1. FDA’s Perspective on the “Pharmaceutical cGMPs for the 21st Century” Initiative David J. Horowitz, Esq. Director, CDER/FDA, Office of Compliance Advisory Committee for Pharmaceutical Science, Manufacturing Subcommittee May 21, 2003

2. 2 Overview Why did FDA undertake this initiative? –Challenges –Opportunities What is the scope of the initiative? What are the goals of the initiative? –External goals –Internal goals –Other guiding principles

3. 3 Why Did FDA Undertake this Initiative? The last major changes to FDA’s system for regulating drug quality occurred 25 years ago, when FDA substantially changed its cGMP regulations. Other incremental shifts since that time include the approach to manufacturing changes and application submission review under FDAMA and SUPAC.

4. 4 Why Did FDA Undertake this Initiative? (cont’d) Significant changes in the environment of pharmaceutical regulation have occurred over the last 25 years--including challenges and opportunities. Challenges: –Larger role for pharmaceuticals in health care and increased number of products Greater number, and wider range, of drugs being manufactured

5. 5 Number of Domestic Drug cGMP Inspections (excluding pre-approval inspections) 1980 - 2003

6. 6 Why Did FDA Undertake this Initiative? (cont’d) –Globalization of the pharmaceutical industry Increase in foreign manufacturing sites –Dramatic advances in pharmaceutical science, including the application of biotechnology to drug discovery and manufacturing More complex and diverse manufacturing Large number of manufacturing supplements submitted for Agency review

7. 7 Why Did FDA Undertake this Initiative? (cont’d) Opportunities: –Major advances in manufacturing science and technology Adoption of these advances less prevalent in pharmaceutical sector –Significant advances in the science of quality management, including quality systems approaches

8. 8 Why Did FDA Undertake this Initiative? (cont’d) Explicitly incorporated into FDA’s device regulations; implicit in HACCP Systems-based drug inspection program –Advances in application of risk analysis and risk management (including IT revolution) More systematically applied outside pharmaceutical sector Risk management approaches to regulatory compliance gaining wider acceptance: EPA, Customs, OSHA, & IRS

9. 9 What is the Scope of the Initiative? Involves all aspects of FDA’s regulation of product quality, not just GMPs –Submission review-CMC –Inspection –Standard setting Directly involves CDER, CBER, CVM, and ORA

10. 10 What is the Scope of the Initiative? (Cont’d) Applies to human and veterinary pharmaceuticals and human biological drugs. Two-year initiative: announced August 2002; Six month progress report issued February 2003.

11. 11 What are the Goals of the Initiative? External Goals: –Facilitate and encourage the adoption in pharmaceutical manufacturing of the latest advances and innovations in: Manufacturing science and technology Quality management, including quality systems approaches Risk management approaches –Facilitate innovation and availability of safe/effective drugs

12. Task Groups

13. 13 What are the Goals of the Initiative? (cont’d) Primary Internal Goals (for FDA): –Implementing internal quality systems approach to the regulation of drug quality Achieve greater coordination and synergy from better integration of the submission review and facility inspection components Enhance coordination between Field and Centers, and among Centers

14. 14 What are the Goals of the Initiative? (cont’d) Enhance consistency in applying science-based standards for both the submission review and facility inspection programs. –FDA workgroup on internal quality systems –Implementing systematic risk management approaches to all aspects of drug quality regulation, including standard-setting, review, and inspection (including work-planning)

15. 15 What are the Goals of the Initiative? (cont’d) Identify parameters and processes that are critical for drug quality, as well as those that are insignificant for drug quality. Ensure that FDA resources are used most effectively and efficiently to address the most significant public health risks. Adjust the level of regulatory scrutiny commensurate with risk –Work-planning: prioritizing sites for inspection; compliance program revision –Comparability protocols –Clarifying Part 11(electronic records) requirements

16. 16 What are the Goals of the Initiative? (cont’d) –Enhancing the scientific underpinnings of all aspects of the Agency’s regulation of drug quality More science and risk-based manufacturing guidance Learn from “process knowledge” gained in the design/development phase Greater opportunities for specialization, training, and cross-cutting teams

17. 17 What are the Goals of the Initiative? (cont’d) –Pharmaceutical inspectorate –Product specialists on inspections –PAT initiative Other internal guiding principles: –Improved internal and external communications Scientific workshops, advisory committees Dispute resolution process 483 clarification Center review of GMP warning letters

18. 18 What are the Goals of the Initiative? (cont’d) –Greater emphasis on international harmonization Presented to ICH Steering Committee in September Topic for July ICH meeting –Strong public health protection Initiative will not interfere with strong enforcement or existing standards, even as we are examining and revising our approaches