1. Moving Towards the “Desired State”: Scientific Gap Analysis Ajaz S. Hussain, Ph.D. Deputy Director, Office of Pharmaceutical Science, CDER, FDA 20 October 2004, ACPS Meeting

2. Good Pharmaceutical Quality – an acceptably low risk of failing to achieve the derived clinical attributes Janet Woodcock, MD Acting Deputy Commissioner for Operations October 6, 2004

3. How Do We Link Measurement and Risk? Quality by Design (QbD) Derive multivariate model during development Confirm during clinical phase Janet Woodcock, MD Acting Deputy Commissioner for Operations October 6, 2004

4. Quality System Final link between product and customer-driven quality attributes Integrate product & process knowledge on ongoing basis Assure ongoing control Enable continuous improvement Janet Woodcock, MD Acting Deputy Commissioner for Operations October 6, 2004

5. Summary Future definitions of quality should be probabilistic in nature Science management, risk-management and quality management are important FDA must be leaders in this arena Janet Woodcock, MD Acting Deputy Commissioner for Operations October 6, 2004

6. Horizontal (Systems) View R&DManufacturing ReviewInspection Quality of the interface between functional units determines the effectiveness and efficiency of the process The interface can be “handoffs between functions” and often is in need for better coordination Rapid and broad movement of information and knowledge sharing is necessary for process optimization From “Technology Transfer” to “Knowledge Transfer”

7. http://amptiac.alionscience.com/pdf/2001MaterialEase13.pdf

8. Current State Today C,M,C Design information available in applications is limited and varied Today C,M,C Design information available in applications is limited and varied High degree of uncertainty High degree of uncertainty Critical variables and process controls Critical variables and process controls Process validation Process validation Focus on in-process and product testing Focus on in-process and product testing Risk coverage post approval Risk coverage post approval Supplements are a means for risk mitigation Supplements are a means for risk mitigation Traditional use of “market standards” as release tests – not very effective for process understanding and continuous improvement Traditional use of “market standards” as release tests – not very effective for process understanding and continuous improvement Variable test methods for physical characteristics Variable test methods for physical characteristics Less than optimal “systems” perspective and approach Less than optimal “systems” perspective and approach Low efficiency and high cost of drug development and manufacturing Low efficiency and high cost of drug development and manufacturing Continuous improvement is difficult (or not possible) Continuous improvement is difficult (or not possible)

9. John C Berridge, FDA’s Manufac. Subcommittee Meeting, July 2004

10. Information and Knowledge for Regulatory Assessment & Decision Process Quality & Performance - Design relationships Quality & Performance - Design relationships Impact of formulation & process factors on performance Impact of formulation & process factors on performance Specifications based on “mechanistic” understanding Specifications based on “mechanistic” understanding Ability to effect continuous improvement Ability to effect continuous improvement Continuous “real time” quality assurance Continuous “real time” quality assurance

11. Design Process Design is about doing things consciously, and not because they have always been done in a certain way Design is about doing things consciously, and not because they have always been done in a certain way It is about comparing alternatives to select the best possible solution It is about comparing alternatives to select the best possible solution It is about exploring and experimenting in a structured way It is about exploring and experimenting in a structured way http://www.designcouncil.org.uk

12. Design is about doing things consciously Intended Use Route of administration Patient population ….. Product Design Design Specifications (Customer requirements) Manufacturing Process Design and Control Capability Ability to reliably and consistently deliver the target product design specifications ProductPerformance: Design specifications reliably and consistently deliver the therapeutic objectives

13. ICH Q8: CTD-Q (P2) Drug Substance or API Intended Use Route of administration Patient population ….. Product Design Design Specifications (Customer requirements) P2.1 and 2.6 P2.2, 2.4, 2.5, 2.6 Drug Product Container Closure System Microbiological Attributes Compatibility (e.g., recon) Manufacturing Process Components of drug product P2.3 Manufacturing Process Development

14. Design Thinking Design thinking makes the user paramount, ensuring that the services we end up will do the job they're supposed to as well as delighting the customer Design thinking makes the user paramount, ensuring that the services we end up will do the job they're supposed to as well as delighting the customer Design thinking and methods provide new routes to better public services that meet people's needs and deliver value for money. Design thinking and methods provide new routes to better public services that meet people's needs and deliver value for money. http://www.designcouncil.org.uk

15. Quality & Performance - Design relationships Conventional vs Novel Design Conventional vs Novel Design Utility of prior knowledge Utility of prior knowledge From similar drug products From similar drug products Pharmaceutical development information on prototypes and selected novel design Pharmaceutical development information on prototypes and selected novel design “Level” of mechanistic understanding “Level” of mechanistic understanding Pre-formulation program Pre-formulation program Mechanism of degradation Mechanism of degradation Mechanism of absorption; BCS Class Mechanism of absorption; BCS Class Physical characterization Physical characterization Ability to reliably predict performance – confirm as you progress (e.g., scale-up,…) - Design of development protocol Ability to reliably predict performance – confirm as you progress (e.g., scale-up,…) - Design of development protocol

16. Quality & Performance - Design relationships Level of understanding increases over time Level of understanding increases over time Structured empirical approach Structured empirical approach Use of prior knowledge to identify and select a design space for characterization Use of prior knowledge to identify and select a design space for characterization For example; Failure Mode Effect Analysis For example; Failure Mode Effect Analysis Initial conditions for screening experiments Initial conditions for screening experiments Characterization and modeling experiments (including – interactions) Characterization and modeling experiments (including – interactions) Impact of formulation & process factors on performance Impact of formulation & process factors on performance Design of clinical trial material and clinical trial information Design of clinical trial material and clinical trial information Shelf-life Shelf-life

17. James E. Seely, Ph. D., Amgen Colorado. US Arden House 2004

18. Robust Design (after Taguchi) Principle – improving the quality of a product by minimizing the effects of variation without eliminating the causes. Robust design has become one of the powerful tools to assist designers to make reliable decisions under uncertainty. Phadke, M.S., Quality Engineering using Robust Design. Prentice Hall, Englewood, New Jersey, 1989 Du, X. and Chen, W. Methodology for managing Effect of uncertainty in simulation-based systems Design. AIAA J 38: 1471 (2000).

19. Performance of a Solids Processing Units AIChE Journal 47: 107-125 (2001) Material Characteristics Hamaker constant Dielectric constant Young’s modulus Particle Attributes PSD Shape Composition Equipment Design Geometry Constituent parts Material properties Operating Conditions Speed of moving parts Temperature Humidity Bulk Mechanical Properties Angle of repose Unconfined yield stress Forces Acting on Particles Adhesion forces Impact forces Performance of a Unit

20. aaps Annual Meeting20 ICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT DISSOLUTION What specific test conditions and acceptance criteria are appropriate? [IR] dissolution significantly affect BA? Develop test conditions and acceptance distinguish batches with unacceptable BA YES NO YES NO YES NO Do changes in formulation or manufacturing variables affect dissolution? Are these changes controlled by another procedure and acceptance criterion? Adopt appropriate test conditions and acceptance criteria without regard to discriminating power, to pass clinically acceptable batches. Adopt test conditions and acceptance criteria which can distinguish these changes. Generally, single point acceptance criteria are acceptable. How? What? Why? How do we currently establish dissolution specifications

22. aaps Annual Meeting22 ICH Q6A DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT DISSOLUTION What specific test conditions and acceptance criteria are appropriate? [IR] dissolution significantly affect BA? Develop test conditions and acceptance distinguish batches with unacceptable BA YES NO YES NO YES NO Do changes in formulation or manufacturing variables affect dissolution? Are these changes controlled by another procedure and acceptance criterion? Adopt appropriate test conditions and acceptance criteria without regard to discriminating power, to pass clinically acceptable batches. Adopt test conditions and acceptance criteria which can distinguish these changes. Generally, single point acceptance criteria are acceptable. Overall Risk-based CMC: Why? Overall CMC Systems approach (e.g., link to morphic form, particle size, stability failure mechanisms) CMC: Why? Then How? Clin. Pharm. What? Design of Manufacturing and Controls How (reliable)? Product Design (Postulate - Confirmed Based on mechanism and/or empirically) So what?

23. Static Manufacturing “Within” (Change Target setting) “Outside”

24. Making and Reporting Manufacturing Changes: Current Regulations Section 506A of the Act and § 314.70 provide for four reporting categories based on Section 506A of the Act and § 314.70 provide for four reporting categories based on “……potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product.” “……potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product.” “Substantial” potential- Major change – Prior Approval Supplement “Substantial” potential- Major change – Prior Approval Supplement “Moderate” potential - Moderate change - Changes Being Effected in 30 Days or Changes Being Effected “Moderate” potential - Moderate change - Changes Being Effected in 30 Days or Changes Being Effected “Minimal” potential – Minor change -Annual Report “Minimal” potential – Minor change -Annual Report No change – no reporting - “beyond the variation already provided for in the application.” No change – no reporting - “beyond the variation already provided for in the application.” “Connection To Risk”

25. “Design Space” = f (Intended Use * Design * Control * Risk) Quality System Risk Classification Process Design & Control Specifications Product Design Intended Use Design Requirements Reliability To Deliver Design Requirements Assessment Based on ICH Q8 Information/Knowledge ICH Q9 Risk Tools

26. Pharmaceutical Quality System Chemistry Manufacturing Controls CGMPs Clinical Pharm/Tox Clin Pharm & Bio Continuous Learning and Improvement Drug Safety PAC Process Capability CMC “Design and Knowledge Space” Clinical “Design & Knowledge Space” CGMP “Design & Knowledge Space”

27. CGMP Initiative http://www.fda.gov/cder/gmp/index.htm "Prove it" "Say what you do" "Do what you say" "Improve it“ Continuous Improvement Innovation "Unable to prove" Why? "Corrective and Preventive Actions" http://www.fda.gov/cder/gmp/gmp2004/manufSciWP.pdf

28. Frontiers in Chemical [& Pharmaceutical] Engineering 1905-1915: Industrial Chemistry 1925: Unit Operations 1935 - Material & Energy Balances 1945 - ChE Thermodynamics & Process Control 1955 - Applied Kinetics & Process Design 1965 – Transport phenomena, Process dynamics, Process Engineering, Computer Technology 2000 – : Molecular Transformations, Multi-Scale Analysis, Systems view 1960’s Industrial Pharmacy Chemical Engineering Pharmaceutical Engineering Unit Ops ChE Science Systems Engineering Brian Scarlett 2001 and http://mit.edu/che-curriculum/2003/index.html

29. Draft Guidance for Industry Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations http://www.fda.gov/cder/guidance/6452dft.doc Traditional goals Non-traditional goals (risk based, flexibility, robustness, scalability, continuous improvement, innovation, efficiency,….)Characteristics Complexity, uncertainty Relationships (between goals & characteristics) Knowledge and information centric relationships Fundamental issues Systems Engineering – Quality Systems

30. Managing Professional Intellect A corporation’s success today lies more in its intellectual and system capabilities than in its physical assets A corporation’s success today lies more in its intellectual and system capabilities than in its physical assets Cognitive knowledge (know-what) Cognitive knowledge (know-what) Advanced skills (know-how) Advanced skills (know-how) System understanding (know-why) System understanding (know-why) Self-motivated creativity (care-why) Self-motivated creativity (care-why) Increasing Value Quinn, Anderson, and Finkelstein. HBR, April 1996

31. Managing Professional Intellect Recruit the best Recruit the best Force intensive early development Force intensive early development Constantly increase professional challenge Constantly increase professional challenge Evaluate and weed Evaluate and weed Capturing knowledge in systems Capturing knowledge in systems Overcome professionals’ reluctance to share information Overcome professionals’ reluctance to share information Organize around intellect Organize around intellect Quinn, Anderson, and Finkelstein. HBR, April 1996

32. Immediate Educational Needs Introduction to statistical quality control Introduction to statistical quality control And not a “biostatistics” And not a “biostatistics” Understanding variability Understanding variability Molecular pharmaceutics and biopharmaceutics Molecular pharmaceutics and biopharmaceutics Engineering principles Engineering principles Risk assessment and communication Risk assessment and communication Systems approaches and thinking Systems approaches and thinking Intro to Deming and others Intro to Deming and others Team building and communication Team building and communication

33. “Coming together is a beginning….. Keeping together is progress…. Working together is a success……” --- Henry Ford