1. Pharmaceutical Manufacturing Subcommittee of the ACPS Ajaz S. Hussain, Ph.D. ACPS Meeting October 22, 2002

2. Ensuring Product Quality and Performance Assurance of quality Assurance of unchanged performance characteristics Product Specifications Tests, controls and cGMP Safety & Efficacy Additional Tests - PAC System USP

3. Background Information Pharmaceutical manufacturing –Critical component –Quality and efficiency –R&D and Manufacturing –Review and Inspection FDA’s PAT initiative FDA’s initiative “cGMP for the 21 st Century”

4. Manufacturing Subcommittee Provide input/advice to CDER/FDA –Science based CMC and cGMP policy development –Continued development of the PAT initiative –cGMP for the 21st Century: A Risk Based Approach

5. Manufacturing Subcommittee Modeled after the PAT Subcommittee –Core membership based on expertise in manufacturing and quality assurance Some members of the PAT subcommittee will be invited to participate (sunset PAT Subcommittee) –Focused working groups or fact finding groups (sunset after assignment is completed) Initial topics –Selected immediate steps outlined in the cGMP for the 21st Century concept paper

6. Pharmaceutical cGMP’s for the 21 st Century: A Risk Based Approach Over the last two decades …. –Increased number of pharmaceuticals and their greater role in health care –Decreased frequency of inspections –FDA’s accumulation of experience with, and lessons learned from, various approached to product quality –Advances in pharmaceutical sciences and manufacturing technology –Application of biotechnology –Advances in the science and management of “Quality” –Globalization of industry

7. Pharmaceutical cGMP’s for the 21 st Century A science and risk-based approach to product quality regulation incorporating an integrated quality systems approach –incorporate most up-to-date concepts of risk management and scientific advances –encourage innovation and continuous improvement –ensure that submission review and cGMP inspection are coordinated and synergistic –consistency and effective utilization of resources

8. Pharmaceutical cGMP’s for the 21 st Century Guiding Principles –Risk-based orientation –Science-based policies and standards –Integrated quality systems orientation –International cooperation –Strong Public Health Protection

9. Steps Outlined  Perform an external review of the existing cGMP program and product review practices, including evaluation of potential inconsistencies in implementation  Reassess and reevaluate our current scientific approach to both the product review process and the cGMP program to achieve a consistent, integrated systems approach to product quality regulation  Enhance the scientific approach of cGMPs to emphasize risk-based control point analysis and to facilitate the latest innovations in pharmaceutical engineering

10. Immediate Steps Holding scientific workshops with key stakeholders Enhancing expertise in pharmaceutical technologies (e.g., pharmaceutical engineering and industrial pharmacy) by additional training and hiring, and by leveraging external expertise Encouraging innovation within the existing framework of statutory provisions and regulations by allowing certain changes in the manufacturing process without prior review/approval (e.g., comparability protocols)

11. Immediate Steps Evaluating the optimal mechanisms to effectively and efficiently communicate deficiencies to industry, including content, consistency, disclosure, and education Shifting the agency lead on implementation of Part 11 to CDER, with continued involvement from the other Centers and ORA Including product specialists, as needed, as a part of inspection teams

12. Immediate Steps Having Centers provide a scientific and technical review of all drug cGMP Warning letters Developing a technical dispute resolution process that integrates technical experts from the Centers and addresses perceived inconsistencies between Centers Emphasizing a risk-based approach in the work planning process Improving the operations of Team Biologics

13. Drug GMP Task Groups Short Term Milestones (6 months or less)

14. Manufacturing Subcommittee Discussion topics (examples) –Definitions/Common understanding Risk-based approach (in the context of manufacturing) Integrated Systems approach Science-based approach Science of Quality/ Modern Quality thinking? …….

15. Some Definitions: Webster’s Art: the power of performing certain actions especially as acquired by experience, study, or observation Empirical: Relying on experience or observations alone often without due regard for system and theory Science: Accumulated and accepted knowledge that has been systematized and formulated with reference to the discovery of general truths or the operation of general laws

16. System: A regularly interacting or interdependent group of items forming a unified whole; an organized set of doctrines, ideas, or principles usually intended to explain the arrangement or working of the systematic whole; marked by thoroughness and regularity Risk: Possibility of loss or injury; the chance of loss or the perils… also the degree of probability of such loss Some Definitions: Webster’s

17. What is Quality? (Quality Progress: July 2001) Eight gurus: Crosby, Deming, Feigenbaum, Ishikawa, Juran, Pirsig, Shewhart, Taguchi –Level I: Producing products or delivering services whose measurable characteristics satisfy a fixed set of specifications that are usually numerically defined –Level II: Independent of any of their measurable characteristics, level two quality products are those that satisfy customer expectations for their use or consumption

18. Manufacturing Subcommittee Discussion topics (examples) –Approaches for enhancing the scientific basis of regulatory policies Example: Regulatory approaches regarding aseptic manufacturing - ensure sound scientific basis for cGMP inspection practices –Science based risk assessment and management Example: Development and implementation of concepts such as risk-based control point analysis and “quality by design” –Integrated systems approach to product quality regulation Establishment of specifications, validation, quality assurance, management of changes, continuous improvement, and innovation –Controversial topics such as general (industry wide and not just one company) unresolved scientific/technical disputes between industry and FDA

19. Questions for the ACPS Advice/In-put –Goals and objectives –Process Core members –2 ACPS members –8-10 expert participants representing stakeholders Working Groups/ Fact Finding Groups –Evaluation