Requirements for the Quality of API from FDA Perspective

1. Requirements for the Quality of API from FDA Perspective Brenda Uratani, Ph.D. FDA Assistant Country Director, China API Conference- March 2010- Beijing

2. Today’s agenda • Introducing the FDA China Office • FDA’s requirements for API manufacturing • Selected Topics and Issues of Most Concern • FDA Initiatives on API manufacturing and drug safety API Conference- March 2010- Beijing

3. Challenges Significant demand in resources for inspections Consequences of globalization, including more foreign manufacturing and clinical trials sites Greater complexity associated with manufacturing FDA concern about the state of industry compliance and insufficient investment in manufacturing and quality systems API Conference- March 2010- Beijing

4. FDA International Efforts API Conference- March 2010- Beijing

5. Beyond Our Borders Initiative • FDA in-country offices • Awareness • Capacity building • Standards/inspections • Collaboration • Leveraging opportunities • Locations: • China, India, EU, Latin America, Middle East • Leveraging projects • Pilots/Info sharing • EMEA pilot API Conference- March 2010- Beijing

6. FDA China OfficeIn-Country Staff Beijing • Chris Hickey, Office Director • Mike Kravchuk, Deputy (device) • Brenda Uratani (drug) • Irene Chan (food) Shanghai • Charles Ahn (drug inspection) • BJ Marciante (device inspection) Guangzhou • Dennis Doupnik (food inspection) • Dennis Hudson (food inspection) API Conference- March 2010- Beijing

7. Agreements Between HHS and SFDA: Key Provisions API Conference- March 2010- Beijing Signed December 2007 • Key Provisions: • All Chinese Producers of Designated Drugs and Devices Required to Register with SFDA • Goal: Certify Products Exported to the United States Meet FDA Standards • Joint Training/Capacity Building • Greater/More Rapid Information Sharing • Greater Access to Facilities • Product Integrity: Tracking System of Products Likely to Be Counterfeited • Strengthened FDA, SFDA Collaboration Under WHO Auspices • Implementation Focus on Specific Set of Drugs, Devices

8. FDA China Office What Are We Doing? API Conference- March 2010- Beijing • Continuing to Strengthen Working Relations with SFDA • Engage in Strategic Capacity Building of, Confidence Building with SFDA, Provincial and Municipal Authorities • Work with Regulated Industry re: Exports to U.S., FDA Standards and Processes  • Monitor and Report on Conditions and Events that Might Affect the Safety and Quality of FDA-Regulated Products • Regulatory Reform/Legal Assistance • Increasing inspections at facilities that manufacture FDA-regulated goods; and

9. CGMPRequirements & Principlesfor API Manufacturing API Conference- March 2010- Beijing

10. CGMP • C” = currentdynamic and evolve over time • “GMP” = Good Manufacturing Practices • Minimal standards • Not “best” practices unless “best” is, in fact, current minimal. API Conference- March 2010- Beijing

11. FDA Requirements for APIHistorical Perspectives • 21 CFR 211: Current good manufacturing practice for finished pharmaceuticals • FD &C Act Sec 501 (a)(2)(B): drug • ICH Q7A: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (November 2000) • FDA has been inspecting API for decades API Conference- March 2010- Beijing

12. Quality Management Personnel Buildings and Facilities Process Equipment Documentation and Records Material Management Production & In-Process Controls Packaging & Identification Labeling of APIs & Intermediates Storage & Distribution Laboratory Controls Validation Change Control Rejection & Re-Use of Materials Complaints and Recalls Contract manufacturers (including Laboratories) Agents, Brokers, Traders, Distributors, Repackers, and Relabellers API Manufactured by Cell Culture-Fermentation API for Use in Clinical Trials ICH Q7A API Conference- March 2010- Beijing

13. Potential Problems from Non-Compliance with CGMP Super-potency or Subpotency Impurities Contamination Safety and Efficacy effects API Conference- March 2010- Beijing

14. Some Issues of most concern • Day-to-day implementation of CGMP • Quality system management • Understanding the product and the process • Can’t “test” quality into the product • Material management • Equipment qualification and use API Conference- March 2010- Beijing

15. Day-to-day Implementation of CGMP Eliminate variability Achieving Process Consistency is of utmost importance to ensure quality of each batch API Conference- March 2010- Beijing

16. Quality management API Conference- March 2010- Beijing

17. Fundamental Quality Management Principles • Strong commitment to drug quality and patient safety • Strong “believer” in the value of CGMP • Understand the importance and impact of quality management, control, and implementation API Conference- March 2010- Beijing

18. Quality System ICH Q10 Concepts 3.1.3 Commercial Manufacturing “The pharmaceutical quality system should assure that the desired product quality is routinely met, suitable process performance is achieved, the set of controls are appropriate, improvement opportunities are identified and evaluated, and the body of knowledge is continually expanded” API Conference- March 2010- Beijing

19. PharmaceuticalQuality System • The Quality System is the foundation for the drug manufacturing systems • Quality system model integrates manufacturing systems API Conference- March 2010- Beijing

20. Quality System • Deviations & investigations • Change control • Training • Audit/ review • Annual product review • Contract agreement • Document control API Conference- March 2010- Beijing

21. Quality SystemCritical Commitment from Top Management • Understand & recognize the value of quality system • Strong commitment on producing safe and effective product- decision to release or reject of batch justified by data and science (responsibility of QA) • Clear communication and promotionfrom top management on importance of quality to all employees and units of operation • Implementation and enforcement on quality system API Conference- March 2010- Beijing

22. Pharmaceutical Quality SystemLifecycle Approach • Process performance and product quality monitoring system; • Corrective action and preventive action (CAPA) system; • Change management system; • Management review of process performance and product quality. API Conference- March 2010- Beijing

23. Lifecycle Approach Validation, maintenance, and continuous improvement of product quality • 5% pre-approval • 95% Post-approval API Conference- March 2010- Beijing

24. Product Life Cycle Comparability Protocol Evaluation Risk Assessment/ Mitigation Propose CGMP Adherence Formal Experimental Design (DOE) Monitor (CAPA Continuous Improvement Innovation) Identify (Critical/ Key Attributes/ Parameters) Post-Approval Risk Assessment/ Mitigation Confirm (Control/ Predict) PAT PAT Conformance/ Validation Studies API Conference- March 2010- Beijing

25. Investigation & DeviationsAdd Value & Impact Quality • Learn from mistakes • Prevent recurrences: corrective action & preventive action (CAPA) • Build knowledge: variability reduction, continuous improvement in product quality API Conference- March 2010- Beijing

26. What is Change Control? Changes are managed by the firm: • Evaluates everyday changes to the manufacturing facility, equipment, personnel, improvements, and minor adjustments to the process. • All changes must always be done with a written protocol under the change control system including approval by QA • Have procedures in place for the execution of the change in an orderly manner • Evaluate the impact of the change • Document the change and results Adequacy of changes are evaluated by FDA during inspection API Conference- March 2010- Beijing

27. Change Control • Process • Process improvement /adjustment • Personnel practice • Operational procedures • Equipment/ Facility/ Utilities • Document, examples • Revision/ updating of: • SOP • Analytical worksheet • Batch record API Conference- March 2010- Beijing

28. Training • Qualified employee to perform the assigned task • Strict implementation of the established procedures • Supervision • Periodic re-evaluation • Continuing education in training API Conference- March 2010- Beijing

29. Audit/ Review Annual Product Review • Regular trending reviews and evaluation of process and product • Evaluation of stability, recalls, OOS, product complaints, returns • Risk assessment, mitigation before occurrence of serious consequences • Ensure operation is maintained in an ongoing state of control • Knowledge gained for continuous improvement in product life cycle API Conference- March 2010- Beijing

30. Contract Agreement • Clear contractual agreements on: • Responsibilities of each party • Effective communication on all issues that potentially impact drug quality • Adequate qualification, auditing and regular periodic evaluations of contractors • Notification to FDA for changes in contractors API Conference- March 2010- Beijing

31. Document Controls A most critical element to support acceptability of a production batch and GMP compliance Not just a bureaucratic exercise to satisfy FDA REQUIRE ORIGINAL RECORDS as the task (operation) is being performed, not a re-copying of the original. Data must not be altered • Production: batch records • QC: testing records Violations: Serious Consequences API Conference- March 2010- Beijing

32. Documentation • All SOP (especially production batch record) should be in sufficient detail for the operator to carry out the task in a consistent manner • Changes in SOP must be reviewed and approved by QA API Conference- March 2010- Beijing

33. Material Management API Conference- March 2010- Beijing

34. ICH Q7A: Materials Management Manufacturers of intermediates and/or API should have a system for evaluating the suppliers of critical material Materials should be purchased against an agreed specification, from a suppliers, approved by the quality unit(s) If the supplier of a critical material is not the manufacturer of that material, the name and address of that manufacturer should be known by the intermediate and/or API manufacturer. Changing the source of supply of critical raw materials should be treated according to Section 13, Change Control. API Conference- March 2010- Beijing

35. Material Controls • Raw materials • Intermediates • Components • API • Manufacturing materials • e.g., sterilizing filters • Facility materials • e.g., HEPA filters API Conference- March 2010- Beijing

36. Equipment Management API Conference- March 2010- Beijing

37. Qualification of Equipment Issues especially pertain to: • Adequate IQ, OQ, PQ • Old equipment?? • Instruction and training of operation for use of equipment • Establish regular maintenance, calibration and maintain documentation of these activities API Conference- March 2010- Beijing

38. Supply Chain Management API Conference- March 2010- Beijing

39. Supply Chain Management • Identify critical control points (areas) and implement adequate controls to ensure integrity of the supply of raw materials, component, excipients, API, drug product through procurement, manufacturing and distribution. • Tamper resistant • Serialization • testing API Conference- March 2010- Beijing

40. Regulatory Actions for non-GMP compliant firms • Warning Letters • Withholding Approval • Import Detentions and Alerts • Seizures • Injunctions • Prosecutions IMPACT: Product NOT suitable for use. API Conference- March 2010- Beijing

41. Thank You Brenda Uratani Brenda.uratani@fda.hhs.gov API Conference- March 2010- Beijing