance
Opportunities exist for application throughout LM processes
2015 book by Feroz Jameel Susan Hershenson Mansoor Khan and Sheryl
Martin-Moe on QbD for Biopharmaceutical DP Development AAPS Press
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
copy2016 Genentech
Highlights of Team Discussions
Common industry practices with respect to analytical methods
Risk assessment of analytical methods typically not carried out
Check box approach to method validation utilizing existing guidances and
acceptance criteria
Opportunities exist in designing methods foreseeing changes in instrument
product that may come up down the road
Single source inputs (eg kits equipment) in analytical methods becomes
self-restrictive to QbD application and downstream flexibility
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
copy2016 Genentech
Highlights of Team Discussions
Opportunities to improve QbD adoption more holistically
CQA outcomes of QbD workflows are sometimes not readily accepted For example
Charge variants even when demonstrated as not CQAs likely require specification control for process consistency
If PSD is not identified as a CQA permissibility of greater variation in incoming material is still questioned
Reduced stability testing is an opportunity but difficult to implement ndash regulatory requests on omitted tests
Several countries would only allow actual experience for specification setting even if the scientifically and risk based justifiable approach would allow wider range
This reduces process capability and undermines wider QbD adoption
Process understanding
Not all processes could be understood to the same extent depending on maturity of underlying science
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
copy2016 Genentech
Highlights of Team Discussions
Challenges
Shrinking CMC timelines with clinical acceleration
Many companies apply QbD principles in workflow but donrsquot explicitly state so in their filings because regulators may not allow design space concepts in control strategy and specifications
Differences in global regulatory environment and reluctance in acceptance of the outcomes
Opportunities
In silico approaches including modeling and simulation
Platform formulations standardized scale-down process simulations
Consensus understanding of attributes that can commonly be predicted or not can help For example
Small molecule chemical degradation reactions are easier to predict while physical changes such as hardness and dissolution are not
Large molecule aggregation is hard to predict
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
Evolving QbD Trends in Regulatory Filings
22LL
Rakhi B Shah MS PhDBranch chief
Office of Pharmaceutical Manufacturing Assessment OPMA (formerly OPF)OPQCDERFDA
PQRI BTC Webinar Oct 10 2019
Disclaimer This presentation reflects the views of the speaker and should not be construed to represent the views or policies of FDA
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
23
Outline
bull Quality by Design (QbD)ndash Focus on patients (Clinically relevant specifications)ndash Risk based Assessment (Tools and approaches)ndash Real Time Release Testing (RTRT)ndash Regulatory flexibility (Design space Comparability protocol ICH
Q12)ndash Questions based Review (QbR)ndash FDA guidance
bull Summary
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
24
Quality by Design (QbD)
ndash Product designed to meet the needs of the patientndash Process designed to consistently delivery quality product that is necessary for clinical
performance
Defining quality target product profile (QTPP)
Designing product and manufacturing processes
Identifying critical quality attributes (CQAs) process parameters amp sources of variability
Controlling manufacturing processes to produce consistent quality over time
Quality should be built into the product from early on
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
25
QbD Focus on Patients
Clinically Relevant Specifications (CRS)
bull takes into consideration the clinical impact of variations in the CQA and process parameters to assure a consistent safety and efficacy profile
bull CRS approach typically followed to set the genotoxic impurities limits
bull CRS also used to set dissolution specs
bull To ensure in vitro standards are relevant to in vivo expectations
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
26
QbD Risk based Assessment
bull Initial identification of high risk facilities and high risk unit operations
bull Risk based assessment of proposed design and implementation approach of the control strategy with a focus on high risk unit operations and facilities
bull Documentation of final risk assessment including any process andor facility related residual risks and life cycle considerations
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
27
Designing a Robust Process
Problems detected after they
occur throughproduct testing and
inspection
Reproducible process within
narrow operatingranges
Robust amp reproducible
process
Low High
Low
High
PROCESS UNDERSTANDING
PRO
CESS
CON
TRO
L
High potential for failures
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
28
Quality Risk Management
Modified from ICH Q9
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
29
QRM tools Fishbone (Ishikawa) Diagram
Tablet dissolution
Plant
Raw materials Manufacturing
Analytical
API
Diluent
Disintegrant
Blending
Granulation
Compression
Coating
Sampling
Instrument RH
Temp
Location
Operator
Method
Size
LOD
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
30
QRM tools Failure Mode Effect Analysis (FMEA)
RPN = Occurrence (O) X Severity (S) X Detactability (D)
bullAPI Characteristics extremely low solubility multiple polymorphsbullDP Formulation medium API loading no overages antioxidant used hygroscopicgrowth-promoting excipientsgt70bullManufacturing Process Wet milling of API in suspension with excipients dissolved in water dry milling of granules high shear blending with MCC encapsulationInitial Risk Identification
PRODUCT PROPERTY
CQAS O S D Initial
Risk (Risk Factor) - CommentsNotes
Physical stability(Solid state of drug product)
3 3 4 36bull (S) - Poor aqueous solubility bull (O) - Multiple polymorphs exists
Chemical Stability 2 3 4 24 bull (O) - No trending at CRT and accelerated storage conditionsbull (O) - Antioxidant present in formulation
Assay 2 3 3 18 bull (O) - No API overage
Content uniformity 2 2 4 16
bull (O) - medium API loadingbull (O) - Manufacturing process involves wet milling dry milling
blending in high shear granulator and encapsulation
Microbial Limits 3 3 3 27 bull (O) - Formulation includes gt 70 hygroscopic andor growth promoting excipients no specification
Dissolution (Low solubility API) 4 3 5 60
bull (D) - 3 SLS used in dissolution media due to low solubility Dissolution method used for DP release specification is based on USP and may not be discriminating
Note RLD and other generics are manufactured as a spray-dried dispersion
30
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
31
FMEA-risk mitigation
31
PRODUCT PROPERTY
CQAS
InitialRisk
RankingComments Updated
Risk Comments
Dissolution 60(High)
Low solubility drug surfactant used in dissolution media
Medium
(O) PSD control established post wet milling dry milling and final blend based upon development data and the bioequivalence batch manufacturing data
(O) ndash Low risk of polymorphic conversion during manufacturing lowers risk of BE (dissolution) failure XRD confirms polymorphic form at release and after accerlated stabiltiy studies
(D) ndash Detectability remains low (high risk) such that the risk level is mitigated to medium to reflect that post-approval change evaluation should carefully consider the impact of any changes with respect to the control strategy already in place
Mitigation of the Probability of Occurrence of Dissolution Failure Risk
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
32
QbD Real Time Release testing (RTRt)
PAT guidance 2004
bull RTRt is the ability to evaluate and ensure quality of in-process andor final product based on process data Typically include a valid combination of measured material attributes and process controls (ICH Q8 (R2)
bull In RTRt material attributes are measured and controlled along with process parameters Material attributes can be assessed using direct andor indirect process analytical methods
bull RTRt is an element of the control strategy amp is a modern approach to manufacturing and control
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
33
RTRt examples in regulatory submissions
bull On-line or at-line measurements of tablet assay and content uniformity
bull Models as surrogate for traditional release testsndash For example for dissolution assay particle size
bull Use of process signatures as surrogates for traditional testing
bull Identity testing on tablet cores
bull Use of Multivariate Statstical process control (MSPC) to understand current state of the process and lsquoflagrsquo deviations
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
34
Traditional method vs RTRt to measure BUCU
courtesy Chatterjee S Interphex Japan 2018
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
35
Example Surrogate Dissolution Model in RTRt
courtesy Kurtyka B IFPAC 2019
PROCESS DATA
RAW MATERIAL DATA
PC1
PC2 B
1
B2B3
B4
Multivariate Model(eg MSPC)
Quantitative Predictionby PLS
Predicted
Mea
sure
d
Calibration Data
Manufacturing Data
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
36
QbD Design of Experiments (DoE) amp Design Space
bullA systematic planned approach to solving problems by gaining information through carefully planned experiments or studies
bullThese studies have adequate statistical properties to be able to
-accurately measure the effects of formulation amp process factors on the key response variable(s) (iedissolution content uniformity etc)
-be able to tell if these factor effects are real (above the noise level) and if so to accurately quantify these effects
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
37
DoEs from Regulatory Submissions
Data mining efforts
bull Initial ANDA submission date from
01012012 to 12312016
bull Criteria Single API IR Tablet ER Tablet IR
Capsule and ER Capsule
bull Total NDA 132 total of NDA using QbD 94
(74) total of NDAs using DoE 75 (80)
bull Total ANDA 606 total of ANDA using QbD
527 (87) total of ANDAs using DoE 210
(40)
Results
bull For NDAs
~20 DoEs with no issues acceptable
~ 40 with minor to moderate issues
~ 40 with major issues and unacceptable
DoEs
bull For ANDAs
~ 35 DoEs with no issues acceptable
~46 with minor to moderate issues
~ 20 with major issues and unacceptable
Bai et al J Pharm Innovation 2009
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
38
Examples of DoEs from SubmissionsOptimization of solubilizer conc using central composite design
Robustness of excipient composition
A screening DoE of 12 runs was conducted using 5 excipients at 2 levels (high and low)
No other informationrisk assessment presented by the applicant
A 23 factorial design with center points performed to optimize the conc of solubilizer Drug release from granules at 30 mins used as a response (CQA)
Blend properties (bulk and tapped density Hausner index and angle of repose) and capsule properties (manufacturability appereance weight variation content uniformity and dissolution) were found to be acceptable for all DoE runs
No results provided no plots provided by the applicant
Within studied conc range no effect on dissolution so the range was considered as Proven Acceptable Range (PAR)
the proposed formulation was found to be robust towards variations in amounts of excipients and do not adversely affect the quality of the drug product
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
39
DoEs in regulatory submissions
Common concerns found from submissions
bull No justification provided for selection of input
factors levels (absolute values) of input factors
are not properly selected
bull No experiment design and results table
experiment design not appropriate
bull No data analysis reportedData analysis not
properly conducted
bull No proposed design space for input factors
bull No exhibit batch data on the proposed design
space
bull dissolution time pointmethod not properly
selected
Common questions from regulators
bull How were design space and control space established for each unit operation
bull Is the design space for each unit operation independent of equipment design and batch size
bull How does control space relate to design space
bull How does control space relate to operational ranges in the Master Batch Record
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
40
QbD Regulatory flexibility
bull Working within the design space is not considered a change
bull Proposed by applicant and approved by regulator
bull Degree of regulatory flexibility is predicted on the level of relevant scientific knowledge provided
Design space
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
41
QbD Regulatory flexibility
bull A CP is a comprehensive prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity strength quality purity and potency of a drug product as these factors may relate to the safety or effectiveness of the product (ie product quality)
bull A CP can facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution and promote continuous improvement
Comparability Protocol (CP)
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
42
QbD Regulatory flexibility
From draft ICH Q12bull The PACMP is a regulatory tool that providespredictability regarding the information required tosupport a CMC change and the type of regulatorysubmission based on prior agreement between theMAH and regulatory authority Such a mechanismenables planning and implementation of futurechanges to Established Conditions in an efficient andpredictable manner
Comparability protocol is a type of PACMP
Post Approval Change Management Protocol (PACMP)
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
43
Comparability Protocols in NDAs
Example of change category typicallycovered via Comparability Protocols
- Manufacturing process parameters- Container Closure- In-process controls- Components and composition
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
44
QbD Support Scientific InnovationEmerging Technology Team (ETT)
Early Engagement (Pre‐submission)ndash Face-to-face meeting(s) with ETT involvement ndash provided upfront scientific input under the Emerging Technology Program
bull Pre‐Operational Visit (POV) if neededndash Participation by OPQ (including the ETT member(s)) andor ORA members
bull Integrated Quality Assessment (IQA)ndash Interdisciplinary team with experts in Drug Substance Drugproduct ProcessFacility Biopharm andor Inspectionndash ETT member as a Co-Application Technical Lead
bull Pre‐Approval Inspection (PAI)ndash Conducted by team members from OPQ (including the ETTMember(s)) and ORA
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
45
ETT program progress
bull Recent approvals in which ETT played a critical role
-First 3D printed drug product in 2015-First FDA-approved drug product to switch from a legacy batch process to continuous manufacturing in 2016-5 continuous manufacturing applications approved to date
bull Approx 50 requests accepted to the ETT since the launch of the program in late 2014
ndash Received over 100 ETT proposals
FDA experience with ET
bull CM of drug substancebull CM of drug productbull End-to-end CMbull Pharmacy-on-demandbull Model-based control strategy for CMbull Continuous aseptic spray dryingbull 3D printingbull Ultra long-acting oral formulationbull Advanced lyophilization techniquesbull End-to-end integrated bioprocessbull Comprehensive product testing using
a single multi-attribute assay
httpswwwfdagovAboutFDACentersOfficesOfficeofMedicalProductsandTobaccoCDERucm523228htm
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
46
Examples of QbD questions under Question based Reviews for ANDAs
bull Define target product quality profile-What attributes should the drug product possess
bull Design and develop product and manufacturing process to meet target product quality profile-How was the product designed to have these attributes -Why was the process selected
bull Identify and control critical raw material attributes process parameters and sources of variability-How were critical process parameters identified monitored and controlled
bull The process is monitored and adapted to produce consistent quality over time-What are in-process tests andor controls that ensure each step is successful
Quality by Design
Quality Overall
Summary
Novel RiskAssessment
QbR Questions
Post Approval Changes
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
47
FDA Quality related guidance amp initiatives
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
48
Summary
Aspects Traditional QbD
Pharmaceutical development
Empirical univariate experiments Systematic multivariate experiments
Manufacturing process
Fixed validation on 3 initial full-scale batches focus on
reproducibility
Adjustable within design space continuous verification focus on
control strategy amp robustness
Process control In-process testing for gono-go offline analysis wslow response
PAT utilized for feedback amp feed forward real time
Product specification Primary means of quality control based on batch data
Part of the overall quality control strategy based on desired product
performance Control strategy Mainly by intermediate and end
product testing Risk-based controls shifted upstream real-time release
Lifecycle management
Reactive to problems amp OOS post-approval changes needed
Continuous improvement enabled within design space
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
49
Acknowledgements
bull Zhijin Chenbull Sharmista Chatterjeebull Lawrence Yubull Bogdan Kurtykabull Rapti Madurawebull OPMA and OPQ Assessment Team
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
50
Thank You
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
Addressing Content Uniformity Challenge for Low Strength
Entecavir Tablet Formulations
October 10 2019
Divyakant Desai PhDResearch Fellow
Bristol-Myers Squibb Co
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
Why a QbD approach was needed APIbull Difficult synthesisbull Expensive APIbull Control of particle size during crystallization
was difficultbull Millingmicronization was not preferred due
potent nature and exposure related concernsTabletbull Containment issues during the
manufacturingbull Low tablet strengths- content uniformity
concerns 52
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
Entecavir Tablet Formulations
bull Tablet strengths 01 mg 05 mg 10 mgbull Tablet weights 200 mg 200 mg and 400 mgbull Indication treatment for HBV virusbull Extreme precautions during the tablet manufacturing
53
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
Entecavir bull Free basebull Very potent moleculebull Band 5- tight exposure
controlbull BCS class IIIbull Various salts evaluated-did
not offer any advantage over free base
pKa 28 and 96Solubility at RT gt 24 mgmL (pH 1-7)
NN
NHN
O
H2N
OH
OH
54
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
pH-solubility profile of entecavir at 25degC
55
0
2
4
6
8
10
12
1 3 5 7 9 11 pH
Solu
bilit
y (m
gm
L)
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
Entecavir solubility in different solvents
56
Solvent Solubility at 25degplusmn 05degC
mgmL USP definition
Water 24 Slightly soluble
Isopropanol 24 Slightly soluble
Ethanol 38 Slightly soluble
Methanol 70 Slightly soluble
Polyethylene glycol 300 129 Sparingly soluble
Propylene glycol 219 Sparingly soluble
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
Common approaches to improve tablet content uniformity bull Reducing the particle size
bull Millingbull Micronization
bull Dissolving the API in a granulating fluidbull Solubility in waterbull pH-adjustmentbull Solubility in pharmaceutically acceptable
solvents A Novel approach
57
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
Possible manufacturing approaches explored for entecavir tablet formulations
Approach Advantages Issues1 Spray coating on particles bull Minimizes loss of drug bull Complicated process2 Ordered mixing bull Enclosed system bull Potential segregation issues
bull Micronized API3 Wet granulation with micronized drug
bull Minimizes segregation issues
bull Micronized API
4 Wet granulation with API dissolved in SLSpoloxamer
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
5 Wet granulation with API dissolved in hydro-alcoholic solvents
bull API characteristics have minimum impact
bull Did not achieve enough API solubility
6 Wet granulation with API dissolved in aqueous povidone solution (50-70degC)
bull API characteristics have minimum impact
bull Minimizes segregation issues
bull Significant improvement in solubility
bull Good potency and control uniformity control
bull Maintaining povidone solution temperature above 40degC during the wet granulation process
58
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
Enhancement in solubility of entecavir with increase in povidone concentration and temperature
59
0
1
2
3
4
5
6
7
8
0 5 10 15 20 25 30 35
So
lub
ility
x 1
0^-4
(M
)
PVP Concentration x 10^-4 (M)
25 degC
50 degC
70 degC
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
60
TimeHours
Solution weight change ()
before and after putting in oven
Amount mgmL InitialIndividual
sampleAverage of
two samples
Initial - 1063 1062 1000- 1062
200 004 1081 1081 1018002 1082
400 001 1064 1063 1001001 1063
600 001 1065 1065 1002001 1066
2100 001 1066 1061 999001 1056
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
61
0
5
10
15
20
25
30
35
0 3 6 9 12 15 18 Povidone ( ww)
Ent
ecav
ir (m
gm
L)
25degC 50degC 70degC
Target for 05 and 1 mg tablets
Target for 01 mg tablets
Desai et al Pharmaceutical Development amp Technology 2012
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
Entecavir Tablet Formulation
62
Ingredient Function in the formulation(ww)
Entecavir API 025
Lactose monohydrate amp microcrystalline cellulose
diluents 9275
Crospovidone disintegrant 400
Povidone binder 25
Magnesium stearate lubricant 05
Purified water granulating fluid qs
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
Entecavir Tablet Content Uniformity
63
0
1
2
3
4
5
6
MicronizedAPI
(Reference)
Lot 3 Lot 4 Lot 5 Lot 6 Lot 7 Lot 8 Lot 1 Lot 2
Batch size 2 kg Traditional wetgranulation 05 mg strength
Batch size 172 kg 05 mg strength Batch size 141 kg 01 mg strength
Entecavir dissolved in PVP solution
RSD
52
09
30
1814 13
27
083 09
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
64
12774degC
25076degC
25946degC
30175degC
-20
-15
-10
-05
00
05
Heat
Flo
w (W
g)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
10624degC
14494degC 20780degC
24479degC
-25
-20
-15
-10
-05
00
05
Heat
Flow
(Wg
)
0 50 100 150 200 250 300 350Temperature (degC)
Exo Up Universal V43A TA Instruments
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
65
5 10 15 20 25 30
Two-Theta (deg)
0
1000
2000
3000
4000
5000
6000
7000
Inte
nsity
(Cou
nts)
[34105SD] 20047501 47423123c[33132SD] 200475 4747302121
Entecavir Bulk Drug
Entecavir re-crystallized from 15 ww aqueous povidone solution
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
Summarybull A QbD mindset enabled the team to come up
with a novel approach to improve entecavir tablet content uniformity
bull Entecavir solubilization by povidone removed the need for API particle size control and therefore millingmicronization
bull Once entecavir was dissolved in povidone solution It reduced the dusting which helped in minimizing the personnel exposure to the potent API
bull The manufacturing process was successfully scaled-up for commercial manufacture of tablets
66
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
Acknowledgement
Danping LiAbizer HarianawalaHang GuoMing HuangOmar SprockelPeter Timmins
67
Reference Desai et al Pharmaceutical Development amp Technology 2012
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
Dissolution Rate Justification by PBPK Modeling for Lesinurad TabletsXavier PepinPQRI Webinar 10th October 2019
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
Outlook
bull What is a PBPK model and how it developed bull Setting clinically relevant dissolution test and specificationsbull A vision for the future of in silico modelling
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
What is a Physiological Based PK (PBPK) model
Real tissue volume and compositionsScalable from animal to human disease or population modelsImpact of enzymes transporters dynamics of fluid pH transithellip
70
VENO
US
BLO
OD
Adipose
GIT
Brain
Lungs
ARTER
IALB
LOO
D
Skeleton
CLH
Heart
SpleenLiver
Kidneys
Muscles
Pancreas
CLU
Skin
Tyroid
Other
Q Adipose
Q Lungs
Q Brain
Q Skeleton
Q Heart
Q Hepatic (arterial)
Q Hepatic (portal) Q Spleen
Q GIT
Q Kidneys
Q Muscles
Q Pancreas
Q Tyroid
Q Skin
Q other
Processes identified mechanisticallyHandled simultaneously
How to we develop a ldquovalidated modelrdquo
Model Qualification (EMA only) Model set-up Model verification and modificationModel validationModel useSubmission of model and all raw data (FDA only)
FDA guidance on ldquoPhysiologically Based Pharmacokinetic Analyses mdash Format and Content Guidance for Industryrdquohttpswwwfdagovregulatory-informationsearch-fda-guidance-documentsphysiologically-based-pharmacokinetic-analyses-format-and-content-guidance-industry
EMA guideline on ldquoGuideline on the reporting of physiologically based pharmacokinetic (PBPK) modelling and simulationrdquo (from 1st July 2019)httpswwwemaeuropaeuendocumentsscientific-guidelineguideline-reporting-physiologically-based-pharmacokinetic-pbpk-modelling-simulation_enpdf
71
What to evaluate with PBAM or PBBM tools
72
bull Batches bioequivalence biowaiversbull Acceptable product specifications acceptable content of excipientsbull Edge of failure for Critical Material Attributes and Critical Process
Parameters
Operating range
Safe space
CMA1 or CPP1
CM
A2 o
r CPP
2
Knowledge space
Edge of failure
Clinical reference
Size of the safe space
Justified specifications
Regulatory flexibility
Biopharmaceutical properties - Lesinurad
Biopharm properties pKa 32 (25degC acid) Log P 285 Solubility = 6 ugmL at 37degC ( pH 16) Estimated human Peff = ~ 3 10-4 cmsec fup = 2 BP = 055 Limited impact of bile salts on solubility
BCS II
Dissolution of drug products
QC dissolution method 900 mL pH 45 acetate buffer plus 1 sodium lauryl sulfate (SLS) as
the dissolution medium in USP Apparatus 2 at 75 rpm The solubility of lesinurad in this media is 177 mgmL
FDA challenged the proposed dissolution
specification
Proposed spec dissolutionQ = 80 at 30 minutes
BE study MPAC vs 12A015 PBPK model
Modellingstrategy
Separate clinical dataset for validation from that of model setup
Model verification is optional if changes are needed
Choices of options
76
bull A Use of in vitro dissolution data to fit a particle size distribution set formulation to DR to delayed release enteric coated tablet
bull B Use of in vitro dissolution data to fit one Weibull function per batch where the dosage form is switched to CR dissolved
bull C Use of in vitro dissolution data to fit a Weibull function per batch where the dosage form is switched to CR Undissolved with drug substance particle size distribution
bull D Use of in vitro dissolution data to fit a Z-factor which accounts for the dose volume and solubility and set formulation to DR to delayed release enteric coated tablet
For all options stomach residence and gastric emptying patterns are fitted to the observed PK profiles
Only Option A allowed to reproduce the non bioequivalence observed with
ELAB vs 12A015
Integration of dissolution data
77
bull Option A ndash Fit of particle size distribution and upload in G+ as an input for each batch of DP
In vivo dissolution is calculated on the basis of local pH and volumes using ldquoDP particle sizerdquo
Virtual trial set up
78
bull GastroPlus V90bull N=25 healthy subjectsbull Fasted statebull Cross overbull Caveat Stomach pH and transit
are the same in cross over bull Add some variability to stomach
pH and transit timendash Random function in Excel
directly in the stc file
Virtual trial set up stomach pH
79
Virtual trial set up stomach residence time
80
Model verification ndash Ability to reproduce non BE
81
bull Virtual trial to test 12A015 ELAB and MPAC
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI
Geomean Ratio 90 CI
ELAB vs 12A015 0805 (0796 0814) 0876 (0869 0883)
MPAC vs 12A015 0987 (0977 0998) 1000 (0990 101)
ELAB vs 12A015 Compared well with measured ratios of 0800 for Cmax and 0881 for AUCinfin
Model use ndash Design space for dissolution of Lesinurad tablets
82
bull Add a virtual batch A to test the edge of failure
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI Geomean Ratio 90 CI
Virtual Batch A vs 12A015 0992 (0990 0993) 0989 (0988 0990)
Safe space defined
Use of safe space to allow flexibility in specification setting Duzalloreg Q80 45 min for lesinurad
Conclusions and perspectives
Current PBPK absorption models caveats
84
Continuous improvementValidation of guidelines best inputs cross industry validation (eg ARA Food effect)
Within and between subject variabilityUnderstanding variability with biomarkers of physiology
BenefitsSound justification of specificationsldquosafe spacerdquo and regulatory flexibility (PA site changes formulations changes specification changes)Significant savings amp avoidance of unnecessary human testingIdentification of LCM opportunities
85
A vision for the future of absorption modelling
Run a pilot clinical study with different drug products Build a mechanistic absorption model to explain observed exposure
Introduction of biomarkers Understand subject variability and reduce it (system parameters)Move from statistical approach of PK data to mechanistic understanding of individual data
Move from mechanistic understanding of populations to personalized medicine
Mechanistic integration of dissolution (P-PSD Z-factor) The right biomarker for the right drug pH transit bile salt enzyme expression etc Use Individual disposition parameters
Run virtual cross-over BE trials to define edge of failure of CMA and CPP on larger populations with right variability of key parameters
Thanks
Ardea BiosciencesColin RowlingsAnna EidelmanDon Treacy
AstraZenecaTalia FlanaganDavid HoltSimon Hartas
Questions
Confidentiality Notice This file is private and may contain confidential and proprietary information If you have received this file in error please notify us and remove it from your system and note that you must not copy distribute or take any action in reliance on it Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful AstraZeneca PLC 1 Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0AA UK T +44(0)203 749 5000 wwwastrazenecacom
87
PQRI BTC WebinarOctober 2019
88
Time for Questions
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
-
What to evaluate with PBAM or PBBM tools
72
bull Batches bioequivalence biowaiversbull Acceptable product specifications acceptable content of excipientsbull Edge of failure for Critical Material Attributes and Critical Process
Parameters
Operating range
Safe space
CMA1 or CPP1
CM
A2 o
r CPP
2
Knowledge space
Edge of failure
Clinical reference
Size of the safe space
Justified specifications
Regulatory flexibility
Biopharmaceutical properties - Lesinurad
Biopharm properties pKa 32 (25degC acid) Log P 285 Solubility = 6 ugmL at 37degC ( pH 16) Estimated human Peff = ~ 3 10-4 cmsec fup = 2 BP = 055 Limited impact of bile salts on solubility
BCS II
Dissolution of drug products
QC dissolution method 900 mL pH 45 acetate buffer plus 1 sodium lauryl sulfate (SLS) as
the dissolution medium in USP Apparatus 2 at 75 rpm The solubility of lesinurad in this media is 177 mgmL
FDA challenged the proposed dissolution
specification
Proposed spec dissolutionQ = 80 at 30 minutes
BE study MPAC vs 12A015 PBPK model
Modellingstrategy
Separate clinical dataset for validation from that of model setup
Model verification is optional if changes are needed
Choices of options
76
bull A Use of in vitro dissolution data to fit a particle size distribution set formulation to DR to delayed release enteric coated tablet
bull B Use of in vitro dissolution data to fit one Weibull function per batch where the dosage form is switched to CR dissolved
bull C Use of in vitro dissolution data to fit a Weibull function per batch where the dosage form is switched to CR Undissolved with drug substance particle size distribution
bull D Use of in vitro dissolution data to fit a Z-factor which accounts for the dose volume and solubility and set formulation to DR to delayed release enteric coated tablet
For all options stomach residence and gastric emptying patterns are fitted to the observed PK profiles
Only Option A allowed to reproduce the non bioequivalence observed with
ELAB vs 12A015
Integration of dissolution data
77
bull Option A ndash Fit of particle size distribution and upload in G+ as an input for each batch of DP
In vivo dissolution is calculated on the basis of local pH and volumes using ldquoDP particle sizerdquo
Virtual trial set up
78
bull GastroPlus V90bull N=25 healthy subjectsbull Fasted statebull Cross overbull Caveat Stomach pH and transit
are the same in cross over bull Add some variability to stomach
pH and transit timendash Random function in Excel
directly in the stc file
Virtual trial set up stomach pH
79
Virtual trial set up stomach residence time
80
Model verification ndash Ability to reproduce non BE
81
bull Virtual trial to test 12A015 ELAB and MPAC
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI
Geomean Ratio 90 CI
ELAB vs 12A015 0805 (0796 0814) 0876 (0869 0883)
MPAC vs 12A015 0987 (0977 0998) 1000 (0990 101)
ELAB vs 12A015 Compared well with measured ratios of 0800 for Cmax and 0881 for AUCinfin
Model use ndash Design space for dissolution of Lesinurad tablets
82
bull Add a virtual batch A to test the edge of failure
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI Geomean Ratio 90 CI
Virtual Batch A vs 12A015 0992 (0990 0993) 0989 (0988 0990)
Safe space defined
Use of safe space to allow flexibility in specification setting Duzalloreg Q80 45 min for lesinurad
Conclusions and perspectives
Current PBPK absorption models caveats
84
Continuous improvementValidation of guidelines best inputs cross industry validation (eg ARA Food effect)
Within and between subject variabilityUnderstanding variability with biomarkers of physiology
BenefitsSound justification of specificationsldquosafe spacerdquo and regulatory flexibility (PA site changes formulations changes specification changes)Significant savings amp avoidance of unnecessary human testingIdentification of LCM opportunities
85
A vision for the future of absorption modelling
Run a pilot clinical study with different drug products Build a mechanistic absorption model to explain observed exposure
Introduction of biomarkers Understand subject variability and reduce it (system parameters)Move from statistical approach of PK data to mechanistic understanding of individual data
Move from mechanistic understanding of populations to personalized medicine
Mechanistic integration of dissolution (P-PSD Z-factor) The right biomarker for the right drug pH transit bile salt enzyme expression etc Use Individual disposition parameters
Run virtual cross-over BE trials to define edge of failure of CMA and CPP on larger populations with right variability of key parameters
Thanks
Ardea BiosciencesColin RowlingsAnna EidelmanDon Treacy
AstraZenecaTalia FlanaganDavid HoltSimon Hartas
Questions
Confidentiality Notice This file is private and may contain confidential and proprietary information If you have received this file in error please notify us and remove it from your system and note that you must not copy distribute or take any action in reliance on it Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful AstraZeneca PLC 1 Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0AA UK T +44(0)203 749 5000 wwwastrazenecacom
87
PQRI BTC WebinarOctober 2019
88
Time for Questions
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
-
Biopharmaceutical properties - Lesinurad
Biopharm properties pKa 32 (25degC acid) Log P 285 Solubility = 6 ugmL at 37degC ( pH 16) Estimated human Peff = ~ 3 10-4 cmsec fup = 2 BP = 055 Limited impact of bile salts on solubility
BCS II
Dissolution of drug products
QC dissolution method 900 mL pH 45 acetate buffer plus 1 sodium lauryl sulfate (SLS) as
the dissolution medium in USP Apparatus 2 at 75 rpm The solubility of lesinurad in this media is 177 mgmL
FDA challenged the proposed dissolution
specification
Proposed spec dissolutionQ = 80 at 30 minutes
BE study MPAC vs 12A015 PBPK model
Modellingstrategy
Separate clinical dataset for validation from that of model setup
Model verification is optional if changes are needed
Choices of options
76
bull A Use of in vitro dissolution data to fit a particle size distribution set formulation to DR to delayed release enteric coated tablet
bull B Use of in vitro dissolution data to fit one Weibull function per batch where the dosage form is switched to CR dissolved
bull C Use of in vitro dissolution data to fit a Weibull function per batch where the dosage form is switched to CR Undissolved with drug substance particle size distribution
bull D Use of in vitro dissolution data to fit a Z-factor which accounts for the dose volume and solubility and set formulation to DR to delayed release enteric coated tablet
For all options stomach residence and gastric emptying patterns are fitted to the observed PK profiles
Only Option A allowed to reproduce the non bioequivalence observed with
ELAB vs 12A015
Integration of dissolution data
77
bull Option A ndash Fit of particle size distribution and upload in G+ as an input for each batch of DP
In vivo dissolution is calculated on the basis of local pH and volumes using ldquoDP particle sizerdquo
Virtual trial set up
78
bull GastroPlus V90bull N=25 healthy subjectsbull Fasted statebull Cross overbull Caveat Stomach pH and transit
are the same in cross over bull Add some variability to stomach
pH and transit timendash Random function in Excel
directly in the stc file
Virtual trial set up stomach pH
79
Virtual trial set up stomach residence time
80
Model verification ndash Ability to reproduce non BE
81
bull Virtual trial to test 12A015 ELAB and MPAC
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI
Geomean Ratio 90 CI
ELAB vs 12A015 0805 (0796 0814) 0876 (0869 0883)
MPAC vs 12A015 0987 (0977 0998) 1000 (0990 101)
ELAB vs 12A015 Compared well with measured ratios of 0800 for Cmax and 0881 for AUCinfin
Model use ndash Design space for dissolution of Lesinurad tablets
82
bull Add a virtual batch A to test the edge of failure
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI Geomean Ratio 90 CI
Virtual Batch A vs 12A015 0992 (0990 0993) 0989 (0988 0990)
Safe space defined
Use of safe space to allow flexibility in specification setting Duzalloreg Q80 45 min for lesinurad
Conclusions and perspectives
Current PBPK absorption models caveats
84
Continuous improvementValidation of guidelines best inputs cross industry validation (eg ARA Food effect)
Within and between subject variabilityUnderstanding variability with biomarkers of physiology
BenefitsSound justification of specificationsldquosafe spacerdquo and regulatory flexibility (PA site changes formulations changes specification changes)Significant savings amp avoidance of unnecessary human testingIdentification of LCM opportunities
85
A vision for the future of absorption modelling
Run a pilot clinical study with different drug products Build a mechanistic absorption model to explain observed exposure
Introduction of biomarkers Understand subject variability and reduce it (system parameters)Move from statistical approach of PK data to mechanistic understanding of individual data
Move from mechanistic understanding of populations to personalized medicine
Mechanistic integration of dissolution (P-PSD Z-factor) The right biomarker for the right drug pH transit bile salt enzyme expression etc Use Individual disposition parameters
Run virtual cross-over BE trials to define edge of failure of CMA and CPP on larger populations with right variability of key parameters
Thanks
Ardea BiosciencesColin RowlingsAnna EidelmanDon Treacy
AstraZenecaTalia FlanaganDavid HoltSimon Hartas
Questions
Confidentiality Notice This file is private and may contain confidential and proprietary information If you have received this file in error please notify us and remove it from your system and note that you must not copy distribute or take any action in reliance on it Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful AstraZeneca PLC 1 Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0AA UK T +44(0)203 749 5000 wwwastrazenecacom
87
PQRI BTC WebinarOctober 2019
88
Time for Questions
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
-
Dissolution of drug products
QC dissolution method 900 mL pH 45 acetate buffer plus 1 sodium lauryl sulfate (SLS) as
the dissolution medium in USP Apparatus 2 at 75 rpm The solubility of lesinurad in this media is 177 mgmL
FDA challenged the proposed dissolution
specification
Proposed spec dissolutionQ = 80 at 30 minutes
BE study MPAC vs 12A015 PBPK model
Modellingstrategy
Separate clinical dataset for validation from that of model setup
Model verification is optional if changes are needed
Choices of options
76
bull A Use of in vitro dissolution data to fit a particle size distribution set formulation to DR to delayed release enteric coated tablet
bull B Use of in vitro dissolution data to fit one Weibull function per batch where the dosage form is switched to CR dissolved
bull C Use of in vitro dissolution data to fit a Weibull function per batch where the dosage form is switched to CR Undissolved with drug substance particle size distribution
bull D Use of in vitro dissolution data to fit a Z-factor which accounts for the dose volume and solubility and set formulation to DR to delayed release enteric coated tablet
For all options stomach residence and gastric emptying patterns are fitted to the observed PK profiles
Only Option A allowed to reproduce the non bioequivalence observed with
ELAB vs 12A015
Integration of dissolution data
77
bull Option A ndash Fit of particle size distribution and upload in G+ as an input for each batch of DP
In vivo dissolution is calculated on the basis of local pH and volumes using ldquoDP particle sizerdquo
Virtual trial set up
78
bull GastroPlus V90bull N=25 healthy subjectsbull Fasted statebull Cross overbull Caveat Stomach pH and transit
are the same in cross over bull Add some variability to stomach
pH and transit timendash Random function in Excel
directly in the stc file
Virtual trial set up stomach pH
79
Virtual trial set up stomach residence time
80
Model verification ndash Ability to reproduce non BE
81
bull Virtual trial to test 12A015 ELAB and MPAC
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI
Geomean Ratio 90 CI
ELAB vs 12A015 0805 (0796 0814) 0876 (0869 0883)
MPAC vs 12A015 0987 (0977 0998) 1000 (0990 101)
ELAB vs 12A015 Compared well with measured ratios of 0800 for Cmax and 0881 for AUCinfin
Model use ndash Design space for dissolution of Lesinurad tablets
82
bull Add a virtual batch A to test the edge of failure
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI Geomean Ratio 90 CI
Virtual Batch A vs 12A015 0992 (0990 0993) 0989 (0988 0990)
Safe space defined
Use of safe space to allow flexibility in specification setting Duzalloreg Q80 45 min for lesinurad
Conclusions and perspectives
Current PBPK absorption models caveats
84
Continuous improvementValidation of guidelines best inputs cross industry validation (eg ARA Food effect)
Within and between subject variabilityUnderstanding variability with biomarkers of physiology
BenefitsSound justification of specificationsldquosafe spacerdquo and regulatory flexibility (PA site changes formulations changes specification changes)Significant savings amp avoidance of unnecessary human testingIdentification of LCM opportunities
85
A vision for the future of absorption modelling
Run a pilot clinical study with different drug products Build a mechanistic absorption model to explain observed exposure
Introduction of biomarkers Understand subject variability and reduce it (system parameters)Move from statistical approach of PK data to mechanistic understanding of individual data
Move from mechanistic understanding of populations to personalized medicine
Mechanistic integration of dissolution (P-PSD Z-factor) The right biomarker for the right drug pH transit bile salt enzyme expression etc Use Individual disposition parameters
Run virtual cross-over BE trials to define edge of failure of CMA and CPP on larger populations with right variability of key parameters
Thanks
Ardea BiosciencesColin RowlingsAnna EidelmanDon Treacy
AstraZenecaTalia FlanaganDavid HoltSimon Hartas
Questions
Confidentiality Notice This file is private and may contain confidential and proprietary information If you have received this file in error please notify us and remove it from your system and note that you must not copy distribute or take any action in reliance on it Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful AstraZeneca PLC 1 Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0AA UK T +44(0)203 749 5000 wwwastrazenecacom
87
PQRI BTC WebinarOctober 2019
88
Time for Questions
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
-
Modellingstrategy
Separate clinical dataset for validation from that of model setup
Model verification is optional if changes are needed
Choices of options
76
bull A Use of in vitro dissolution data to fit a particle size distribution set formulation to DR to delayed release enteric coated tablet
bull B Use of in vitro dissolution data to fit one Weibull function per batch where the dosage form is switched to CR dissolved
bull C Use of in vitro dissolution data to fit a Weibull function per batch where the dosage form is switched to CR Undissolved with drug substance particle size distribution
bull D Use of in vitro dissolution data to fit a Z-factor which accounts for the dose volume and solubility and set formulation to DR to delayed release enteric coated tablet
For all options stomach residence and gastric emptying patterns are fitted to the observed PK profiles
Only Option A allowed to reproduce the non bioequivalence observed with
ELAB vs 12A015
Integration of dissolution data
77
bull Option A ndash Fit of particle size distribution and upload in G+ as an input for each batch of DP
In vivo dissolution is calculated on the basis of local pH and volumes using ldquoDP particle sizerdquo
Virtual trial set up
78
bull GastroPlus V90bull N=25 healthy subjectsbull Fasted statebull Cross overbull Caveat Stomach pH and transit
are the same in cross over bull Add some variability to stomach
pH and transit timendash Random function in Excel
directly in the stc file
Virtual trial set up stomach pH
79
Virtual trial set up stomach residence time
80
Model verification ndash Ability to reproduce non BE
81
bull Virtual trial to test 12A015 ELAB and MPAC
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI
Geomean Ratio 90 CI
ELAB vs 12A015 0805 (0796 0814) 0876 (0869 0883)
MPAC vs 12A015 0987 (0977 0998) 1000 (0990 101)
ELAB vs 12A015 Compared well with measured ratios of 0800 for Cmax and 0881 for AUCinfin
Model use ndash Design space for dissolution of Lesinurad tablets
82
bull Add a virtual batch A to test the edge of failure
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI Geomean Ratio 90 CI
Virtual Batch A vs 12A015 0992 (0990 0993) 0989 (0988 0990)
Safe space defined
Use of safe space to allow flexibility in specification setting Duzalloreg Q80 45 min for lesinurad
Conclusions and perspectives
Current PBPK absorption models caveats
84
Continuous improvementValidation of guidelines best inputs cross industry validation (eg ARA Food effect)
Within and between subject variabilityUnderstanding variability with biomarkers of physiology
BenefitsSound justification of specificationsldquosafe spacerdquo and regulatory flexibility (PA site changes formulations changes specification changes)Significant savings amp avoidance of unnecessary human testingIdentification of LCM opportunities
85
A vision for the future of absorption modelling
Run a pilot clinical study with different drug products Build a mechanistic absorption model to explain observed exposure
Introduction of biomarkers Understand subject variability and reduce it (system parameters)Move from statistical approach of PK data to mechanistic understanding of individual data
Move from mechanistic understanding of populations to personalized medicine
Mechanistic integration of dissolution (P-PSD Z-factor) The right biomarker for the right drug pH transit bile salt enzyme expression etc Use Individual disposition parameters
Run virtual cross-over BE trials to define edge of failure of CMA and CPP on larger populations with right variability of key parameters
Thanks
Ardea BiosciencesColin RowlingsAnna EidelmanDon Treacy
AstraZenecaTalia FlanaganDavid HoltSimon Hartas
Questions
Confidentiality Notice This file is private and may contain confidential and proprietary information If you have received this file in error please notify us and remove it from your system and note that you must not copy distribute or take any action in reliance on it Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful AstraZeneca PLC 1 Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0AA UK T +44(0)203 749 5000 wwwastrazenecacom
87
PQRI BTC WebinarOctober 2019
88
Time for Questions
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
-
Choices of options
76
bull A Use of in vitro dissolution data to fit a particle size distribution set formulation to DR to delayed release enteric coated tablet
bull B Use of in vitro dissolution data to fit one Weibull function per batch where the dosage form is switched to CR dissolved
bull C Use of in vitro dissolution data to fit a Weibull function per batch where the dosage form is switched to CR Undissolved with drug substance particle size distribution
bull D Use of in vitro dissolution data to fit a Z-factor which accounts for the dose volume and solubility and set formulation to DR to delayed release enteric coated tablet
For all options stomach residence and gastric emptying patterns are fitted to the observed PK profiles
Only Option A allowed to reproduce the non bioequivalence observed with
ELAB vs 12A015
Integration of dissolution data
77
bull Option A ndash Fit of particle size distribution and upload in G+ as an input for each batch of DP
In vivo dissolution is calculated on the basis of local pH and volumes using ldquoDP particle sizerdquo
Virtual trial set up
78
bull GastroPlus V90bull N=25 healthy subjectsbull Fasted statebull Cross overbull Caveat Stomach pH and transit
are the same in cross over bull Add some variability to stomach
pH and transit timendash Random function in Excel
directly in the stc file
Virtual trial set up stomach pH
79
Virtual trial set up stomach residence time
80
Model verification ndash Ability to reproduce non BE
81
bull Virtual trial to test 12A015 ELAB and MPAC
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI
Geomean Ratio 90 CI
ELAB vs 12A015 0805 (0796 0814) 0876 (0869 0883)
MPAC vs 12A015 0987 (0977 0998) 1000 (0990 101)
ELAB vs 12A015 Compared well with measured ratios of 0800 for Cmax and 0881 for AUCinfin
Model use ndash Design space for dissolution of Lesinurad tablets
82
bull Add a virtual batch A to test the edge of failure
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI Geomean Ratio 90 CI
Virtual Batch A vs 12A015 0992 (0990 0993) 0989 (0988 0990)
Safe space defined
Use of safe space to allow flexibility in specification setting Duzalloreg Q80 45 min for lesinurad
Conclusions and perspectives
Current PBPK absorption models caveats
84
Continuous improvementValidation of guidelines best inputs cross industry validation (eg ARA Food effect)
Within and between subject variabilityUnderstanding variability with biomarkers of physiology
BenefitsSound justification of specificationsldquosafe spacerdquo and regulatory flexibility (PA site changes formulations changes specification changes)Significant savings amp avoidance of unnecessary human testingIdentification of LCM opportunities
85
A vision for the future of absorption modelling
Run a pilot clinical study with different drug products Build a mechanistic absorption model to explain observed exposure
Introduction of biomarkers Understand subject variability and reduce it (system parameters)Move from statistical approach of PK data to mechanistic understanding of individual data
Move from mechanistic understanding of populations to personalized medicine
Mechanistic integration of dissolution (P-PSD Z-factor) The right biomarker for the right drug pH transit bile salt enzyme expression etc Use Individual disposition parameters
Run virtual cross-over BE trials to define edge of failure of CMA and CPP on larger populations with right variability of key parameters
Thanks
Ardea BiosciencesColin RowlingsAnna EidelmanDon Treacy
AstraZenecaTalia FlanaganDavid HoltSimon Hartas
Questions
Confidentiality Notice This file is private and may contain confidential and proprietary information If you have received this file in error please notify us and remove it from your system and note that you must not copy distribute or take any action in reliance on it Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful AstraZeneca PLC 1 Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0AA UK T +44(0)203 749 5000 wwwastrazenecacom
87
PQRI BTC WebinarOctober 2019
88
Time for Questions
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
-
Integration of dissolution data
77
bull Option A ndash Fit of particle size distribution and upload in G+ as an input for each batch of DP
In vivo dissolution is calculated on the basis of local pH and volumes using ldquoDP particle sizerdquo
Virtual trial set up
78
bull GastroPlus V90bull N=25 healthy subjectsbull Fasted statebull Cross overbull Caveat Stomach pH and transit
are the same in cross over bull Add some variability to stomach
pH and transit timendash Random function in Excel
directly in the stc file
Virtual trial set up stomach pH
79
Virtual trial set up stomach residence time
80
Model verification ndash Ability to reproduce non BE
81
bull Virtual trial to test 12A015 ELAB and MPAC
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI
Geomean Ratio 90 CI
ELAB vs 12A015 0805 (0796 0814) 0876 (0869 0883)
MPAC vs 12A015 0987 (0977 0998) 1000 (0990 101)
ELAB vs 12A015 Compared well with measured ratios of 0800 for Cmax and 0881 for AUCinfin
Model use ndash Design space for dissolution of Lesinurad tablets
82
bull Add a virtual batch A to test the edge of failure
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI Geomean Ratio 90 CI
Virtual Batch A vs 12A015 0992 (0990 0993) 0989 (0988 0990)
Safe space defined
Use of safe space to allow flexibility in specification setting Duzalloreg Q80 45 min for lesinurad
Conclusions and perspectives
Current PBPK absorption models caveats
84
Continuous improvementValidation of guidelines best inputs cross industry validation (eg ARA Food effect)
Within and between subject variabilityUnderstanding variability with biomarkers of physiology
BenefitsSound justification of specificationsldquosafe spacerdquo and regulatory flexibility (PA site changes formulations changes specification changes)Significant savings amp avoidance of unnecessary human testingIdentification of LCM opportunities
85
A vision for the future of absorption modelling
Run a pilot clinical study with different drug products Build a mechanistic absorption model to explain observed exposure
Introduction of biomarkers Understand subject variability and reduce it (system parameters)Move from statistical approach of PK data to mechanistic understanding of individual data
Move from mechanistic understanding of populations to personalized medicine
Mechanistic integration of dissolution (P-PSD Z-factor) The right biomarker for the right drug pH transit bile salt enzyme expression etc Use Individual disposition parameters
Run virtual cross-over BE trials to define edge of failure of CMA and CPP on larger populations with right variability of key parameters
Thanks
Ardea BiosciencesColin RowlingsAnna EidelmanDon Treacy
AstraZenecaTalia FlanaganDavid HoltSimon Hartas
Questions
Confidentiality Notice This file is private and may contain confidential and proprietary information If you have received this file in error please notify us and remove it from your system and note that you must not copy distribute or take any action in reliance on it Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful AstraZeneca PLC 1 Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0AA UK T +44(0)203 749 5000 wwwastrazenecacom
87
PQRI BTC WebinarOctober 2019
88
Time for Questions
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
-
Virtual trial set up
78
bull GastroPlus V90bull N=25 healthy subjectsbull Fasted statebull Cross overbull Caveat Stomach pH and transit
are the same in cross over bull Add some variability to stomach
pH and transit timendash Random function in Excel
directly in the stc file
Virtual trial set up stomach pH
79
Virtual trial set up stomach residence time
80
Model verification ndash Ability to reproduce non BE
81
bull Virtual trial to test 12A015 ELAB and MPAC
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI
Geomean Ratio 90 CI
ELAB vs 12A015 0805 (0796 0814) 0876 (0869 0883)
MPAC vs 12A015 0987 (0977 0998) 1000 (0990 101)
ELAB vs 12A015 Compared well with measured ratios of 0800 for Cmax and 0881 for AUCinfin
Model use ndash Design space for dissolution of Lesinurad tablets
82
bull Add a virtual batch A to test the edge of failure
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI Geomean Ratio 90 CI
Virtual Batch A vs 12A015 0992 (0990 0993) 0989 (0988 0990)
Safe space defined
Use of safe space to allow flexibility in specification setting Duzalloreg Q80 45 min for lesinurad
Conclusions and perspectives
Current PBPK absorption models caveats
84
Continuous improvementValidation of guidelines best inputs cross industry validation (eg ARA Food effect)
Within and between subject variabilityUnderstanding variability with biomarkers of physiology
BenefitsSound justification of specificationsldquosafe spacerdquo and regulatory flexibility (PA site changes formulations changes specification changes)Significant savings amp avoidance of unnecessary human testingIdentification of LCM opportunities
85
A vision for the future of absorption modelling
Run a pilot clinical study with different drug products Build a mechanistic absorption model to explain observed exposure
Introduction of biomarkers Understand subject variability and reduce it (system parameters)Move from statistical approach of PK data to mechanistic understanding of individual data
Move from mechanistic understanding of populations to personalized medicine
Mechanistic integration of dissolution (P-PSD Z-factor) The right biomarker for the right drug pH transit bile salt enzyme expression etc Use Individual disposition parameters
Run virtual cross-over BE trials to define edge of failure of CMA and CPP on larger populations with right variability of key parameters
Thanks
Ardea BiosciencesColin RowlingsAnna EidelmanDon Treacy
AstraZenecaTalia FlanaganDavid HoltSimon Hartas
Questions
Confidentiality Notice This file is private and may contain confidential and proprietary information If you have received this file in error please notify us and remove it from your system and note that you must not copy distribute or take any action in reliance on it Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful AstraZeneca PLC 1 Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0AA UK T +44(0)203 749 5000 wwwastrazenecacom
87
PQRI BTC WebinarOctober 2019
88
Time for Questions
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
-
Virtual trial set up stomach pH
79
Virtual trial set up stomach residence time
80
Model verification ndash Ability to reproduce non BE
81
bull Virtual trial to test 12A015 ELAB and MPAC
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI
Geomean Ratio 90 CI
ELAB vs 12A015 0805 (0796 0814) 0876 (0869 0883)
MPAC vs 12A015 0987 (0977 0998) 1000 (0990 101)
ELAB vs 12A015 Compared well with measured ratios of 0800 for Cmax and 0881 for AUCinfin
Model use ndash Design space for dissolution of Lesinurad tablets
82
bull Add a virtual batch A to test the edge of failure
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI Geomean Ratio 90 CI
Virtual Batch A vs 12A015 0992 (0990 0993) 0989 (0988 0990)
Safe space defined
Use of safe space to allow flexibility in specification setting Duzalloreg Q80 45 min for lesinurad
Conclusions and perspectives
Current PBPK absorption models caveats
84
Continuous improvementValidation of guidelines best inputs cross industry validation (eg ARA Food effect)
Within and between subject variabilityUnderstanding variability with biomarkers of physiology
BenefitsSound justification of specificationsldquosafe spacerdquo and regulatory flexibility (PA site changes formulations changes specification changes)Significant savings amp avoidance of unnecessary human testingIdentification of LCM opportunities
85
A vision for the future of absorption modelling
Run a pilot clinical study with different drug products Build a mechanistic absorption model to explain observed exposure
Introduction of biomarkers Understand subject variability and reduce it (system parameters)Move from statistical approach of PK data to mechanistic understanding of individual data
Move from mechanistic understanding of populations to personalized medicine
Mechanistic integration of dissolution (P-PSD Z-factor) The right biomarker for the right drug pH transit bile salt enzyme expression etc Use Individual disposition parameters
Run virtual cross-over BE trials to define edge of failure of CMA and CPP on larger populations with right variability of key parameters
Thanks
Ardea BiosciencesColin RowlingsAnna EidelmanDon Treacy
AstraZenecaTalia FlanaganDavid HoltSimon Hartas
Questions
Confidentiality Notice This file is private and may contain confidential and proprietary information If you have received this file in error please notify us and remove it from your system and note that you must not copy distribute or take any action in reliance on it Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful AstraZeneca PLC 1 Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0AA UK T +44(0)203 749 5000 wwwastrazenecacom
87
PQRI BTC WebinarOctober 2019
88
Time for Questions
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
-
Virtual trial set up stomach residence time
80
Model verification ndash Ability to reproduce non BE
81
bull Virtual trial to test 12A015 ELAB and MPAC
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI
Geomean Ratio 90 CI
ELAB vs 12A015 0805 (0796 0814) 0876 (0869 0883)
MPAC vs 12A015 0987 (0977 0998) 1000 (0990 101)
ELAB vs 12A015 Compared well with measured ratios of 0800 for Cmax and 0881 for AUCinfin
Model use ndash Design space for dissolution of Lesinurad tablets
82
bull Add a virtual batch A to test the edge of failure
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI Geomean Ratio 90 CI
Virtual Batch A vs 12A015 0992 (0990 0993) 0989 (0988 0990)
Safe space defined
Use of safe space to allow flexibility in specification setting Duzalloreg Q80 45 min for lesinurad
Conclusions and perspectives
Current PBPK absorption models caveats
84
Continuous improvementValidation of guidelines best inputs cross industry validation (eg ARA Food effect)
Within and between subject variabilityUnderstanding variability with biomarkers of physiology
BenefitsSound justification of specificationsldquosafe spacerdquo and regulatory flexibility (PA site changes formulations changes specification changes)Significant savings amp avoidance of unnecessary human testingIdentification of LCM opportunities
85
A vision for the future of absorption modelling
Run a pilot clinical study with different drug products Build a mechanistic absorption model to explain observed exposure
Introduction of biomarkers Understand subject variability and reduce it (system parameters)Move from statistical approach of PK data to mechanistic understanding of individual data
Move from mechanistic understanding of populations to personalized medicine
Mechanistic integration of dissolution (P-PSD Z-factor) The right biomarker for the right drug pH transit bile salt enzyme expression etc Use Individual disposition parameters
Run virtual cross-over BE trials to define edge of failure of CMA and CPP on larger populations with right variability of key parameters
Thanks
Ardea BiosciencesColin RowlingsAnna EidelmanDon Treacy
AstraZenecaTalia FlanaganDavid HoltSimon Hartas
Questions
Confidentiality Notice This file is private and may contain confidential and proprietary information If you have received this file in error please notify us and remove it from your system and note that you must not copy distribute or take any action in reliance on it Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful AstraZeneca PLC 1 Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0AA UK T +44(0)203 749 5000 wwwastrazenecacom
87
PQRI BTC WebinarOctober 2019
88
Time for Questions
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
-
Model verification ndash Ability to reproduce non BE
81
bull Virtual trial to test 12A015 ELAB and MPAC
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI
Geomean Ratio 90 CI
ELAB vs 12A015 0805 (0796 0814) 0876 (0869 0883)
MPAC vs 12A015 0987 (0977 0998) 1000 (0990 101)
ELAB vs 12A015 Compared well with measured ratios of 0800 for Cmax and 0881 for AUCinfin
Model use ndash Design space for dissolution of Lesinurad tablets
82
bull Add a virtual batch A to test the edge of failure
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI Geomean Ratio 90 CI
Virtual Batch A vs 12A015 0992 (0990 0993) 0989 (0988 0990)
Safe space defined
Use of safe space to allow flexibility in specification setting Duzalloreg Q80 45 min for lesinurad
Conclusions and perspectives
Current PBPK absorption models caveats
84
Continuous improvementValidation of guidelines best inputs cross industry validation (eg ARA Food effect)
Within and between subject variabilityUnderstanding variability with biomarkers of physiology
BenefitsSound justification of specificationsldquosafe spacerdquo and regulatory flexibility (PA site changes formulations changes specification changes)Significant savings amp avoidance of unnecessary human testingIdentification of LCM opportunities
85
A vision for the future of absorption modelling
Run a pilot clinical study with different drug products Build a mechanistic absorption model to explain observed exposure
Introduction of biomarkers Understand subject variability and reduce it (system parameters)Move from statistical approach of PK data to mechanistic understanding of individual data
Move from mechanistic understanding of populations to personalized medicine
Mechanistic integration of dissolution (P-PSD Z-factor) The right biomarker for the right drug pH transit bile salt enzyme expression etc Use Individual disposition parameters
Run virtual cross-over BE trials to define edge of failure of CMA and CPP on larger populations with right variability of key parameters
Thanks
Ardea BiosciencesColin RowlingsAnna EidelmanDon Treacy
AstraZenecaTalia FlanaganDavid HoltSimon Hartas
Questions
Confidentiality Notice This file is private and may contain confidential and proprietary information If you have received this file in error please notify us and remove it from your system and note that you must not copy distribute or take any action in reliance on it Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful AstraZeneca PLC 1 Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0AA UK T +44(0)203 749 5000 wwwastrazenecacom
87
PQRI BTC WebinarOctober 2019
88
Time for Questions
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
-
Model use ndash Design space for dissolution of Lesinurad tablets
82
bull Add a virtual batch A to test the edge of failure
Predicted Cmax Predicted AUC (0-96)
Geomean Ratio 90 CI Geomean Ratio 90 CI
Virtual Batch A vs 12A015 0992 (0990 0993) 0989 (0988 0990)
Safe space defined
Use of safe space to allow flexibility in specification setting Duzalloreg Q80 45 min for lesinurad
Conclusions and perspectives
Current PBPK absorption models caveats
84
Continuous improvementValidation of guidelines best inputs cross industry validation (eg ARA Food effect)
Within and between subject variabilityUnderstanding variability with biomarkers of physiology
BenefitsSound justification of specificationsldquosafe spacerdquo and regulatory flexibility (PA site changes formulations changes specification changes)Significant savings amp avoidance of unnecessary human testingIdentification of LCM opportunities
85
A vision for the future of absorption modelling
Run a pilot clinical study with different drug products Build a mechanistic absorption model to explain observed exposure
Introduction of biomarkers Understand subject variability and reduce it (system parameters)Move from statistical approach of PK data to mechanistic understanding of individual data
Move from mechanistic understanding of populations to personalized medicine
Mechanistic integration of dissolution (P-PSD Z-factor) The right biomarker for the right drug pH transit bile salt enzyme expression etc Use Individual disposition parameters
Run virtual cross-over BE trials to define edge of failure of CMA and CPP on larger populations with right variability of key parameters
Thanks
Ardea BiosciencesColin RowlingsAnna EidelmanDon Treacy
AstraZenecaTalia FlanaganDavid HoltSimon Hartas
Questions
Confidentiality Notice This file is private and may contain confidential and proprietary information If you have received this file in error please notify us and remove it from your system and note that you must not copy distribute or take any action in reliance on it Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful AstraZeneca PLC 1 Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0AA UK T +44(0)203 749 5000 wwwastrazenecacom
87
PQRI BTC WebinarOctober 2019
88
Time for Questions
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
-
Conclusions and perspectives
Current PBPK absorption models caveats
84
Continuous improvementValidation of guidelines best inputs cross industry validation (eg ARA Food effect)
Within and between subject variabilityUnderstanding variability with biomarkers of physiology
BenefitsSound justification of specificationsldquosafe spacerdquo and regulatory flexibility (PA site changes formulations changes specification changes)Significant savings amp avoidance of unnecessary human testingIdentification of LCM opportunities
85
A vision for the future of absorption modelling
Run a pilot clinical study with different drug products Build a mechanistic absorption model to explain observed exposure
Introduction of biomarkers Understand subject variability and reduce it (system parameters)Move from statistical approach of PK data to mechanistic understanding of individual data
Move from mechanistic understanding of populations to personalized medicine
Mechanistic integration of dissolution (P-PSD Z-factor) The right biomarker for the right drug pH transit bile salt enzyme expression etc Use Individual disposition parameters
Run virtual cross-over BE trials to define edge of failure of CMA and CPP on larger populations with right variability of key parameters
Thanks
Ardea BiosciencesColin RowlingsAnna EidelmanDon Treacy
AstraZenecaTalia FlanaganDavid HoltSimon Hartas
Questions
Confidentiality Notice This file is private and may contain confidential and proprietary information If you have received this file in error please notify us and remove it from your system and note that you must not copy distribute or take any action in reliance on it Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful AstraZeneca PLC 1 Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0AA UK T +44(0)203 749 5000 wwwastrazenecacom
87
PQRI BTC WebinarOctober 2019
88
Time for Questions
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
-
Current PBPK absorption models caveats
84
Continuous improvementValidation of guidelines best inputs cross industry validation (eg ARA Food effect)
Within and between subject variabilityUnderstanding variability with biomarkers of physiology
BenefitsSound justification of specificationsldquosafe spacerdquo and regulatory flexibility (PA site changes formulations changes specification changes)Significant savings amp avoidance of unnecessary human testingIdentification of LCM opportunities
85
A vision for the future of absorption modelling
Run a pilot clinical study with different drug products Build a mechanistic absorption model to explain observed exposure
Introduction of biomarkers Understand subject variability and reduce it (system parameters)Move from statistical approach of PK data to mechanistic understanding of individual data
Move from mechanistic understanding of populations to personalized medicine
Mechanistic integration of dissolution (P-PSD Z-factor) The right biomarker for the right drug pH transit bile salt enzyme expression etc Use Individual disposition parameters
Run virtual cross-over BE trials to define edge of failure of CMA and CPP on larger populations with right variability of key parameters
Thanks
Ardea BiosciencesColin RowlingsAnna EidelmanDon Treacy
AstraZenecaTalia FlanaganDavid HoltSimon Hartas
Questions
Confidentiality Notice This file is private and may contain confidential and proprietary information If you have received this file in error please notify us and remove it from your system and note that you must not copy distribute or take any action in reliance on it Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful AstraZeneca PLC 1 Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0AA UK T +44(0)203 749 5000 wwwastrazenecacom
87
PQRI BTC WebinarOctober 2019
88
Time for Questions
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
-
85
A vision for the future of absorption modelling
Run a pilot clinical study with different drug products Build a mechanistic absorption model to explain observed exposure
Introduction of biomarkers Understand subject variability and reduce it (system parameters)Move from statistical approach of PK data to mechanistic understanding of individual data
Move from mechanistic understanding of populations to personalized medicine
Mechanistic integration of dissolution (P-PSD Z-factor) The right biomarker for the right drug pH transit bile salt enzyme expression etc Use Individual disposition parameters
Run virtual cross-over BE trials to define edge of failure of CMA and CPP on larger populations with right variability of key parameters
Thanks
Ardea BiosciencesColin RowlingsAnna EidelmanDon Treacy
AstraZenecaTalia FlanaganDavid HoltSimon Hartas
Questions
Confidentiality Notice This file is private and may contain confidential and proprietary information If you have received this file in error please notify us and remove it from your system and note that you must not copy distribute or take any action in reliance on it Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful AstraZeneca PLC 1 Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0AA UK T +44(0)203 749 5000 wwwastrazenecacom
87
PQRI BTC WebinarOctober 2019
88
Time for Questions
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
-
Thanks
Ardea BiosciencesColin RowlingsAnna EidelmanDon Treacy
AstraZenecaTalia FlanaganDavid HoltSimon Hartas
Questions
Confidentiality Notice This file is private and may contain confidential and proprietary information If you have received this file in error please notify us and remove it from your system and note that you must not copy distribute or take any action in reliance on it Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful AstraZeneca PLC 1 Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0AA UK T +44(0)203 749 5000 wwwastrazenecacom
87
PQRI BTC WebinarOctober 2019
88
Time for Questions
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
-
Confidentiality Notice This file is private and may contain confidential and proprietary information If you have received this file in error please notify us and remove it from your system and note that you must not copy distribute or take any action in reliance on it Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful AstraZeneca PLC 1 Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0AA UK T +44(0)203 749 5000 wwwastrazenecacom
87
PQRI BTC WebinarOctober 2019
88
Time for Questions
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
-
PQRI BTC WebinarOctober 2019
88
Time for Questions
Please indicate at the beginning of your typed question if possible which presenter your question is directed to Ajit Rakhi Desai or Xavier
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
-
PQRI BTC WebinarOctober 2019
89
Thank you for attending the webinar
For more information on PQRI visit our website at wwwpqriorg
Questions Contact the PQRI Secretariat at PQRISecretariatpqriorg
Call for VolunteersIf you or your company is a member of a PQRI member organization (CHPA FDA Health Canada IPEC-Americas PDA or USP) and you would to participate in any of the PQRI Technical Committees please contact the PQRI Secretariat (PQRISecretariatpqriorg) for further information
- PQRI Biopharmaceutics Technical Committee 2019 Webinar Series
- Slide Number 2
- Slide Number 3
- Slide Number 4
- Slide Number 5
- Slide Number 6
- Slide Number 7
- Slide Number 8
- What Does PQRI Do
- Slide Number 10
- Slide Number 11
- Slide Number 12
- Slide Number 13
- Slide Number 14
- PQRI QbD WG Team
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Highlights of Team Discussions
- Slide Number 22
- Outline
- Quality by Design (QbD)
- QbD Focus on Patients
- QbD Risk based Assessment
- Designing a Robust Process
- Quality Risk Management
- QRM tools Fishbone (Ishikawa) Diagram
- QRM tools Failure Mode Effect Analysis (FMEA)
- FMEA-risk mitigation
- QbD Real Time Release testing (RTRt)
- RTRt examples in regulatory submissions
- Traditional method vs RTRt to measure BUCU
- Example Surrogate Dissolution Model in RTRt
- QbD Design of Experiments (DoE) amp Design Space
- DoEs from Regulatory Submissions
- Examples of DoEs from Submissions
- DoEs in regulatory submissions
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- QbD Regulatory flexibility
- Comparability Protocols in NDAs
- QbD Support Scientific Innovation
- ETT program progress
- Examples of QbD questions under Question based Reviews for ANDAs
- FDA Quality related guidance amp initiatives
- Summary
- Acknowledgements
- Thank You
- Addressing Content Uniformity Challenge for Low Strength Entecavir Tablet Formulations
- Why a QbD approach was needed
- Entecavir Tablet Formulations
- Entecavir
- pH-solubility profile of entecavir at 25degC
- Entecavir solubility in different solvents
- Common approaches to improve tablet content uniformity
- Possible manufacturing approaches explored for entecavir tablet formulations
- Enhancement in solubility of entecavir with increase in povidone concentration and temperature
- Stability of Entecavir in 15 ww Aqueous PVP Solution at 75degC
- Effect of temperature and PVP concentration on the solubility of entecavir in aqueous PVP solutions
- Entecavir Tablet Formulation
- Entecavir Tablet Content Uniformity
- DSC of ldquoas isrdquo and re-crystallized entecavir from PVP
- X-ray Diffraction of Re-crystallized Entecavir and ldquoas isrdquo Entecavir
- Summary
- Acknowledgement
- Dissolution Rate Justification by PBPK Modeling for Lesinurad Tablets
- Outlook
- What is a Physiological Based PK (PBPK) model
- How to we develop a ldquovalidated modelrdquo
- What to evaluate with PBAM or PBBM tools
- Biopharmaceutical properties - Lesinurad
- Dissolution of drug products
- Modelling strategy
- Choices of options
- Integration of dissolution data
- Virtual trial set up
- Virtual trial set up stomach pH
- Virtual trial set up stomach residence time
- Model verification ndash Ability to reproduce non BE
- Model use ndash Design space for dissolution of Lesinurad tablets
- Conclusions and perspectives
- Current PBPK absorption models caveats
- A vision for the future of absorption modelling
- Thanks
- Slide Number 87
- Slide Number 88
- Slide Number 89
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