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Kelly Canter, PhD Right the First Time Program Office Pfizer Inc., Groton, CT

Utilizing RM in a Submission for Developing Critical Process Parameters and Critical to Quality Attributes. Kelly Canter, PhD Right the First Time Program Office Pfizer Inc., Groton, CT FDA/Industry Statistics Workshop September 2006. Outline. QbD Terminology and Value Proposition

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Kelly Canter, PhD Right the First Time Program Office Pfizer Inc., Groton, CT

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  1. Utilizing RM in a Submission for Developing Critical Process Parameters and Critical to Quality Attributes Kelly Canter, PhD Right the First Time Program Office Pfizer Inc., Groton, CT FDA/Industry Statistics WorkshopSeptember 2006

  2. Outline • QbD Terminology and Value Proposition • Risk Assessment Process (Case Study) • Experiments, PAT and Prioritization • Creation of Design Space

  3. Alignment of ICH Q(8) • Enhanced knowledge of product performance . . . • Establish range of material attributes, processing options & process parameters • Demonstrated product/process understanding • Results from PAT, DOE, Science of Scaling • Appropriate application of risk management principles • Establish Design Space • Flexible regulatory approaches • Risk based regulatory decisions • Mfg. process improvements w/in approved design space • Real time quality control Reduce product release tests

  4. Quality by Design – “Right First Time” Process Understanding Continuous Improvement Process Control Process Control Strategy Process Capability Monitoring Commercializable Manufacturing Process (API or DP) e.g. Cpk Change Control Strategy and Implementation Continuous Improvement (Process Changes) • Risk Assessment • Prioritized Experimental Plans • Prioritized PAT Plans Regulatory Filing/Approval Experimentation /Method Dev/Documentation Design Space Definition Launch

  5. Work Impact During Development Decrease ICH re-do’s Decrease Validation re-do’s Decrease Clinical Batch re-do’s Transparent assessment of risk Prioritization Why Do QbD?(Value Proposition) Getting at the Right Process Knowledge = Value to Pfizer, FDA and Patients • Improvements to our Products and Processes • Decrease Variability • Assure market supply • Faster change implementation • Science support Quality investigtations • Reduce COG • Streamline regulatory reviews (S&E) • Framework for decreased regulatory burden • Standardization

  6. Process Understanding People Process Parameters Quality Attributes Inputsto the process control variability of the Output Equipment I N P U T S (X) y = ƒ(x) Measurement y Process OUTPUT Materials Environment J. Scott, ASTM, London 2004

  7. What is a Quality Attribute? • Definitions • Quality Attribute • A physical, chemical or micorbiological property or characteristic of a material. • Key Quality Attribute (KQA) • Potential to impact product quality or process effectiveness • Evaluated by an associated analytical method. • Critical Quality Attribute (CQA) • impacts the safety or efficacy of a drug products

  8. What is a Process Parameter? • Definitions • Process Parameters • Broadly defined as machines, materials, people, processes, measurements and environments • Key Process Parameter (KPP) • Influences product quality or process effectiveness • Critical Process Parameter (CPP) • Influences a CQA and that must be controlled within predefined limits to ensure the API or product meets its pre-defined limits

  9. Risk Assessment Work Process

  10. Risk Assessment and PrioritizationDecide what’s important to evaluate Quality Attributes Process Parameters Many X’s Many Y’s • Process • Consensus decisions • Use process experience • Use project process knowledge • Focus on the “Voice of the Customer” • Process • Cause and Effect Matrix with “Effects” focused on KQAs Vital Few Y’s: Key Quality Attributes Vital Few X’s: Key Process Parameters

  11. Process Understanding Experimentation Risk Assessment Prioritization Experimental Planning The QbD Work Process at a “High Level”

  12. Risk Assessment Case Study Dry Granulation Tablet

  13. Risk Assessment Objectives • Gain agreement on process scope • Decide what’s important to evaluate • Prioritize parameters based on risk • Gain agreement on high level experimental strategy • Identify and prioritize PAT applications

  14. Risk Assessment Risk Assessment Work Process

  15. R&D Co-Facilitator API Analytical Formulation* Chemical DP Analytical Formulation Chemical* Ext. Subject matter experts PAT R&D Statistician Scribe (workbook) Line management Team Co-Leader Pfizer Global Manufacturing Co-Facilitator API Tech Services DP Tech Services Manufacturing Supervisor QC QA Team Co-Leader Subject matter experts PAT PGM Line management Risk Assessment Meeting Participants

  16. Risk Assessment Work Flow Create a Process Map with Focus Areas Identify all Quality Attributes and Determine How To Measure Identify and Prioritize all Process Parameters (KPPs) Group KPPs into Experiments Create PAT Prioritization Matrix Document Yellow font =Pre-work required.

  17. Risk AssessmentStep 1. Create a Process MapDescribes the composition and boundaries of each focus area. Process Step Commercial Manufacture Boundaries Raw Material Dispensing CP-526, 555-18, Cellulose microcr, PH200, Calcium Hydrogrenphosphate (amhydrous), colloidal Silicon dioxide, Croscarmellose Sodium Raw Material Dispensing Focus Area 1 Preblending 300 L bin15 minutes Initial Blend Initial Blend Comil0.8 mm sieve Focus Area 2 Sieving De-lumped Unlubed Blend De-lumped Unlubed Blend 300 L bin2 minutes Focus Area 3 Lube Blend Lubed Blend Dry Granulation and Blend Bepex K 200/50Roll: Deep Pocket Screen Size: 0.8 mm Lubed Blend Focus Area 4 Unlubed Granulation Blending 300 L bin3 minutes Unlubed Granulation 300 L bin3 minutes Focus Area 5 Lube Blend Final Blend Final Blend Focus Area 6 Compression IMA Comprima 300 Tablet Cores Tablet Cores Focus Area 7 Film Coating Glatt GC 1250 Film Coated Tablets

  18. Risk AssessmentStep 2. Identify QAs and How MeasuredStep 3. Identify and Prioritize PPsFocus Area 4 - Dry Granulate + Blend

  19. Risk AssessmentStep 4. Group Key PPs by ExperimentsFocus Area 4 - Dry Granulate + Blend Unit Op1 Unit Op2 KQA1 KQA2 KQA3 KQA4 KQA5 KPP1 KPP2 KPP3 KPP4 KPP5 Experiment3 Experiment1 Experiment2 Next step: Prioritize Experiments Raw Materials Define Process Flowchart . . . . . . . … Define Focus Areas . . . . . . . … Identify KQAs and Associated Measurement . . . . . . . … Identify and Prioritize KPPs Define Experiments . . . . . . . …

  20. Risk AssessmentStep 5. Create PAT Prioritization MatrixFocus Area 4 - Dry Granulate and Blend

  21. Risk AssessmentStep 6. Document the Process Understanding Risk Assessment Experimental Strategy Protocols Primary Data Scientific Reports Global Document Management System

  22. Initial Risk Assessment Complete

  23. Experimental Planning The Work Process Risk Assessment

  24. Experimental Planning“Example DOE”Focus Area 4 - Dry Granulate + Blend

  25. DOE Regression ModelsModel Coefficients (p - values)

  26. Requirements to Map Design Space

  27. Rationale for Process Ranges within Design Space (0.8 mm Mill Screen Size and 50 rpm Granulator Speed) Yellow Region: Acceptable combinations of process parameters. Unacceptable space

  28. Rationale for Process Ranges within Design Space Contour Map – Bypass Weight % • Bypass weight loss is highest in upper left quadrant of Roll Force vs Gap Width 3.8 Statistics and Model 3.2 2.6 Gap Width (mm) 2.0 1.4 4 6 8 10 12 Roll Force Unacceptable space

  29. Conclusions from DOE (D-Optimal) • Increasing roll force improved (lowered RSD) granulation and tablet uniformity. • Increasing roll force also reduced % bypass • However, increasing roll force increased the tablet compressional force required (Safety Margin 8.5 kN) • Acceptable process range for roll force is 5-9 kN (see Design Space)

  30. Prioritization The Work Process Risk Assessment Experimental Planning

  31. Experimental Strategy & Prioritization Example Fractional Factorial (Focus Areas1&2) Central Composite Focus Areas 1&2) 1 Full Factorial w/center Add axial points to Full Factorial 3 2 Gage R&R (Focus Area 3) FMEA (Focus Areas 2&3) 4 Etc…

  32. Experimentation The Work Process Risk Assessment Prioritization Experimental Planning

  33. Building Models: KQA = f (KPP1, KPP2, …KPPi)Conclusions: • Operating target and ranges were identified for each of the following key parameters, key attributes: • Roll force (KPP1) • Impacts particle size, blend uniformity, tablet uniformity (KQA1, KQA2, KQA3) • Gap width (KPP2) • Impacts tablet uniformity (KQA3) • Screen size (KPP3) • Impacts sieve cut uniformity (KQA4) • Granulator speed (KPP4) • Not significant for KQAs investigated

  34. Control-, Design- and Knowledge space Knowledge Space Knowledge Space Design Space Control Space Proven Acceptable Range Normal Operating Range

  35. Design Space

  36. Acknowledgements • Chris Sinko • Roger Nosal • Jim Spavins • Vince McCurdy • Tom Garcia • Christina Grillo • Mary Am Ende • Dan O’Connell

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