The FDA Regulatory & Compliance Symposium

1. The FDA Regulatory & Compliance Symposium Managing Risks – From Pipeline to Patient August 24-26, 2005

2. cGMP Good for Business But Who is Enforcing Who? Presented By: Anthony C. Celeste Senior Vice President Kendle/AAC August 25, 2005

3. Why GMPs? • Historical Perspective • Early concepts • Development of GMP concept(s) • Legislative Mandate 1962 • Regulation development • June 1963 • 1968 “Intensified Drug Inspection Program” • January 1971 Federal Register (Final Regulations) • September 1978 umbrella cGMP Regulations

4. Industry View of GMPs • FDA Inconsistency • Investigator expertise • “Level the playing field”

5. GMP Benefits to Industry • Good business practices • Build in quality • Enhance reputation • Cut compliance costs • Overall savings • Avoidance of problems and bad publicity

6. FDA Enforcement Statistics • Summary of FDA Actions/Activities • 1999 - 2003

7. Source of Data: Recall Operations Staff, Division of Compliance Management and Operations, Office of Enforcement, HFC-210 Recalls = Products Recalled [Center Classification Determined by Product Type] Description Description

8. Source of Data: Program Evaluation Branch, DPEM, Office of Resource Management, HFC-42Note: Does not include Office of Criminal Investigations data. Description Description

9. Source of Data: Program Evaluation Branch, DPEM, Office of Resource Management, HFC-42 Note: Does not include Office of Criminal Investigations data. Description

10. Source of Data: Division of Compliance Management and Operations, Office of Enforcement, HFC-210 Description Source of Data: Recall Operations Staff, Division of Compliance Management and Operations, Office of Enforcement, HFC-210

11. Description Source of Data: Recall Operations Staff, Division of Compliance Management and Operations, Office of Enforcement, HFC-210

12. FDA Actions • Significance of numbers? • Risk Management • Changing role of GMPs • cGMPs for the 21st century

13. Risk • Probability of occurrence of harm and the severity of that harm • Includes concepts of “hazard” and “exposure” • What is the relevant “harm”? • Unsafe or ineffective drugs • Reduction in safety/effectiveness • Clinically significant • Reduction in drug quality

14. Risk Management • “Systematic application of management policies, procedures and practices to the tasks of analyzing, evaluating and controlling risk” • ISO 14971, Sections 2.13 and 2.18

15. Risk Management • Risk Assessment • Relationship between process knowledge and process risk

16. Risk Management • Risk Control • Option analysis • Corrective and preventive actions • Prioritize • Implementation • Residual risk evaluation • Overall risk evaluation

17. Risk Management • Post-Production Information • Post-production experience • Review of risk management experience

18. Risk Assessment • An assessment of the product to determine: • The probability of occurrence of harm from someone using your product • The consequences of that harm and how severe it may be

19. Risk Management • Major Themes • Focus cGMP requirements on public health risks • Ensure FDA’s essential work does not impede innovation by industry • Enhance the consistency and predictability of FDA’s approach • Relevance of risk management to compliance activities

20. Elements Impacting FDA Inspections • cGMP Inspections • Work planning (address risks) • Investigator qualifications • Communication of Findings • Evaluate Warning Letters and FDA-483s • Dispute Resolution • Rollback of 21 CFR Part 11 • Encourage Best Practices • Process Analytical Technology (PAT)

21. CDER Compliance Public Health Mission • CDER has stated that its primary mission is ensuring that safe and effective drugs are available to the American public. • CDER’s Office of Compliance advances CDER’s mission primarily by protecting Americans from unsafe or ineffective drugs.

22. Pharmaceutical GMPs for the 21st Century • February 20, 2003, FDA provided a progress report on various aspects of its GMP initiative, Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach. • Integrating a risk-based approach applies to all aspects of the initiative, including various aspects of the GMP inspection programs.

23. What They Look At: Focus of FDA’s Inspection • Revise compliance programs to implement risk-based targeting • Focus inspection on areas most likely to uncover GMP deviations with greatest public health significance • Statistically-based auditing for areas not known to be high risk

24. What They Look At: Focus of FDA’s Inspection • Use risk assessment tools in evaluating significance of GMP deviations for further regulatory action • Account for potential failures in a process – “Quality by Design”

25. CAPA • “Corrective and Preventive Actions” • One very effective way of managing risk

26. Industry’s Role • Participation with FDA • Innovation and technical advances • Quality management

27. Participation with FDA • Provide review, comment on guidelines and proposals • Critical Path Initiative • PAT • Participate in committee deliberations (PDA, ISPE, Pharma, etc.) • Training FDA Investigators/Reviewers

28. Innovation and Technical Advances • Share research and development initiatives in manufacturing • Work with FDA on technical improvements • Process Analytical Technology

29. Quality Management • Who is management? • Results of poor management • Proactive system(s)

30. Who is Management • Level in organization that is responsible for: • Hiring and firing, especially in quality area • Organize and respond to audit and inspection findings • Control availability of resources dollars and personnel.

31. Management Responsibilities • Assure employee training and understanding • Implement and document corrective actions • Assure proper communications and decision making

32. Results of Poor Management • Lack of adequately qualified and well trained employees • Poor quality systems in place • Non-conforming manufactured products (GMPs)

33. Penalties for Non-Compliance • FDA action • Company’s reputation • Effect on business

34. Lessons Learned • Those who cannot remember the past are doomed to repeat it. • But the real challenge is quantifying the past for commitment to memory. • If some is GOOD – more is BETTER.