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Process Validation for Biotech Products – the C li P ti Compliance Perspective Linda Ng, Ph.D. Office of Manufacturing and Product Quality, Office of Compliance CDER US FDA Office of Compliance, CDER, US FDA New Paradigms for Process Validation - A Practical Approach CMC Strategy Forum, CASSS January 28 2013 January 28, 2013

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Page 1: Process Validation for Biotech Products – the Cli P ...c.ymcdn.com/sites/ · Process Validation for Biotech Products – the Cli P tiCompliance Perspective ... Process Validation

Process Validation for Biotech Products – the

C li P tiCompliance Perspective

Linda Ng, Ph.D.Office of Manufacturing and Product Quality,

Office of Compliance CDER US FDAOffice of Compliance, CDER, US FDANew Paradigms for Process Validation - A Practical Approach

CMC Strategy Forum, CASSSJanuary 28 2013January 28, 2013

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Process Validation (PV)

Collection and evaluation of data from theCollection and evaluation of data, from the process design stage through commercial

production which establishes scientificproduction, which establishes scientific evidence that a process is capable of

i t tl d li i lit d tconsistently delivering quality product.

Guidance for Industry - Process Validation: General Principles and Practices, y p ,January 2011

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The PV guidance covers• Human Drugs• Veterinary Drugs• Veterinary Drugs• Biological and biotechnology

P d tProducts• Finished Products and Active

Pharmaceutical Ingredients• Combination (Drug and Medical Device) ( g )

Products

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FDA encourages the use of• Modern pharmaceutical development

conceptsconcepts• Quality risk management

Q li ll f h• Quality systems at all stages of the manufacturing process lifecycle

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A Successful Validation PProgram

• Understand the sources of variationUnderstand the sources of variation• Detect the presence and degree of variation• Understand the impact of variation of the• Understand the impact of variation of the

process and ultimately on product attributesControl the variation in a manner• Control the variation in a manner commensurate with the risk it represents in the process and productthe process and product

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PV RequirementProcess Validation for Active Pharmaceutical Ingredients or Drug g gSubstance is enforceable under the Statute

Statutory cGMP provision at 501(a)(2)(b) ofStatutory cGMP provision at 501(a)(2)(b) of the Federal Food, Drug, and Cosmetic Act;

– drugs must be made in accordance with current good manufacturing practice.

No regulations exist for APIs/drug substance b t CGMP id il bl ICH Q7but CGMP guidance available - ICH Q7

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PV Requirement cont’d• Manufacturing process be designed and

controlled to assure that in-process materials and the finished product meet predeterminedand the finished product meet predetermined quality requirements and do so consistently and reliably

§211.100(a) §211.100(b) §211.42§ 211 160(b)(3) §211 180( ) §211 63§ 211.160(b)(3) §211.180(e) §211.63§211.165(c) §211.165(d) §211.68§211 165(a)§211.165(a)

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Process Validation ActivitiesStage 1 – Process Design

The commercial process is defined during this stage based on knowledge gained through developmentbased on knowledge gained through development and scale-up activities

Stage 2 – Process Qualification gDuring this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing

Stage 3 – Continued Process Verification Ongoing assurance is gained during routine production that the process remains in a state ofproduction that the process remains in a state of control

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Stage 2 Process Qualification

• Facility Design and Utilities/Equipment QualificationQualification

• Process Performance Qualification (PPQ)Combines qualified facility utilities &Combines qualified facility, utilities & equipment Trained personnelTrained personnel Control procedures Components to product commercial batchesComponents to product commercial batches

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Stage 3 Continued Process Verification (CPV)Verification (CPV)

Continual assurance that process remains in a state of controlstate of control• System(s) to detect and monitor unplanned

variationvariation• Meets CGMP requirements §211.180(e)

Evaluate on-going process and product dataEvaluate on going process and product dataTake action to correct, anticipate and prevent problems

• Data be statistically trended and reviewed by trained personnel

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Where to Submit?

For biotechnological processes, … the data provided in support of process validation is included as part of the marketing application (ICH Q11 3.2.S.2.5).

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Overlap of oversight –BLA review and CGMP programp g

• The original product development, process design, (Stage 1) and initial process qualification (Stage 2) studies are evaluated as part of the BLA reviewstudies are evaluated as part of the BLA review

• During pre-approval/surveillance inspection, investigators determine if the current manufacturing process (Stage 3) is performing as planned/predictedprocess (Stage 3) is performing as planned/predicted

control strategy properly targeted and working as intended?state of control established and maintained?state of control established and maintained?identity, strength, quality, purity and potency of product on the market assured?Compare (Stage 3) against the Stage 1 and Stage 2Compare (Stage 3) against the Stage 1 and Stage 2 data and predictions

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Objective of Process ValidationValidation

• Biotech products are complex and heterogeneous; knowledge of how productheterogeneous; knowledge of how product attributes affect the safety and efficacy of the product is crucial to aid study designproduct is crucial to aid study design

• Process remains in a state of control during commercial manufacturecommercial manufacture

• A lifecycle approach should be implemented

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Why ‘lifecycle’ matters?

• Rational, scientific process design. Quality, safety, and efficacy are designed into the product

• Demonstrate that the process works consistently• Maintain process control during routine

productionK l d d t ti d t l f i bilit d iKnowledge, detection, and control of variability during manufacturing Quality cannot be adequately assured by end productQuality cannot be adequately assured by end product testing alone

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Differences and similarities between Comparability and PPQbetween Comparability and PPQ

Protocols/Reports

??

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Comparability Protocol• Describe the tests and studies that will be

performed, including the analytical d d t it i th t illprocedures and acceptance criteria that will

be met to demonstrate that specified CMC changes do not adversely affect the productchanges do not adversely affect the product.

• Reduced reporting category for future reporting of the specified CMC changesreporting of the specified CMC changes

• Facilitate the subsequent implementation and reporting of post approval CMC changes, p g p pp g ,resulting in faster product into distribution

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PPQ Protocol• Develop and complete in Stage 2 of PV• Specifies the manufacturing conditionsSpecifies the manufacturing conditions,

controls, testing and expected outcomes• Should be reviewed and approved in• Should be reviewed and approved in-

house before implementation

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Comparability vs. PPQ• Objective is different

Reduce filing type for comparability reportReduce filing type for comparability reportSupport the process validation study for PPQ

• Likely the data in the reports overlap• Likely the data in the reports overlapBoth address the identity, strength, quality, purity or potency of the productpurity or potency of the productDesign the tests to cover an understanding of the complexity and heterogeneity of theof the complexity and heterogeneity of the product

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More on PPQA systematic approach to development that begins with defined objectives, and emphasizes product and process understanding, andproduct and process understanding, and process control, based on sound science and quality risk management (ICH Q8(R2))

Understand the product processes andUnderstand the product, processes and controls Understand the procedures that generate the p gdata to support the quality of the productFocus on designing useful tests

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More on PPQ cont’dControl Strategy (ICH Q10)• Assures process performance and product

qualityquality• Includes parameters and attributes related to

drug substance and drug product materialsI l d t f ilit d i t• Includes components, facility and equipment operating conditions

• Includes in-process controls, finished product p , pspecification, and the related procedures and frequency of monitoring and control

Analytical tests play a critical roleAnalytical tests play a critical role

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Successful PPQ• Confirms the process design• Demonstrates commercial manufacturingDemonstrates commercial manufacturing

process will perform as expected• Permits commercial distribution of drug• Permits commercial distribution of drug

product

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Batch Type to Support ValidationValidation

B. Principles Specific to Biotechnological/Biological Drug Substance (7.2), ICH Q11( )

– Information in dossier in support of process validation usually contains both commercial scale process validation studies and small scale studiesvalidation studies and small scale studies.

– Process validation batches should be representative of the commercial process.D t t th t th ll l d l i– Demonstrates that the small scale model is an appropriate representation of the proposed commercial scale.

– Batches are scalable and representative

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Number of PV Runs• Should depend on the complexity of the

process or the magnitude of the process p g pchange being considered.

• Justify based on the science andJustify based on the science and understanding of the process

• Justify using quality design of the tests to• Justify using quality design of the tests to support validation

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FDA’s Expectations • Contact the appropriate Center/Division to

determine the type of PV information to ypinclude in the submission

• Take advantage of the meetings availableTake advantage of the meetings available• The Agency has the option of granting or

denying meeting requestsdenying meeting requests

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BLA/NDA Milestone Meetings

Pre-IND EOP CMCEnd of Phase

(EOP) 1CMC specificPre NDA/BLA(EOP) 1

EOP 2Pre NDA/BLA

EOP 2a

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Types of Meeting• Type A Meeting

– Stalled product development– Occur within 30 days

• Type B Meetingyp g– Milestone development– Occur within 60 days

• Type C Meeting– General guidanceg– Occur within 75 days

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ICHQ8/Q9/Q10Points to Consider*Points to Consider

Section 7. Process Validation/ ContinuousProcess Verification (CPV)( )

Principles from ICH Q8(R2), Q9 and Q10 can support an alternative process

lid ti h d li blvalidation approach and are applicable to drug substance and drug product More holistic approach across theMore holistic approach across the product lifecycle, including Continuous Process Verification

* (R2) December 2011

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Warning Letters% WL/inspections *% WL/inspections

Fiscal Year 2011 Fiscal Year 2012Fiscal Year 2011• International

Fiscal Year 2012• International

3.4%• Domestic

3.8• Domestico est c

2.6%o est c

1.3%

* Agency internal data

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Inspectional Observations • Difficulty with growing cells• Bacteria contaminationBacteria contamination• Equipment malfunction with interruption in

serviceservice• Lack of understanding in material

tibilit f d b t d dcompatibility for drug substance and drug product

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Process Understanding and P d t Q litProduct Quality

Poor quality drugs on the market, evidenced by recalls complaints and other indicatorsby recalls, complaints and other indicators, from supposedly “validated” processes point to a lack of process understanding andto a lack of process understanding and adequate process control.

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Conclusions• Focus on process validation study design• Design the tests to cover anDesign the tests to cover an

understanding of the complexity and heterogeneity of the product andheterogeneity of the product and manufacturing process

• Meet with Agency to obtain concurrence• Meet with Agency to obtain concurrence on study design as appropriate

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FDA Guidances• Process Validation: General Principles and

Practices, January 2011• Sterile Drug Products Produced by Aseptic

Processing, September 2004C bilit P t l P t i D• Comparability Protocols Protein Drug Products and Biological Products -Chemistry Manufacturing and ControlsChemistry, Manufacturing, and Controls Information, In Draft May 2003

• Formal Meetings Between the FDA andFormal Meetings Between the FDA and Sponsors or Applicants, May 2009

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ICH Guidances• ICH Q7 GMP Guidance for Active

Pharmaceutical Ingredients, August 2001• ICH Q8(R2) Pharmaceutical Development• ICH Q8(R2) Pharmaceutical Development,

November 2009• ICH Q9 Quality Risk Management, June Q Q y g ,

2006• ICH Q10 Pharmaceutical Quality System,

Step April 2009Step April 2009• Q8, Q9 and Q10 Questions and Answers

(R4) November 2011(R4), November 2011

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ICH Guidances cont’d• Q8, Q9 and Q10 Questions and Answers

Appendix: Q&As from Training Sessions (Q8,Appendix: Q&As from Training Sessions (Q8, Q9 & Q10 Points to Consider), July 2012ICH-Endorsed Guide for ICH Q8/Q9/Q10 Implementation Working Group Points to Consider (R2), December 2011

• ICH Q11 Development and Manufacture of Drug Substances, November 2012g

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Websites• http://www.fda.gov/Drugs/GuidanceCompli

anceRegulatoryInformation/Guidances/ucg ym064971.htm

• http://www fda gov/Drugs/GuidanceComplihttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065005 htmm065005.htm

• http://www.ich.org/products/guidelines/quality/article/quality guidelines htmllity/article/quality-guidelines.html

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Acknowledgment

• Jeffery Baker • Teddi Lopezy• Bo Chi• Bobby Chun

p• Grace McNally• Paula Katzy

• Mary Farbman• Tamara Felton

• Diane Raccasi• Patrick SwannTamara Felton

• Brian HasselbalchPatrick Swann

• Steven Wolfgang

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ApplicantsApplicants FDAFDA

Quality Drug Quality Drug ProductsProducts

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