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Compliant Formulation Development – The Key to Successful Pharma Development
Oberägeri, May 4th 2012Dr. R. Rogasch
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Regulatory Requirements in Formulation Development
EU Scientifc Guidance Documents – EMA (Clinical, CMC, Procedural)
EP7 – General Chapters, Monographs
US FDA Guidance Documents – (Clinical, CMS, Procedural)
USP – General Chapters and Methods (Dissolution Method Development, IVIVC –requirements, Statistical Methodology)
ICH Q8/Q9/Q10
3
Regulatory Requirements in Formulation Development
• EU Scientifc Guidance Documents – Formulation Development
IMP Procedure (pre-clinical data, dossier submission requirements, clinical studies)
CMC requirements (specifications, stability data, pre-process validation)
Bioequivalence or Biowaiver approach
4
Regulatory Requirements in Formulation Development
• EU EP7 requirements – Generic Drug Development - Legal status of monographs
• Monographs are “official standards”
• The Convention on the Elaboration of a European Pharmacopoeia makes the texts of thePh. Eur. mandatory in all signatory parties
• The pharmaceutical legislation in the European Unionmakes monographs obligatory standards(2001/83/EC, 2001/81/EC)
• Monographs may be accepted as suitable standardseven when not obligatory
5
Regulatory Requirements in Formulation Development
• EU EP7 requirements – Generic Drug Development - example
Do Ph. Eur. specifications apply throughout shelf-life?
• A: Yes, specifications apply until time of use for raw materials and throughout period of validity for preparations
• B: No, Ph. Eur. requirements are for release only
From ICH Quality Implementation Working Group - Integrated Implementation Training WorkshopBreakout D: Pharmacopoeial Requirements, Kuala Lumpur, July 2010
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Regulatory Requirements in Formulation Development• EU EP7 requirements – Generic Drug Development - example
Do Ph. Eur. specifications apply throughout shelf-life?
• A: Yes, specifications apply until time of use forraw materials and throughout period of validity for Preparations (EP7, general notices)
• B: No, Ph. Eur. requirements are for release only.
Implications : EP7 mongraph specifications (impurities) are shelf life indicating !
From ICH Quality Implementation Working Group - Integrated Implementation Training WorkshopBreakout D: Pharmacopoeial Requirements, Kuala Lumpur, July 2010
7
ICHQ8/9/10 Paradigm in Formulation Development
Disclaimer
The information within this presentation is based on the ICH Q-IWG members expertise and experience, and represents the views of the ICH Q-IWG members for the purposes of a training workshop.
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QRM as part of development
Ø To assess the critical attributes of § Raw materials§ Solvents§ Active Pharmaceutical Ingredient (API)§ Starting materials§ Excipients§ Packaging materials
Ø To establish appropriate specifications, identify critical process parameters and establish manufacturing controls
ICH Q9
9
II.3: QRM as part of development
Ø To decrease variability of quality attributes:§ reduce product and material defects§ reduce manufacturing defects
Ø To assess the need for additional studies (e.g., bioequivalence, stability) relating to scale up and technology transfer
Ø To make use of the “design space” concept (see ICH Q8)
ICH Q9
10
Key Steps for a product under Quality by Design (QbD)
Product/Process Development
Pharmaceutical Development
PQS & GMPLocal Environment
Commercial Manufacturing
Quality Unit (QP,..) level support by PQS
Manage product lifecycle, including continual improvement
Design Space (DS), RTR testing
Link raw material attributes and process parameters to CQAs and perform Risk Assessment Methodology
Potential CQA (Critical Quality Attribute) identified & CPP (Critical Process Parameters) determined
QTPP : Definition of intended use & productQuality TargetProduct Profile
CPP : CriticalProcess Parameter
CQA : CriticalQuality Attribute
Risk Management
Opportunities
Design to meet CQA using Risk Management & experimental studies (e.g. DOE)DOE : Design of Experiment
Control Strategy
Technology Transfer
Batch ReleaseStrategy
Prior Knowledge (science, GMP, regulations, ..)
Continualimprovement
Product/Process Understanding
QRM principle apply at any stage
Marketing Authorisation
Quality System PQS
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P2 of CTD as part of a regulatory submission
In line with Quality Risk Management ?
EXAMPLE
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Risk Review
Risk
Com
mun
icat
i on
Risk Assessment
Risk Evaluationunacceptable
Risk Control
Risk Analysis
Risk Reduction
Risk Identification
Review Events
Risk Acceptance
InitiateQuality Risk Management Process
Output / Result of theQuality Risk Management Process
Risk
Managem
entt ools
P2 of CTD as Quality Risk Management process ?
Process understanding
Formulation & Process design
Process control Concept
Product release Concept
Review the submission
Regulatory strategy
Manufacturing Concept
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Target Product Profile
Drug substance properties; prior knowledge
Proposed formulation and manufacturing process
Determination of Cause – Effect relationships
(Risk Identification with subsequent Risk Analysis)
Risk-based classification (Risk Evaluation)
Parameters to investigate (e.g. by DOE)(Risk Reduction 1. proposal; 2. verified)
FORMULATION FORMULATION DESIGN SPACEDESIGN SPACE
PROCESS PROCESS DESIGN SPACE DESIGN SPACE
BY UNIT OPERATIONBY UNIT OPERATIONCONTROL CONTROL STRATEGYSTRATEGY
Formulation understanding
Formulation understanding
Proc
ess
unde
rsta
ndin
gPr
oces
s un
ders
tand
ing
Re
Re -- evaluation and confirm
ationevaluation and confirm
ationR
eRe --
eval
uatio
n an
d co
nfirm
atio
nev
alua
tion
and
conf
irmat
ion
Product and process characteristics on the
final drug product
Review events
DevelopmentDevelopm
.O
peration
Research
Phase 1
Phase 2Phase 3
Launch
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Risk Review
Risk Assessment
Risk Evaluationunacceptable
Risk Control
Risk Analysis
Risk Reduction
Risk Identification
Review Events
Risk Acceptance
InitiateQuality Risk Management Process
Output / Result of theQuality Risk Management Process
Ris k
Man age m
e nt too lsRisk
Com
mun
icat
ion
Team
focu
sed
Inte
rnal
cons
ulta
tion
Stak
ehol
deri
nvol
vem
ent
Responsibilities in regulatory operationsIndustry
A) Reviewers
EXAMPLE
B) Inspectorates
15
Formulation Strategies for Phase I/II Clinical Programs –General Outline
The overall sequence for DP development for each phase/clinical trial can be summarized asfollows:
• Define the best formulation, with the choice of excipients based on maximizing the physicaland chemical stability of the API
• Ensure the formulation provides the desired in vitro release of drug
• Conduct pharmacokinetic studies in animals, if models are available that are known to predict clinical responses.
• Define the best manufacturing process for DP
• Place the final DP prototype on accelerated stability in intended packaging
• Conduct GMP manufacture and packaging of clinical DP
• Generate batch release data and certificate of analysis (CoA) for clinical DP
• Initiate an accelerated stability program for clinical DP (batch made at full scale)
• Submit supporting formulation and analytical data as part of the regulatory filing to requestapproval (i.e., from the FDA, EU, etc.) for using the DP in a clinical study
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Formulation Strategies for Phase I/II Clinical Programs –General Considerations Oral Dosage Forms
•Material Property Assessment
•API (solubility, Polymorphism XRD etc.)•PSD (DLS, LLD)•Morphology (SEM)•Compound Dissolution•Flow/cohesion•Powder compaction•Hardness, tensile strength, brittel fracture index•Excipient/API interactions•Degradation Pathways
17
Formulation Strategies for Phase I/II Clinical Programs –General Considerations Oral Dosage Forms
•Bioavailability Enhancement
•API (solubility enhancement)
•PSD (micronization)
•Solubility Screening, w/o partition
•Precipitation inhibition (API/surfactant/polymer combinations)
•Amorphous Dispersions („solid“ solutions, dispersion in polymer matrix)
•Coatings (multi-particulates in capsules)
•Lipid Systems (fat-matrix, SEDDS, SMEDDS, liposomal carrier)
18
Formulation Strategies for Phase I/II Clinical Programs –IR-Oral Dosage Forms
•Capsule, Tablet (IR dosage forms)
•Direct compression
•Dry Granulation
•Wet Granulation
•Tabletting/Capsule Filling
•Film Coating
•Hot Melt Extrusion
19
Formulation Strategies for Phase I/II Clinical Programs –CR - Oral Dosage Forms
•Capsule, Tablet (CR dosage forms)
•Matrix
•Multiparticulates
•Soft Gel Capsules
•Liquid filled Capsules
•Fuctional Film Coating
•Hot Melt Extrusion
•Osmotic Systems
20
Formulation Strategies for Phase I/II Clinical Programs –Solid Orals - Excipients
Unit dose to contain powders or controlled release pellets
1%-5%GelatinHPMCPolysaccharides
Capsules
Improves powder flow and prevents static charging
Less than 1%Fumed silicaTalc
Glidants
Tailors drug release rate10%-95%HPMCPolyethylene oxidePolyvinylpyrrolidone (PVP)
Controlled release/matrix
Aids in breakup of tablets or granules in aqueous media
Less than 5%Sodium starch glycolateCroscarmellose sodium Crospovidone
Disintegrants
Prevents sticking of formulation to processing surfaces
Less than 2%Magnesium stearate Stearic acidGlyceryl behenate
Lubricants
Provides strength in dry and wet processing of powders
5%-10%Hydroxypropyl cellulose (HPC)HPMCPovidone
Binders
Imparts compressibility and tensile strength to tablets
10%-95%MannitolMicrocrystalline cellulose Starch
Ductile fillers
Imparts hardness and strength to tablets
10%-95%LactoseCalcium phosphate, dibasic
Brittle fillers
FunctionApproximate ranges (%)MaterialsExcipient type
Formulation ExcipientsSolid Orals
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Formulation Strategies for Phase I/II Clinical Programs –Solid Orals - Excipients
Cosmetic or controlled release coatings1%-30%HPMCCellulose acetate , Ethylcellulose, Polymeric acrylates
Coating ingredients Film polymers
Cosmetic appearance, marketingLess than 2%Titanium dioxide, Iron oxides, Dyes and lakes
Colorants
Hide unpleasant drug taste, essential for chewable formulations
1%-5%SucroseAspartameMannitolFlavors
Taste masking agents
Mitigate chemical degradation, oxidation
Less than 1%BHT/BHACitric acid
Chemical stabilizers
Improve solubility and wettability of hydrophobic drugs and improve bioavailability
0.5%-5%Poloxamer 407SLSCyclodextrinsHPMC and acid derivativesHPC
Solubilizers, dispersants, precipitation inhibitors
22
Formulation Strategies for Phase I/II Clinical Programs –Solid Orals - Excipients
Improve processability, Prevent sticking
Less than 1% Less than 0.5%
Glycerol triacetate, Fatty acid salts, esters, Polyethylene glycol,Talc
Plasticizers, Anti-tack agent
23
Formulation Strategies for Phase I/II Clinical Programs –Parenteral Dosage Forms
•Parenteral/injectable Solutions (lyophilization)
•Colloidal Suspensions (peptides, proteins)
•Emulsions
•Liposomal Systems
•Suspensions
24
Formulation Strategies for Phase I/II Clinical Programs –Liquid Orals/Parenterals Excipients
Maintain osmolarity for parenterals, adjust viscosity, mechanical stability for lyophilized cakes
Less than 10%Sodium chloride Hydroxypropylmethylcellulose (HPMC)Mannitol Dextrose
Bulking agents
Maintain pH for optimum solubility, and comfort for injectableformulations
Enough for adjusting to desired pH
Sodium chloride Sodium acetate Sodium phosphate (and corresponding acids) Sodium hydroxide
Buffering agents
Helps with poorly aqueous soluble drugs
20%-50%EthanolPolyethylene glycol
Propylene glycol N-Methylpyrrolidone
Cosolvents
Main solubilizing/suspending vehicle for all components
50%-90%WaterVegetable oils
Polyethylene glycol Propylene glycol
Diluent
FunctionApproximate ranges (%)
MaterialsExcipient type
25
Formulation Strategies for Phase I/II Clinical Programs –Oral Liquid/Parenteral - Excipients
Sweeteners Masking of drug tast
Less than 2%
Sucrose, aspartame Peppermint oil, flavors
Flavoring/tastemasking
Antioxidants, free radical scavengers
Less than 2%
Butylatedhydroxytoluene/anisole(BHT/BHA)Citric acid/citrate
Chemical stabilizers
Prevent microbial growthLess than 2%
Benzyl alcohol Methyl/ propyl parabensBenzalkoniumchloride Thimerosal
Preservatives
Bind metal impurities to prevent complexation and reactions
Less than 1%
Edetate sodium (EDTA) Citric acid/citrate
Chelating agents
Improve drug solubility, emulsification, suspension of drug particles, prevent precipitation
Less than 5%
Hydroxypropyl-beta-cyclodextrinSulfobutylether-beta-cyclodextrin
HPMCPolaxamer 407Sodium lauryl sulfate
(SLS)PhospholipidsCremophorsLabrasolVitamin E TPGS
Solubilizers/surfactants
26
Project Case Study
The information within this presentation is based on the ICH Q-IWG members expertise and experience, and represents the views of the ICH Q-IWG members for the purposes of a training workshop.
Disclaimer
27
Outline of Presentation
Ø Key Steps for Quality by Design
Ø Case Study Organization
Ø Introducing API and Drug Product § Discussion of concepts of Quality Target Product Profile, processes, composition
Ø Description of API & Drug Product process development § Discussion of illustrative examples of detailed approaches from the case study
Ø Batch release
28
Purpose of Case Study
Ø Illustrative example§ Covers the concepts and integrated implementation of ICH Q8, 9 and
10§ Not the complete content for a regulatory filing
Note: this example is not intended to represent the preferred or required approach.
29
Case Study Organization
30
Basis for Development Information
Ø Fictional active pharmaceutical ingredient (API)
Ø Drug product information is based on the ‘Sakura’ Tablet case study§ Full Sakura case study can be found at
http://www.nihs.go.jp/drug/DrugDiv-E.html
Ø Alignment between API and drug product§ API Particle size and drug product dissolution§ Hydrolytic degradation and dry granulation /direct compression
31
Organization of Content
Ø Quality Target Product Profile (QTPP)
Ø API properties and assumptions
Ø Process and Drug product composition overview
Ø Initial risk assessment of unit operations
Ø Quality by Design assessment of selected unit operations
32
Quality attribute focus
Technical Examples
Ø API
Ø Drug Product
CompressionReal Time
Release testing(Assay, CU, Dissolution)
BlendingAPICrystallization
- Final crystallization step
- Blending- Direct compression
- Particle size control
- Assay and content uniformity - Dissolution
Process focus
33
Process Step Analysis
Ø For each example§ Risk assessment§ Design of experiments
• Experimental planning, execution & data analysis§ Design space definition§ Control strategy§ Batch release
Design ofExperiments
Design Space
Control Strategy
Batch Release
QRM
34
QbD Story per Unit Operation
Process Variables
Design ofExperiments
QualityRisk Management
Illustrative Examples of Unit Operations:
QTPP & CQAs
Design Space
Control Strategy
Batch Release
CompressionReal Time
Release testing(Assay, CU, Dissolution)
BlendingAPICrystallization
35
Introducing API and Drug Product
36
Assumptions & Prior Knowledge
Ø API is designated as Amokinol§ Single, neutral polymorph§ Biopharmaceutical Classification System (BCS) class II – low solubility & high permeability§ API solubility (dissolution) affected by particle size
• Crystallization step impacts particle size§ Degrades by hydrolytic mechanism
• Higher water levels and elevated temperatures will increase degradation• Degradates are water soluble, so last processing removal point is the aqueous extraction step• Degradates are not rejected in the crystallization step
Ø In vitro-in vivo correlation (IVIVC) established – allows dissolution to be used as surrogate for clinical performance
Ø Drug product is oral immediate release tablet
37
Quality Target Product Profile (QTPP)Safety and Efficacy Requirements
Appearance, elegance, size, unit integrity and other characteristics
No off-taste, uniform color, and suitable for global marketSubjective Properties
Hydrolysis degradation & dissolution changes controlled by packaging
Degradates below ICH or to be qualified and no changes in bioperformance over expiry period
Chemical and Drug Product Stability: 2 year shelf life (worldwide = 30ºC)
Acceptable API PSDDissolution
PSD that does not impact bioperformance or pharmprocessing
Patient efficacy – Particle Size Distribution (PSD)
Acceptable hydrolysis degradate levels at release, appropriate manufacturing environment controls
Impurities and/or degradatesbelow ICH or to be qualifiedPatient Safety – chemical purity
Identity, Assay and Uniformity30 mgDose
Translation into Quality Target Product Profile (QTPP)Characteristics / RequirementsTablet
QTPP may evolve during lifecycle – during development and commercial manufacture - as new knowledge is gained e.g. new patient needs are identified, new technical information is obtained about the product etc.
38
API Unit Operations
Coupling Reaction
Aqueous Extractions
DistillativeSolvent Switch
Semi ContinuousCrystallization
Centrifugal Filtration
Rotary Drying
Coupling of API Starting Materials
Removes water, prepares API for crystallization step
Addition of API in solution and anti-solvent to a seed slurry
Filtration and washing of API
Drying off crystallization solvents
Removes unreacted materials. Done cold to minimize risk of degradation
Understandformation
& removal of impurities
Example from Case Study
39
Tablet Formulation
Pharmacopoeialor other compendialspecification
40
Drug Product Process
Blending
Lubrication
Compression
Film coating
API and ExcipientsAmokinolD-mannitolCalcium hydrogen phosphate hydrateSodium starch glycolate
LubricantMagnesium Stearate
CoatingHPMC,Macrogol 6000titanium oxideiron sesquioxide
41
Overview of API and Drug Product Case Study Elements
Representative Examples from the full Case Study
42
Overall Risk Assessment for Process
Cou
plin
g R
eact
ion
Aqu
eous
Ex
tract
ions
Dis
tilla
tive
Solv
ent S
witc
hSe
mi-
Con
tinuo
us
Cry
stal
lizat
ion
Cen
trifu
gal
Filtr
atio
n
Rot
ary
Dry
ing
Man
ufac
ture
M
oist
ure
Con
trol
Ble
ndin
g
Lubr
icat
ion
Com
pres
sion
Coa
ting
Pack
agin
g
in vivo performance*Dissolution
AssayDegradation
Content UniformityAppearance
FriabilityStability-chemicalStability-physical
Drug Substance Drug Product
* includes bioperformace of API, and safety(API purity)
• additional study required• known or potential impact to CQA
• known or potential impact to CQA• current controls mitigate risk
• no impact to CQA
Process Steps
CQA
Example from Case Study
43
Overall Risk Assessment for Process
Cou
plin
g R
eact
ion
Aqu
eous
Ex
tract
ions
Dis
tilla
tive
Solv
ent S
witc
hSe
mi-
Con
tinuo
us
Cry
stal
lizat
ion
Cen
trifu
gal
Filtr
atio
n
Rot
ary
Dry
ing
Man
ufac
ture
M
oist
ure
Con
trol
Ble
ndin
g
Lubr
icat
ion
Com
pres
sion
Coa
ting
Pack
agin
g
in vivo performance*Dissolution
AssayDegradation
Content UniformityAppearance
FriabilityStability-chemicalStability-physical
Drug Substance Drug Product
* includes bioperformace of API, and safety(API purity)
• additional study required• known or potential impact to CQA
• known or potential impact to CQA• current controls mitigate risk
• no impact to CQAProcess Steps
CQA
44
API Semi-Continuous CrystallizationØ Designed to minimize hydrolytic degradation (degradate below
qualified levels)§ Univariate experimentation example
• FMEA of crystallization process parameters– High risk for temperature, feed time, water level
• Test upper end of parameter ranges (represents worst case) with variation in water content only and monitor degradation
• Proven acceptable upper limits defined for above parametersNote that in this case study, the distillative solvent switch prior to crystallization and crystallization itself are conducted at lower temperatures and no degradation occurs in these steps
45
API Semi-Continuous CrystallizationØ Designed to control particle size
§ Multivariate DOE example leading to predictive model• FMEA of parameters using prior knowledge
– High risk for addition time, % seed, temperature, agitation• DOE: half fraction factorial using experimental ranges based on QTPP,
operational flexibility & prior knowledge• Design space based on predictive model obtained by statistical analysis of
DOE dataØ Particle size distribution (PSD) qualified in formulation DOE and
dissolution studies
46
Risk Assessment: Particle Size Distribution (PSD) Control
What is the Impact that ------------- will have on PSD? 1) minimal 5) moderate 9) significantWhat is the Probability that variations in ------------ will occur? 1) unlikely 5) moderately likely 9) highly likelyWhat is our Ability to Detect a meaningful variation in --------------- at a meaningful control point? 1) certain 5) moderate 9) unlikely
Unit Operation Parameter
IMPA
CTPR
OB.
Dete
ct
RPNComments
Crystallization Feed Temperature 1 5 1 5
Prior knowledge (slowness of crystallization kinetics) ensures that the hot crystallizer feed will be well dispersed and thermally equilibrated before crystallizing. Hence no impact of feed temp variation on crystal size.
Crystallization Water content of Feed 1 5 5 25 Prior knowledge (solubility data) shows that small variations in water do not affect crystalliation kinetics.
Crystallization Addition Time (Feed Rate) 9 5 9 405Fast addition could result in uncontrolled crystallization. Detection of short addition time could occur too late to prevent this uncontrolled crystallization, and thus impact final PSD.
Crystallization Seed wt percentage 9 5 5 225 Prior knowledge (Chemical Engineering theory) highlights seed wt percentage variations as a potential source of final PSD variation
Crystallization Antisolvent percentage 1 1 1 1Yield loss to crystallization already low (< 5%), so reasonable variations in antisolvent percentage (+/- 10%) will not affect the percent of batch crystallized, and will not affect PSD
Crystallization Temperature 9 5 9 405Change in crystallization temperature is easily detected, but rated high since no possible corrective action (such as, if seed has been dissolved)
Crystallization Agitation (tip speed) 9 5 5 225Prior knowledge indicates that final PSD highly sensitive to Agitation, thus requiring further study.
Crystallization Seed particle size distribution 9 1 1 9 Seed PSD controlled by release assay performed after air attrition milling.
Crystallization Feed Concentration 1 1 1 1 Same logic as for antisolvent percentage
To be investigatedin DOE
47
Options for Depicting a Design Space
Large square represents the ranges tested in the DOE.Red area represents points of failureGreen area represents points of success.
Ø Oval = full design space represented by equation
Ø Rectangle represent ranges§ Simple, but a portion of the design
space is not utilized§ Could use other rectangles within oval
Ø Exact choice of above options can be driven by business factors
Temperature
Pres
sure
Ø For purposes of this case study, an acceptable design space based on ranges was chosen
Seed
wt%
48
API Crystallization: Design Space & Control Strategy
ØControl Strategy should address:§ Parameter controls
• Distillative solvent switch achieves target water content• Crystallization parameters are within the design space
§ Testing• API feed solution tested for water content• Final API will be tested for hydrolysis degradate• Using the predictive model, PSD does not need to be routinely tested since it is
consistently controlled by the process parameters
49
Design Space / Control StrategyParameter controls & Testing
Particle Size Crystallization Temperature 20 to 30ºC Control between 23 and 27ºC
Particle Size Crystallization Feed Time 5 to 15 hours Control via flow rate settings
Particle Size Crystallization Agitation 1.1 to 2.5 m/sQuality system should ensure changes in agitator size result in change to speed setting
Particle Size Crystallization Seed Wt% 1 to 2 wt%Controlled through weigh scales and overcheck
Hydrolysis Degradate
Distillation / Crystallization
Water Content < 1 vol% Control via in-process assay
Particle size will be tested in this example, since the result is includedin the mathematical model used for dissolution.
Example from Case Study
50
Drug Product
Ø Immediate release tablet containing 30 mg Amokinol
Ø Rationale for formulation composition and process selection provided
Ø In vitro-in vivo correlation (IVIVC) determination§ Correlation shown between pharmacokinetic data and dissolution results§ Robust dissolution measurement needed
• For a low solubility drug, close monitoring is important
51
Drug Product Direct Compression Manufacturing Process
Focus of Story
Example from Case Study
Lubrication
52
Initial Quality Risk AssessmentØ Impact of Formulation and Process unit operations on Tablet CQAs
assessed using prior knowledge§ Also consider the impact of excipient characteristics on the CQAs
Drug substance
particle size
Moisturecontent in
manufactureBlending Lubrication Compression Coating Packaging
- Low risk - Medium risk - High risk
DegradationContent uniformityAppearanceFriabilityStability-chemicalStability-physical
in vivo performanceDissolutionAssay
Example from Case Study
53
Drug Product CQA – Dissolution Summary
Ø Quality risk assessment§ High impact risk for API particle size, filler, lubrication and compression
• Fillers selected based on experimental work to confirm compatibility with Amokinol and acceptable compression and product dissolution characteristics
§ API particle size affects both bioavailability & dissolutionØ Multivariate DOE to determine factors that affect dissolution and extent of their
impactØ Predictive mathematical model generated
§ Confirmed by comparison of results from model vs. actual dissolution testingØ Possible graphical representations of this design space
54
Predictive Model for DissolutionA mathematical representation of the design space
Batch 1 Batch 2 Batch 3
Model prediction 89.8 87.3 88.5
Dissolution testing result92.8
(88.4–94.2)90.3
(89.0-102.5)91.5
(90.5-93.5)
Prediction algorithm:Diss = 108.9 – 11.96 × API – 7.556×10-5 × MgSt – 0.1849 × LubT –3.783×10-2 × Hard – 2.557×10-5 × MgSt × LubT
Factors include: API PSD, lubricant (magnesium stearate) specific surface area, lubrication time, tablet hardness (via compression force)Confirmation of model
Example from Case Study
Continue model verification with dissolution testing of production material, as needed
55
Dissolution: Control StrategyØ Controls of input material CQAs
§ API particle size• Control of crystallisation step
§ Magnesium stearate specific surface area• Specification for incoming material
Ø Controls of process parameter CPPs§ Lubrication step blending time within design space§ Compression force (set for tablet hardness) within design space
• Tablet press force-feedback control system
Ø Prediction mathematical model§ Use in place of dissolution testing of finished drug product§ Potentially allows process to be adjusted for variation (e.g. in API particle size)
and still assure dissolution performance
56
Drug Product CQA -Assay & Content Uniformity Summary
Ø Quality risk assessment§ Potential impact for API particle size, moisture control, blending, and lubrication§ Moisture will be controlled in manufacturing environment
Ø Consider possible control strategy approaches§ Experimental plan to develop design space using input material and process factors§ In-process monitoring
Ø Assay assured by weight control of tablets made from uniform powder blend with acceptable API content by HPLC§ Blend homogeneity by on-line NIR to determine blending endpoint, includes feedback loop§ API assay in blend tested by HPLC§ Tablet weight by automatic weight control with feedback loop
57
Blending Process Control Options
Ø Decision on conventional vs. RTR testing
Example from Case Study
58
Process Control Option 2 Blend uniformity monitored using a process analyser
ØOn-line NIR spectrometer used to confirm scale up of blending
ØBlending operation complete when mean spectral std. dev. reaches plateau region§ Plateau may be detected using statistical
test or rules
ØFeedback control to turn off blenderØCompany verifies blend does not
segregate downstream§ Assays tablets to confirm uniformity§ Conducts studies to try to segregate API
0
0.005
0.01
0.015
0.02
0.025
0.03
0.035
0.04
0.045
0 32 64 96 128Revolution (block number)
mea
n sp
ectr
al s
tand
ard
devi
atio
n
Pilot ScaleFull Scale
Plateau region
Number of Revolutions of Blender
Data analysis model will be providedPlan for updating of model available
Acknowledgement: adapted from ISPE PQLI Team
Example from Case Study
59
Batch Release Strategy
Ø Finished product not tested for assay, CU and dissolution Ø Input materials meet specifications and are tested
§ API particle size distribution§ Magnesium stearate specific surface area
Ø Assay calculation§ Verify (API assay of blend by HPLC) X (tablet weight)§ Tablet weight by automatic weight control (feedback loop), %RSD of 10 tablets
Ø Content Uniformity§ On-line NIR criteria met for end of blending (blend homogeneity)§ Tablet weight control results checked
Ø Dissolution§ Predictive model using input and process parameters calculates for each batch that dissolution meets
acceptance criteria§ Input and process parameters used are within the filed design space
• Compression force is monitored for tablet hardness
Ø Water content§ NMT 3% in finished product (not covered in this case study)
60
Drug Product Specifications
Ø Use for stability, regulatory testing, site change, whenever RTR testing is not possibleØ Input materials meet specifications and are tested
§ API PSD§ Magnesium stearate specific surface area
Ø Assay calculation (drug product acceptance criteria 95-105% by HPLC)§ Verify (API assay of blend by HPLC) X (tablet weight)§ Tablet weight by automatic weight control (feedback loop)
• For 10 tablets per sampling point, <2% RSD for weights
Ø Content Uniformity (drug product acceptance criteria meets compendia)§ On-line NIR criteria met for end of blending (blend homogeneity)§ Tablet weight control results checked
Ø Dissolution (drug product acceptance criteria min 85% in 30 minutes)§ Predictive model using input and process parameters for each batch calculates whether dissolution meets acceptance criteria§ Input and process parameters are all within the filed design space
• Compression force is controlled for tablet hardness
Ø Water content (drug product acceptance criteria NMT 3 wt% by KF)
61
Iterative risk assessments
Initial QRAPHA FMEA FMEA FMEA
API Crystallization
Blending
Lubrication
Compression
API PSD
Lubricant
Lubrication time
Hardness
Content uniformity
Beginning DesignSpace
Controlstrategy
Blending time
Lubricant amount
Lubrication time
Pressure
Tablet weight
API PSD model
Blending timeFeedback control
Mg stearate SSA
Lubrication time
Pressure
Automated Weight control
Blend homogeneity
High Risk Medium Risk Low Risk
API PSD
62
Conclusions
Ø Better process knowledge is the outcome of QbD development
Ø Provides the opportunity for flexible change management
Ø Use Quality Risk Management proactively
Ø Multiple approaches for experimental design are possible
Ø Multiple ways of presenting Design Space are acceptable§ Predictive models need to be confirmed and maintained
Ø Real Time Release Testing (RTRT) is an option§ Opportunity for efficiency and flexibility