process analytical technology: neue trends in der pharmaceutischen industrie
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Process Analytical Technology:
Neue Trends in der Pharmaceutischen Industrie
Dr. Fritz ErniNOVARTIS Pharma
Global Quality Operations
CH-4002 Basel, Switzerland
Fritz Erni2
Outline The Vision of the desired state What is PAT and QbD ICH Q8 is a Door Opener for
Describing Quality by Design Including more Science and Risk
Management Introduces the Concept of Design Space Design Space Concept for Analytical
Methods Summary
Fritz Erni
Global Challenges
• Rising Global Regulatory Bar• Consent decrees and enormous fines from
manufacturing compliance deficiencies• Higher safety hurdles for marketing approval• Challenge of Sustaining Product Pipeline &
Flow• Biotech contribution less than expected• Government price control• Challenge of Earning Stakeholders Trust
Fritz Erni
“A Paradigm in Crisis”
Main points from this:
• High tech in R & D
• Relatively low tech in Manufacturing
• It matters
Big Pharma manufacturing costs are $ 90 Bn
Significantly more than R&D
Quality by Design: A Challenge to the Pharma Industry
(CAMP, R. Scherzer. FDA Sci. Board. 4/9/02)
Fritz Erni
PAT in the Wall Street Journal Europe 3.9.03
•FDA Commissioner Mark McClellan :
... You need to improve!
... has room for improvements:Semiconductor industry 1 ppm defectsPharmaceutical industry 5 to 10%
.. Acknowledging the FDA role in inhibiting changes ...
•WSJE on the Lauch of the FDA PAT guideline:
Fritz Erni
Impact Process Capability
Process Capability
2 σ 3 σ 4 σ 5 σ 6 σ
Rejected Batches
31.9 %6.7 %0.7 %1 %o10 ppm
Fritz Erni
Process Understanding
•Pharma •Air Plane
Fritz Erni
Typical Ingredients of a Tablet
Active 5µm
Corn Starch 30µm
Lactose 100µm
MicrocrystallineCellulose 102100µm
Dr. Susanne Keitel
Fritz Erni11
Industry’s Vision to be achieved in 2-5 years
• A single global harmonized:A single global harmonized:− Drug Quality StandardDrug Quality Standard– Interpretation of the Drug Quality StandardInterpretation of the Drug Quality Standard
• A Drug Quality Standard based on:A Drug Quality Standard based on:– Risk ManagementRisk Management– ScienceScience
• Mutual recognition of:Mutual recognition of:– “ “equivalent” quality system evaluationsequivalent” quality system evaluations– CMC review and approval CMC review and approval – Across all 3 regions.Across all 3 regions.
Brussels July 2003
Fritz Erni
Desired State
• Product quality and performance achieved and assured by design of effective and efficient manufacturing processes
• Product specifications based on mechanistic understanding of how formulation and process factors impact product performance
• An ability to effect Continuous Improvement and Continuous "real time" assurance of quality
Fritz Erni
2004
2005
2006
FDA PAT guideline
FDA DraftQuality Systems
FDA : Innovation and ContinuousImprovement in
Pharmaceutical Manufacturing
FDA Pharmaceutical cGMP for the 21st Century – a Risk based Approach
GMP and Regulatory Actions
Expert Working Groups (EWG)ICH
Q8Pharmaceutical Development
Q9Risk Management
Q10 Pharmaceutical Quality System
Update Q6A/B ?
Fritz Erni
FromFrom ‘ ‘blind compliance’ blind compliance’
to to ‘‘science and risk science and risk
based compliance’based compliance’
Ajaz Hussain, FDAAjaz Hussain, FDA
The Paradigm ChangeThe Paradigm Change
Key Key
in the Future ofin the Future of
ManufacturingManufacturing
Process UnderstandingProcess Understanding
Fritz Erni
What? Process Understanding
CAPABILITYLITY,PREDICTABIDESIGN,. INGUNDERSTANDPROCESS
Intended Use 1st PrinciplesModeling
OptimizationContinuous
ImprovementCAPA
Risk based Regulatory Assessment
DISCIPLINEEpidemiologyPharm. Engg.ClinicalClin.PharmPharm/ToxPharmaceuticsChemistryBiology
ORGANIZATIONMarketingInformation TechnologyQuality AssuranceManufacturingRegulatoryDevelopmentDiscovery
TIMETIACCGenericAER/Complaints.ApprovalPhase IIIPhase IIPhase IDiscovery
Ajaz S. Hussain
Fritz Erni
A Process is well understood when…
– all critical sources of variability are identified and explained;
– variability is managed by the process; and,
– product quality attributes can be accurately and reliably predicted over the design space …
• http://www.fda.gov/cder/guidance/6419fnl.htm
The PAT GuidanceThe PAT Guidance
Fritz Erni
Challenges to ‘Understanding’
Understanding involves Measurements
Fritz Erni
Challenges to Analytical Science
The need for increased Process understanding is a massive Boost for Analytical Science
Fritz Erni
Challenges to Analytical Science
adequate Tools?
Fritz Erni
Challenges to Analytical Science
adequate Tools !
Fritz Erni
Challenges to Analytical Science
We need the adequate Tools
Fritz Erni
PAT: Process Understanding
•Improved Process Knowledge to Identify and Remove Sources of Variability
•Identify Critical to Quality parameters
•Process understanding as input to Risk Management
•Control what is critical
Fritz Erni
What is Quality by Design
Elements of a QbD
• Systematic Development Approach• Formulation Understanding• Process Understanding• Packaging Understanding• Application of Quality Risk
Management• Advanced Control Strategy
Fritz Erni
Quality by Design
Conventional PD Quality by Design(ideal)Mainly empirical approach
A systematic approach
Quality assured by end-product testing and inspection
Quality assured by well understood product and process, moving controls upstream without relying on end-product testing as much as possible
Process is fixed, disallowing changes
Flexible process within design space, allowing continuous improvement
Focus on process reproducibility – often avoiding or ignoring variability
Focus on formulation and process robustness – understanding and controlling variability
Limited and simple IPC Extended PAT tools replacing the need for end product testing
Fritz Erni
What is ICH Q8
• Guideline for the description what is in P2
• Describes the minimal Standard for P2
• Opens door to get closer to the ‘Desired State’
• Science based• Includes Risk Management• Continuous improvement• Real Time Release
ICH Q8Door opener for Quality by Design
Fritz Erni
Design Space
The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and
approval.
Design Space• Is Key for claiming Process Understanding
• Process understanding is Key for Quality Risk Management
• QRM is the base for any Control Strategy
Fritz Erni
Design of Experiments (DoE)
Air flowIn
let t
empe
ratu
re
Degradation and fines
Air flowIn
let t
empe
ratu
re
Degradation and fines
Air flowIn
let t
empe
ratu
re
Degradation and fines
Air flow
Inle
t te
mpe
ratu
re
Fines
Air flow
Inle
t te
mpe
ratu
re
Degradation
Air flow
Inle
t te
mpe
ratu
re
Fines
Air flow
Inle
t te
mpe
ratu
re
Fines
Air flow
Inle
t te
mpe
ratu
re
Degradation
Air flow
Inle
t te
mpe
ratu
re
Degradation
Effect of inlet temperature and air flow on degradation and generation of fines
Fritz Erni
Examplain Design Space – Graphical Description
Known edge of failure due to fines
% H2O
2.0%1.5%
18.5%
Drying time
Known edge of failure due to degradation
Regions of uncertainty17.5%
Trajectories describing the boundaries of the design space where product quality is assured
Known edge of failure due to fines
% H2O
2.0%1.5%
18.5%
Drying time
Known edge of failure due to degradation
Regions of uncertainty17.5%
Trajectories describing the boundaries of the design space where product quality is assured
Fritz Erni
Quality Risk Management Q9
and the Control Strategy
Fritz Erni
The Quality Risk Management Process
Risk Review
Ris
k C
om
mu
nic
ati
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
Ris
k M
an
ag
em
en
t too
ls
Fritz Erni
WaterContent
Drying
Granulation
RawMaterials
Compressing
PlantFactors
Operator
Temp/RH
Precompressing
Main Compressing
Feeder Speed
Press Speed
Punch PenetrationDepth
Temp
RH
Air Flow
Shock Cycle
DrugSubstance
P.S.Process Conditions
LOD
Diluents
P.S.LOD
Other
Lubricant
Disintegrant
Binder
Water
Binder
Temp
Spray Rate
Spray Pattern
P.S.
Scrape Down
Chopper Speed
Mixer Speed
Endpoint
PowerTime
Age
Tooling
Operator
Training
Analytical
Method
Sampling
FeedFrame
Cause and Effect Process
Fritz Erni
QRM Tools:Failure Mode Effects Analysis
(FMEA)Risk Assessment
Sub-StepEvent(Failure mode)
Effect
Sev
erit
y (S
)[1
<2<3
]
Pro
bab
ility
(P
)[1
<2<3
<4]
Det
ecta
bili
ty (
D)
[1<2
<3]
Ris
k fa
cto
r (S
*P*D
)
Granulation Drying water contentnot meet specification of degradation
2 3 1 6
Risk Reduction
Actions:Risk reduction strategy
Sev
erit
y (
S)
[1<
2<
3]
Pro
bab
ilit
y (P
)[1
<2<
3<
4]
Det
ecta
bil
ity
(D)
[1<
2<3
]
Ris
k f
acto
r (S
*P*D
)
Ris
k r
edu
cti
on
Comments
introduce online NIR 2 1 1 2 4 indirect measurment
introduce IPC analytic 2 2 1 4 2direct measurement; time consuming
humidity measurement in the exausting air
2 1 2 4 2indirect measurment; unspecifoc
Fritz Erni
Control Strategy• Justification of necessary controls
– Raw Materials Control– In-Process Controls– End Product Controls (if necessary)
• Based on Process and Formulation Understanding
• Drives the Process in the Design Space
• Based on Quality Risk Management• To ensure conforming Quality
according Specifications
Fritz Erni
Control Strategy
Unit OperationsAttributesControls
Content Uniformity NIR
Water Content – NIRParticle size – FBRM
Dispensation
Blending
Fluidized Bed Dryer
Packaging
Tableting
Identity-NIR
Blend Homogeneity -NIR
Granulation
Extent of Wet Massing - Power
Consumption
Air
Scale
Multivariate Model (predictsDisintegration)
Raw Materials
Fritz Erni
Q8 Design Space
Can the design space concept also be
applied to Analytical Methods?
Fritz Erni
Q8 Design Space
What is Analytical Method
Understanding?
Systematic Method DevelopmentHow to find max.no. of peaks at max.crit.resolution
pH of eluent A
tG
AN 1:1 MeOH
Cbuffer
40
70
30‘ 90‘
-0.6 +0.6
x 0.5 x 2.0
x 0.5 x 2.0Chetaeron
T[°C]
„Equal Band Spacing“
Increase speed by higher flowrate and reduced column length
different columns in different lengths(„POPLC“)
Dr.Imre Molnar,Institut für angewandte Chromatography,Berlin, Germany
Fritz Erni
Global Challenges
• Rising Global Regulatory Bar• Consent decrees and enormous fines from
manufacturing compliance deficiencies• Higher safety hurdles for marketing
approval• Industry’s pain for post approval changes• Biotech contribution less than expected• Government price control• Challenge of Earning Stakeholders Trust
Fritz Erni
Industry’s pain for post approval changes
• Many are method changes• Most of the changes are urgent• Many of them are
improvements
• US FDA has recognized the issue– Moheb Nasr (FDA) offers working together with
industry– Industry needs to show interest and takes it up
Fritz Erni
Design Space of a Separation Method
• What do we need to understand?• What does Industry need as flexibility
– Separation parameters fixed or with ranges – Separation parameters as a design space– Variability of HPLC columns included
• How is understanding related to the flexibility– How to put it in a dossier– How is it reviewed and approved
Fritz Erni
Design Space of a Separation Method
• The role of– Method development– Method validation– System suitability
• How to describe the enhanced understanding
• How to describe the design space• How to update the analytical design
space• What is the ‘regulatory flexibility’
Fritz Erni46
Summary The Vision of the desired state What is PAT and QbD ICH Q8 is a Door Opener for
Describing Quality by Design Including more Science and Risk Management
Introduces the Concept of Design Space Design Space Concept for Analytical
Methods
Fritz Erni
Alles zu messen was messbar ist -
Und messbar machen was noch nicht messbar ist!
Galileo Galilei1564-1642
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