1. Manufacturing Subcommittee of the Advisory Committee for Pharmaceutical Science July 20-21, 2004 Ajaz S. Hussain, Ph.D. Deputy Director Office of Pharmaceutical Science CDER, FDA

2. PAT Initiative July 2001 CGMP for 21 st Century Initiative Medical Innovation Critical Path Initiative “Desired State”

3. Dimensions of the FDA’s Initiative on Pharmaceutical Quality for the 21 st Century FDA Unveils New Initiative To Enhance Pharmaceutical Good Manufacturing Practices http://www.fda.gov/bbs/topics/NEWS/2002/NEW00829.htmlhttp://www.fda.gov/bbs/topics/NEWS/2002/NEW00829.html (August 21, 2002 ) Strong Public Health Protection Integrated quality systems orientation Science-based policies and standards Risk-based orientation International cooperation Time

4. Directional Vectors ► Ensure regulatory review and inspection policies are based on state-of-the-art pharmaceutical science ► Encourage new technological advances ► Encourage risk-based approaches that focus both industry and Agency attention on critical areas ► Facilitate modern quality management techniques, including implementation of quality systems ► Enhance the consistency and coordination of FDA's drug quality regulatory programs, in part, by integrating enhanced quality systems approaches into the Agency's business processes and regulatory policies concerning review and inspection activities Second Progress Report and Implementation Plan. http://www.fda.gov/cder/gmp/2ndProgressRept_Plan.htmhttp://www.fda.gov/cder/gmp/2ndProgressRept_Plan.htm (September 3, 2003)

5. Covering the Space Defined by the Directional Vectors Risk Science Preapproval Inspection Compliance Program Dispute Resolution Process Comparability Protocol PAT Pharmaceutical Inspectorate Product Specialists on Inspection Process Aseptic Processing Guidance on CFR Part 11 Systems/Integration ICH P2, QbD, & Risk

6. The Scientific Opportunity ► Pharmaceutical (development and) manufacturing is evolving from an art form to one that is now science and engineering based. ► Effectively using this knowledge in regulatory decisions in establishing specifications and evaluating manufacturing processes can substantially improve the efficiency of both manufacturing and regulatory processes. http://www.fda.gov/cder/gmp/21stcenturysummary.htm

7. The Risk Mitigation and Communication Opportunity ► Intuitive/Subjective to Quantitative  HCCP  FMEA  Quality by Design ► “Reliability is a design engineering discipline which applies scientific knowledge to assure a product will perform its intended function for the required duration within a given environment. This includes designing in the ability to maintain, test, and support the product throughout its total life cycle. Reliability is best described as product performance over time.” http://www.ewh.ieee.org/soc/rs/Reliability_Engineering/index.html

8. The Quality Systems Opportunity A Historical Note on Quality: Milestones in Quality Journey or Lurching from Fad to Fad? ► Sampling Plans (‘50s) ► Zero-Defect Movement (‘60s) ► ISO-9000 (‘80s) ► QS-9000 ► Malcolm Baldrige Award ► European Quality Award ► Total Quality Management ► Six Sigma  The Ultimate Six Sigma - “The Big Q” cGMPs K. R. Bhote and A. K. Bhote. World Class Quality (2000) ISBN 0-8144-0427 Pharmaceutical Quality System for the 21 st Century

9. A Two Year Journey? What is the Destination? ► “Vision 2020 - I can see clearly now” ► The “Desired State” http://www.fda.gov/ohrms/dockets/ac/01/slides/3804s1_02_hussain.ppt

10. Desired State  Product quality and performance achieved and assured by design of effective and efficient manufacturing processes  Product specifications based on mechanistic understanding of how formulation and process factors impact product performance  Continuous "real time" assurance of quality http://www.fda.gov/cder/gmp/21stcenturysummary.htm

11. Desired State  Regulatory policies tailored to recognize the level of scientific knowledge supporting product applications, process validation, and process capability  Risk based regulatory scrutiny relate to the:  level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance, and  the capability of process control strategies to prevent or mitigate risk of producing a poor quality product http://www.fda.gov/cder/gmp/21stcenturysummary.htm

12. Meeting Objectives ► Seek input and advise on charting the most efficient path towards the “desired state”  Review assessment of Chemistry, Manufacturing, and Controls (CMC) sections of submissions  Risk based cGMP Inspections: Selection of Manufacturing sites for inspections

13. What do we wish to accomplish with ICH Q8 ► Ensure Q8 facilitates movement towards the “desired state” we have articulated ► This will  Help us better understand the proposed product and process design and its relation to the intended use ► improve process of establishing regulatory specifications  Improve our ability to identify and understand critical product and process factors ► improve our understanding and confidence in risk mitigation strategies  Allow us to utilize risk based approaches and recognize good science and facilitate continuous improvement  Improve communication and systems thinking ► More efficient review and inspection process  Be a “win win win” for public health, regulators and industry

14. ICH Q8: Integrating QbD and Risk Mitigation Dimensions Risks to Quality Risk of incorrect identity Poor product & process Changes in clinical trial product (Bridging studies) Inadequate Design Specifications (e.g., TDS adhesive attribute) Critical to quality and performance? Risk of unqualified impurities Risk of poor bioavailability Risk of incorrect expiry date Risk of inadequate controls Risks After Approval [Risk of SUPAC,..] [Risk of unrepresentative test samples] [Risk of Inadequate Facility and QS] Intended Use Route of administration Patient population ….. Product Design Design Specifications (Customer requirements) Manufacturing Process and its Control Regulatory Specs. Tests & Controls -Risk Mitigation ICH Q9 Illustrative Examples of points to consider Development Objectives

15. Continuous Improvement – Emerging ICH Q8 “Design Space” Concept ► Multi-dimensional space defined by critical vectors of product quality and performance  Examples of critical vectors ► Robust manufacturing process – consistent, reproducible delivery of product meeting its specifications  Manufacturing options ► Stability (shelf-life) and ► Bioavailability

16. Data based decisions: No Generalization Current CMC Submissions environmental raw material properties process conditions

17. Knowledge based decisions: Improved Ability to Generalize Pharmaceutical Development Knowledge environmental raw material properties process conditions Robust process Stable and Bioavailable product

18. Process Understanding Post approval change Risk CMC regulatory oversight Company’s Quality system cGMP regulatory oversight ICH Q8 ICH Q8&9

19. Process Understanding Risk (P/R) CMC regulatory oversight Company’s Quality system cGMP regulatory oversight Post approval change Continuous Improvement Process Understanding Risk CMC regulatory oversight Company’s Quality system cGMP regulatory oversight PAC to Continuous Improvement Process Understanding Risk CMC regulatory oversight Company’s Quality system cGMP regulatory oversight ICH Q8 + Q9 Proposed ICH Q 10

20. Moving towards the “Desired State” Day 1 ► Update on Current Efforts  ICH Q8, Q9 and proposed Q10  ASTM ► Awareness topic: Filling the gaps – Research planning  Bayesian approaches in CMC?  Critical Path Initiative ► Implementing the concepts developed in ONDC and OGD  Manufacturing Science  Quality by Design

21. Moving towards the “Desired State” Day 2 ► Risk based CGMP Inspections  Update on research study on pharmaceutical industry practices  Pilot model for prioritizing selection of manufacturing sites for inspections  CGMPs for the Production of Phase I INDs ► Efforts on facilitating continuous improvement through reduction in the need for “Prior Approval Supplements”  PAT Example  Comparability protocol concept