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Process Performance QualificationProcess Performance Qualification
Demonstrating a High Degree of Assurance in Stage 2 of the Process Validation Lifecycle g y
Wendy Zwolenski Lambert, CQM/OE, RACy , ,CMC Strategy ForumJanuary 28, 2013
“…aligns process validation activities with a product lifecycle concept…”FDA Guidance for Industry Process Validation: General Principles and Practices, January 2011
A LIFECYCLE Approach to Process Validation?“All h i th lif f d t f th i iti l d l t“All phases in the life of a product from the initial development through marketing until the product’s discontinuation.” ICH Q8(R2)
MThe Validation Group Management
h f h ld d h h h d ff d d“Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree of assurance in its manufacturing process to justify commercial distribution of the product.”
FDA G id f I d P V lid i G l P i i l d P i J 2011
Medical Devices: Context for a “High Degree of Assurance”
FDA Guidance for Industry Process Validation: General Principles and Practices, January 2011
Process Development: What We’ve Always Done (With Enhancements).
Process Performance Qualification: Preparation for the UnexpectedQ p p
Continued Process Verification Quality Planning for Continued Assurance
The views expressed are solely those of the presenter
Gl b l H i ti T k F
High Degree of Assurance in Medical DevicesGlobal Harmonization Task Force“Quality Management Systems – Process Validation Guidance” Referenced: US FDA Guidance for Industry “Process Validation: General Principles and Practices” January 2011
“Process Validation is a term used in the medical device industry to indicate that a process has been subject to such scrutiny that the result of the
b ti ll t d”process …can be practically guaranteed”
“The product should be designed robustly enough to withstand variations in th f t i h ld b bl d t bl tthe manufacturing process…process should be capable and stable to assure continued safe products that perform adequately”
Outlines statistical approaches to consider for achieving confidence.
Process and Product: Design ‐ Capability ‐ Control
www.kadena.af.mil
BinaJect and DuoDote are registered trademarks of Meridian Medical Technologies™, Inc., a Pfizer company.Copyright © 2012 Meridian Medical Technologies™, Inc., a Pfizer company. All rights reserved. DUO464708-01 Nov 2012
“Q li b d l d l b i d fi i h d
BinaJect and DuoDote are registered trademarks of Meridian Medical Technologies™, Inc., a Pfizer company.Copyright © 2012 Meridian Medical Technologies™, Inc., a Pfizer company. All rights reserved. DUO464708-01 Nov 2012
“Quality cannot be adequately assured merely by in‐process and finished product inspection or testing.” FDA Guidance for Industry Process Validation: General Principles and Practices, January 2011
Process Capability and Process Qualification
Theoretical, Simplified ExampleComponent produced by injection molding p p y j g12 cavity mold (each cavity = 1 part)120 second cycle
Injection cycle parameters:• Temperature• Injection Speed• Pressure• Cycle Time
Cycle Validation (PQ) X 3: High, Midpoint, Low
12 t X 0 5 l X 60 i t 360 t
• Cycle Time
12 parts X 0.5 cycles X 60 minutes = 360 partscycle minute hour hour
www.wikipedia.com
Processes yield sufficient numbers of samples to
2880 parts per 8 hour shift! apply traditional statistical methods.
A High Degree of Assurance
Medical Devices • Design and Development Controls
( )
Biopharmaceuticals • Development
P Q lifi ti• Process Validation (IQ, OQ, PQ)• Monitor and Control / Revalidation
• Process Qualification• Continued Process Verification
www.facs.org
Engineering Focus: Adequate Life Science Focus: BiologicalEngineering Focus: Adequate component sample sizes = Heavy reliance on statistical methods.
Life Science Focus: Biological systems, few data = Statistics alone may be impractical.
High Degree of Assurance at End of Stage 2
Stage 1Development
Stage 2Process Qualification
Stage 3Continued Process Verification
“Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree of assurance in its manufacturing process to justify commercial distribution of the product.”
FDA Guidance for Industry Process Validation: General Principles and Practices, January 2011
Which and how much data can be used in conjunction with PPQ data to provide a high degree of assurance? How much commercial scale data is needed?
• Established platform manufacturing ‐ Less?• Contract manufacturing organizations – More?
Can the quality system support an ongoing state of control?Can the quality system support an ongoing state of control?• Has process and product knowledge been integrated into the system?
Development: An Enhanced Approach
The complexity of the molecule and manufacturing processes have necessitated enhanced approaches to development
Process Development and CharacterizationICH Q8
Cell Line QualificationICH Q5A, Q5B, Q5D
Analytical CharacterizationICH Q6B
Clinical ManufacturingICH Q7
ComparabilityICH Q5E
Stability TestingICH Q5C
Risk and Criticality AssessmentsICH Q9
It’s All About Control Strategy
Specifications / Release testingSpecifications / Release testing • Clinical Justification most important • Criticality, process capability and detectability
Analysis and CharacterizationAnalysis and Characterization• Process characterization • Extended product characterization / comparability
Process Control and MonitoringProcess Control and Monitoring• Process and product impurities• Raw materials• Process monitoring / in‐process testing• Controls, set points, ranges, hold times, p , g ,• Process qualification / validation• Process Data Tracking and Trending
UNKNOWN
Derived from: S. Kozlowski, P Swann / Advanced Drug Delivery Reviews 58 (2006)
UNKNOWN
Communicating a High Degree of Assurance
Standardized TerminologyStandardized Terminology
Knowledge Management
Quality PlanningQuality Planning
Perspective on Standardized Terminology
“it was recognized from both industry and regulators that there is a need for standardized terminology and use of ICH nomenclature when present There mightuse of ICH nomenclature when present. There might be a need for additional terms…”
A‐mAb Terminology
“The terms attribute(s)… and parameters(s) are not categorized with respect to criticality… With a lifecycle approach to process validation… the perception of criticality as a continuum rather than a binary state isthe perception of criticality as a continuum rather than a binary state is more useful.”
FDA Guidance for Industry Process Validation: General Principles and Practices, January 2011
A‐mAb: Criticality ContinuumHigh Criticality
Quality Attributes
l bQuality AttributesThe continuum, as opposed to binary classifications ofCritical and Non‐Critical, is thought to “more accuratelyreflect complexity of structure‐function relationshipsand the reality that there is some uncertainty inattribute classification”
Avoids “non‐critical” terminology; ll dmay suggest uncontrolled. Low Criticality
Quality Attributes
Standardized Quality Attribute Terminology
Quality Attribute: “A molecular or product characteristic that is selected for its ability to help indicate the quality of the product…” ICH Q5E
Quality Attributes
Critical Quality
Attributes
No “Nons”
“Since the heterogeneity of these products defines their quality, the degree and profile of this heterogeneity should be characterized to assure lot to lot consistency.” ICH Q6B
Product‐Related Substances: “Molecular variants of the desired product …which are active and have no deleterious effect on the safety and efficacy of the drug product. These variants possess properties comparable to the desired product and are not
id d i i i ” ICH Q6Bconsidered impurities.” ICH Q6B
A‐Mab Process Parameter Classification
Reproduced/Derived from A-mAb Case study
Perspective on Key Process Parameters
Process performance monitoring: M i i i f lMaintaining a state of control
• Monitoring of product quality attributes alone incomplete ‐changes in process performance may represent “early warning sign”
• Monitored, tracked, trended in Continued Process Verification
• Process performance attributes demonstrate inter‐batch consistency
Key process parameters do notKey process parameters do not affect critical quality attributes.
Standardized Terminology: Control and Criticality
If a parameter controllability is highcontrollability is high risk even within the design space, can
this be considered a state of control?state of control?
Should a robust control strategy
provide assurance
?that all process parameters are well-controlled??
“Process parameter criticality is linked to the parameter’s effect on critical p y pquality attribute. It is based on the probability of occurrence and detectability and therefore can change as a result of risk management.”
Standardized Process Parameter Terminology
Functional Relationships and Parameter ClassificationCritical Process Parameters Critical Quality AttributesCritical Process Parameters Critical Quality Attributes
Key Process Parameters Process Performance AttributesNon‐Key Parameters Low Risk of Impact
Documentation and Knowledge Management
“In all stages of the product lifecycle, good project management and good archiving that capture scientific knowledge will make the program more effective and efficient ”efficient.
FDA Guidance for Industry Process Validation: General Principles and Practices, January 2011
Turning Documents into Knowledge
Engaging the Quality Unit early can be a wise investment in managing documents and knowledge!
QA?
Engage the Quality Group to enable knowledge management• Comprehensively communicating a high degree of assurance through
PPQ reports and in regulatory submissions is more likelyk l d h l ( )• Ensure knowledge integration into the quality system (ICH Q10)
Documentation and Knowledge Management
Development Reports
Process Development
AnalyticalReports
Product Characterization
Batch RecordsPilot Scale Production
Qualification ReportsRobustness Studies
FMEA
Technical
Risk AssessmentFMEA Report
SummaryLifecycle Document
PPQ Protocols and Reports: Re‐think the TemplatePPQ Protocols and Reports: Re think the Template
PPQ documents as tools to describe a high degree of assurance • Provide a comprehensive description of the control strategy.
– Include “non‐critical” process variables even though only a subset of parameters and attributes will comprise PPQ
• Describe how the subset of PPQ parameters and attributes demonstrates a state of controlR f i 1 d d di l• Reference appropriate stage 1 data and discuss relevance.
• PPQ Acceptance Criteria– How established and whyHow established and why
TELL THE WHOLE STORY / MAKE NO ASSUMPTIONS
Perspective on Enhanced Sampling
Enhanced sampling and testing to be discontinued after PPQ:• PPQ is fully supportive of the predictive small scale models (impurities:
Protein A, DNA)
Enhanced sampling to continue:Enhanced sampling to continue:• Unexpected results obtained in PPQ • Trends suspected in PPQ data
Plan for data collected FIO (significant variability estimates): • Rationale for continued sampling• Plan for evaluation of accumulated data• Timeframe or amount of data needed to for decision on continuation.
Unexpected Results in PPQ
Feed Rate / Volume
Production Chromatography Operations Drug Substance
Bioreactor Recovery Recovery AEX Recovery Acidic Oxidation Aggregate Volume increased after 1st
Titre(2.7 – 4.0)
yCapture(70-100)
y(90-100)
yCEX
(90-100)Variants(25-35)
(3-10)gg g<4%
Process Performance Attributes Quality Attribute
Critical Quality Attributes
PPQ run to increase tit
Pilot 1 3.5 97 99 80* 25 10 2.0%
Pilot 2 3.9 95 99 90 30 5 3.1%
Pilot 3 3.0 93 95 99 28 7 2.6%
Pilot 4 3.2 91 92 92 27 5 3.0%
titer. What next?
Pilot 5 3.8 98 100 97 30 10 1.9%
Eng 2.6 86 95 98 28 8 3.0
PPQ 2.7 89 98 90 22 7 2.0%
PPQ 3.5 90 97 95 23 9 2.2%PPQ 3.5 90 97 95 23 9 2.2%
PPQ 3.2 91 96 89 25 9 1.8%
Unexpected PPQ Results: High Degree of Assurance in Continued Process Verificationin Continued Process Verification
“… a reduced number of batches cannot adequately capture the expected process variability at commercial manufacturing scale. To provide continued assurance that the process remains in a state of control throughout the life of commercial manufacturing, we will create a multivariate statistical partial f g, pleast squares model (PLS) as part of continued process verification.”
Appropriate Statistical Methods
“PLS is more powerful than standard univariate Statistical p fProcess Control (SPC) approaches in that it ensures that the internal correlations among the different variables are also considered For example if at any given time the titer is lowerconsidered. For example if at any given time the titer is lower than expected for the measured viable cell concentration, the PCA model will be able to detect this as a potential out of norm signal even if both parameters are within their respective univariate ranges.”
Quality System: Alert and Action Limits
“For those parameters that are not built into this PLS modelFor those parameters that are not built into this PLS model, additional monitoring such as univariate SPC charts, and other routine process monitoring will be carried out. Because of its utility as a process monitoring tool, the PLS model will also have alert and action limits; and when the process result exceeds the action limit a deviation will be initiated.”
Quality System and Planning Supports CPV
Management Review
Data Collection and Evaluation
Feedback LoopAdjust Process
Monitoring and Trending
AvFeedback LoopAvoid SurpriseChange Control System
RFeedback Loop
Root Cause Deviation System
Feedback Loop
Qualification
Complaint System
Continued Facility Maintenance
NoFeedback LoopNo overreaction
Plan / ScheduleContinued Facility Maintenance
Thank YouThank You
Acknowledgements
The A‐mAb Case Study TeamAbbott– Abbott
– Amgen– Eli Lilly
G t h– Genentech– GSK– MedImmune
Pfi– Pfizer
