process-validation-past-present-and-opportunities

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PDA 4-26-11 1

Process Validation

Past, Present, and Opportunities...

Mark Witcher, [email protected]

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The Past – A Brief History

• Release testing• Good Manufacturing Practices (1978)• Process defines the product• 1987 PV Guidelines• QRM – Quality Risk Management• Q8, Q9, Q10, PAT, Lifecycle, QbD...• 2009 Draft PV Guidelines

– “Based on experience...”

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Present - Recent Guideline and Policy

• “Process Validation: General Principles and Practices” (January, 2011)

• MAPP 5016.1 CDER – Policy & Procedures “Applying ICH Q8(R2), Q9, Q10 Principles to CMC

Review” (2/8/11)

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2011 PV Guidelines

• Establishes PV Paradigm– Stage #1: Design– Stage #2: Qualification– Stage #3: Verification– References ASTM documents

• ASTM E2500 – “Good Engineering Practices”

– ASTM – E2500-07: “Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment”

2011 PDA Southeast Chapter Spring Conference (April 26, 2011)

Mark F. Witcher, Ph.D. ([email protected]) 1 of 7

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FDA Policy & Procedures – MAPP 5016.1

• Application of Q8, Q9, & Q10 to CMC review– Quality by Design (QbD) encouraged...– “Application” = expectation = enforcement?

• Reasonable extensions– 2011 PV Guidelines– CMC section => wider application?

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Present – Quality by Design (QbD)

• FDA definition: “A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control based on sound science and quality risk management.” - ICH Q8

• Industry – feel good definitions• Old term, new application ...

– Software...• Opportunity for a working definition of QbD

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Present – Process Development

• ICH Q8(R2) – Pharmaceutical Development– Lifecycle– Quality by Design (QbD)– Design Space– Good science & engineering– Continuous improvement

• Opportunity – evolve concepts

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Present –Quality Risk Management

• ICH Q9 – Quality Risk Management (QRM)– Patient risk – awareness! – Ubiquitous application

• Compliance vs. performance– Compliance - poor surrogate end-point– Eye of the beholder



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Present – Quality Risk Management

• QRM - Rarely a satisfying process• Misapplication of risk tools

– Quality of information– Qualitative vs. Quantitative– Lack calibration, feedback methods

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Opportunity - Quality by Design

• Combine 2011 PV Guidelines & E2500• Working QbD definition

– Stage #0: Define– Stage #1: Design– Stage #2: Qualify– Stage #3: Verify

• Wide applicability

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Opportunity - Quality by Design

• Application methodology– All stages “simultaneously”– Phases for iteration:

• Product definition• Cell bank development• Process development• Clinical manufacturing• Commercial production

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QbD Example – Cleaning Process

Design• Removal methods• Cycle design• Agents needed• Equipment config.

Entry Define• Cleaning reqd.• Equipment• Properties • Acceptance criteria

Qualify• How to test?• Sample scheme• Testing

Verify• Monitoring• Release• Data reqd.



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Present – Legacy Products

• 2011 PV Guidelines – Verification issues?– “Can... continually improve processes”– Based on development & experience– Deciding factors:

• Patient exposure• Product lifecycle• Performance

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Opportunity – Q8 QbD

• Incorporate PV Guidelines• Enhanced lexicon• Design Space definition• “Continuous Improvement”

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Opportunity – Q8 Lexicon

• Existing– CQA – Critical Product Quality– CPP – Critical Process Parameter

• New – tools for improvement– CPA – Critical Process Attribute

• Measure of process performance• Yield, throughput

– CCP – Critical Control Parameter• Provide control• Screen CPP for CCPs

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Opportunity – Q8 Design Space

• Continuum of Criticality• Clarification of format• Classification of:

– Parameters – CPP, CCP– Attributes CQA, CPA



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Opportunity – Q8 Continuous Improvement

• Better definition of “improvements”– Reduced variation– Optimization

• Link to PV Stages• Stage #3: Verification

– Links to operations?

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Opportunity – ICH Q9 - QRM

• Patient Risk – awareness – CQA => Patient

• Process performance– Is it risk, or is it impact?– CPP/CCP => CQA => patient– CPP/CCP => CPA => process– Continuous improvement

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Present – ICH Q9 – QRM

• QRM methods:– FMEA – Failure Mode & Effect Analysis

• Rating methods – RPN – Risk Priority Number– Severity, Likelihood, Detectability

– HACCP – Hazard Analysis & Critical Control Point• 7 guiding principles (FMEA, targets, limits, etc.)• 12 steps (training, feedback..., etc.)

– Rarely implemented effectively (lots of work)

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• Adapt QRM methods to analyze impacts– FMEA => CPP vs. CPA/CQA Estimating– HACCP => IACS

• IACS – Impact Analysis & Control Strategy– Incorporate into the QbD paradigm– Estimating interactions, feedback, iterations, etc.– Precursors to DOE

• Most powerful tool



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• Focus on quantitative methods– Calibration of SMEs– Feedback loops (assessment of effectiveness)

• Impact analysis improvements– Fishbone analysis– Process Modeling – Design Space– DOE– Process performance under uncertainty

• Monte Carlo methods– Regression analysis– SPC – Stage #3

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Conclusions

• Greater expectations – ICH-Q8, 9, 10, + PV• Inclusion of legacy products & processes• Opportunities:

– Working definition of QbD– Better QRM tools...

• Balance risk vs. impact– Continuous improvement tools– Many others...



References - Page 1 of 1

References Regulatory Documents FDA Guidance – Process Validation: General Principles and Practices (January, 2011). ASTM – E2500-07: “Standard Guide for Specification, Design, and Verification of

Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment” FDA – MAPP 5016.1 Policy and Procedures: Office of Pharmaceutical Science;

“Applying ICH Q8(R2), Q9, and Q10 Principles to CMC Review” (2/18/2011) ICH Q6B – Specifications: Test Procedures and Acceptance Criteria for

Biotechnology/Biological Products (March, 1999). ICH Q8(R2) - Pharmaceutical Development; (November, 2009) ICH Q9 - Quality Risk Management; FDA web site; June, 2006. ICH Q10 – Pharmaceutical Quality Systems; FDA Website; 9 May, 2007. Pharmaceutical CGMPs for the 21st Century – A Risk-Based Approach; Final Report;

FDA (Sept., 2004). ICH Q8, Q9, & Q10 Questions & Answers (May, 2010). Other References: PDA Tech. Report #42 – Process Validation of Protein Manufacturing (Sept./Oct., 2005). “A - Mab: a Case Study in Bioprocess Development” CMC Biotech Working Group

(V2.1; 10/30/09); from ISPE Website. Hubbard, D. W; The Failure of Risk Management: Why It’s Broken and How to Fix It;

John Wiley & Sons, Inc.; Hoboken, N.J.; (2009). WHO Technical Report Series No. 908, 2003, Annex 7; “Application of Hazard Analysis

and Critical Control Points (HACCP) Methodology to Pharmaceuticals.” McDermott, R. E., R. J. Mikulak, and M. R. Beauregard; The Basics of FMEA; Productivity Press, New York; (1996)

