FDA Foreign Priorities, Inspections and Compliance

1. FDA Foreign Priorities, Inspections and Compliance Bruce Ross, M.A. M.P.H. Director, India Office

2. Agenda • Priorities • Challenges of globalization • cGMPdeficiencies • Comparison • Post inspection regulatory actions

3. Advance Regulatory Science: the science of developing new tools, standards and approaches to assess the safety and effectiveness, quality and performance of FDA-regulated products Strengthen the safety and integrity of the global supply chain A paradigm shift is required to meet this challenge: focus on prevention of threats Innovative analytical tools International capacity building FDA Strategic Priorities 2011-2015

4. Advancing Regulatory Science Modernize Toxicology Stimulate Innovation in Clinical Evaluations 3. Support New Approaches to Improve Product Manufacturing and Quality 4. Ensure FDA Readiness to Evaluate Innovative Emerging Technologies 5. Harness Diverse Data through Information Sciences 6. Implement a New Prevention-Focused Food Safety System to Protect Public Health 7. Facilitate Development of Medical Countermeasures 8. Strengthen Social and Behavioral Science - Make Informed Decisions about Regulated Products

5. Global economic forces are having a dramatic effect on food and drug supply chains. Cross border flows of goods, information and capital are increasing much faster than global GDP. U.S. Imports in 2009: 10-15% of food consumed 30% of drugs by value 80% of API used in US 50% of medical devices Expected annual growth 5-15% Pathway to Global Product Safety and Quality http://www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/GlobalProductPathway/default.htm

6. Four Pillars of the Strategy Create global coalitions of regulators Build global data-information systems and networks and proactively share data with peers Expand intelligence-gathering, with an increased focus on risk analytics Effectively allocate agency resources based on risk, and leveraging government, industry and public and private third parties

7. Globalization Challenges • Explosion of production of FDA-regulated goods • Distinction between domestic and imported products is obsolete • Supply chain more complex, oversight much more difficult • FDA-regulated products originate from more than 150 countries and pass through 300 ports of entry • 130,000 importers • 300,000 foreign facilities • Increase in variety and complexity of imported medical products • Growing demand, yet constrained supply

8. Understanding FDA’s Approach and Expectations • Communicate • Leverage Resources • Establish and use new “tools” • Secure supply chain • Become a global agency • Stop distinguishing between foreign and domestic procedures, policies, and expectations

9. FDA Foreign Offices London Brussels Beijing Headquarters Silver Spring, MD New Delhi Shanghai Amman Mexico City Guangzhou Mumbai San Jose Pretoria Santiago

10. Objectives of FDA’s Foreign Offices • Gain improved knowledge about product manufacturing and transport to the United States; • Leverage knowledge and resources and strengthen capacity to better assure product safety; • Work with regulated industry so they will better understand FDA regulations, standards and guidance; • Coordinate with USG colleagues in-country (e.g., USDA/FAS, DOC/CBP, USAID, USTR,) on approaches to enhance product safety; and • Increase capacity to perform more timely FDA overseas inspections, especially of high risk products.

11. FDA’s Enforcement Priorities • Drug quality in OTCs • Assure investigations (complaints, rejects) are prompt and root causes corrected • Data integrity and quality systems • Supply chain security  • Contract manufacturers • Raw material/excipient vendor qualification programs

12. FDA’s Enforcement Priorities • Combating economically motivated adulterated products/ingredients • Field alert reporting (defect reports) • Contaminated, sub- or super-potent, high-risk compounded drugs • Post-market adverse event reporting

13. Major Inspection Types • Pre-approval • “For-cause” or directed • Post-marketing adverse drug event • CGMP surveillance (routine)

14. Foreign establishments routinely inspected • Manufacturers of drugs, including • API and dosage form • human and animal • biotech, vaccine, etc. (biologicals) • Re-packagers/re-labelers • Independent sterilizers • Independent laboratories

15. FDA’s Inspectorate • 1,700 investigators in our field offices conducting domestic inspections • About 400 investigators and 150 analysts qualified to conduct foreign inspections (all commodities) • Dedicated Foreign Cadres • Drugs • Foods • Medical devices

16. FDA Foreign Inspections since 2008 135%

17. FDA’s Foreign Inspection Accomplishments

18. FDA ForeignInspectionstypes & numbers Factors which result in inspections Pre-Approval Submissions (PEPFAR) Routine surveillance Follow - up Food assessments MOUs/international agreements Import issues Emergencies Foods - 84% Drugs - 63 %

19. FDA Foreign GMP Inspections

20. FDA’sForeignInspections by country, FY 2010 Canada, 94 Italy, 66 Germany, 132 Switzerland, 42 Spain, 40 France, 59 Japan, 71 Others, 66 China, 133 India, 138

21. FY 11 International inspection obligation per program area Drugs – 1249 Devices - 472 Foods - 994 CVM - 88 Biologics - 42 TOTAL – 2825*

22. India inspections (FY 2008-2012)

23. Drug Inspections in India

24. FDA inspection process

25. Inspections… • Are fact finding • Require evidence • Require organization and time management • Are regulatory

26. Purpose of GMP Audits • To ensure that adequate quality systems are maintained. • To assess compliance with the cGMP’s and firm’s standard operating procedures. • To identify problems that can impact product quality. • To assure there is a procedure for investigating non-compliance with the quality system and for prescribing and verifying corrective action. The procedures should include a description of how records of corrective actions are maintained.

27. System Based Inspections • GMP Inspections will follow a system based inspectional approach. The Quality System will always be covered while coverage of the other 5 systems will be rotated. • Quality System • Facilities and Equipment System • Materials System • Production System • Laboratory System • Packaging and Labeling System

28. Product Risk Analysis • Common Elements • Difficulty associated with manufacturing process, products with most critical manufacturing steps (sterile/non-sterile, wet granulation/dry blends, suspensions/solutions Hazard identification • Severity ranking • Probability ranking (with cause identification) • Assessment of risk level for each identified hazard (risk matrix)

29. Inspection objectives • Conduct inspection in accordance with FDA law and regulations Current Good Manufacturing Practice • Accomplish what is necessary per established inspection procedures(“Compliance Programs”) • Follow-up on additional questions/ concerns in inspection assignment

30. CGMP Inspection Programs(Compliance Program Guidance Manuals) Pre-approval: • 7346.832/7352.832, Pre-Approval Inspections/Investigations Post-Approval/Surveillance: • 7356.002, Drug Process Inspections • Sterile Drug Process Inspections • Drug Repackers and relabelers • Radioactive Drugs • Compressed Medical Gases • Active Pharmaceutical Ingredients Process Inspections • Inspections of Licensed Biological Therapeutic Drug Products Refer to: http://www.fda.gov/ICECI/ComplianceManuals/ComplianceProgramManual/default.htm

31. Inspection Participation • Investigators (inspectors) • Analysts (lab experts) • GMP Assessors/Evaluators • Product Reviewers/Assessors • Other Specialists

32. Systems-Based Approach • Quality Systems • Materials Management • Production • Facilities & Equipment • Packaging & Labeling • Laboratory Control

33. Conduct of an inspection • Quality • Annual Product Reviews • List of non-conformance reports • Out-of-specification results • Complaints • Rejected/Aborted/Destroyed batches • Field Alerts (defect reports) • Corrective actions since previous inspection

34. Conduct of an inspection • Materials Management (ingredients & packaging) • Separation and control of materials • Identification of materials • Labeling practices • Sampling of incoming materials • Inventory control systems

35. Conduct of an inspection • Production • Personnel practices • Contemporaneous completion of documents • Written procedures • Calibration stickers for critical equipment • Condition of equipment

36. Conduct of an inspection • Facilities & Equipment • Equipment design • Heating/Ventilation/Cooling systems • Water systems

37. Conduct of an inspection • Packaging and Labeling • Appropriate controls • Line clearance procedures • Visual inspection procedures (sterile products) • Label issuance and reconciliation documents

38. Conduct of an inspection • Laboratory control • Raw data practices • Sample flow • Sample/standard identification • Status of the instruments • Stability • Methods in use

39. Conclusion of an inspection • Formal close out • May include: • Sample collections • Issuance of FDA 483, InspectionalObservations

40. FY 2009 cGMP deficiencies systems cited

41. FY 2011 cGMP deficiencies systems cited

42. Top 10 deficiencies cited 2011 international inspections • Inadequate Quality Systems • Lack of investigations of batches that fail to meet specifications • Lack of written procedures or inadequate SOPs • Inadequate laboratory controls • Un-validated test methods • Inadequate stability program • Inadequate process validation or no process validation • Lack of process controls that validate the performance of manufacturing process • Inadequate validation of equipment cleaning and maintenance cleaning • Inadequate controls of components, intermediates, and raw materials

43. cGMP deficiency observationsfor international inspections

44. FY 2010 cGMP deficiencies cited in India

45. Top 10 deficiencies cited in 2011 in India • Inadequate Quality Systems • Lack of investigations of batches that fail to meet specifications • Deficient records and reports • Inadequate process validation or no process validation • Lack of process controls that validate the performance of manufacturing process • Inadequate laboratory controls • Inadequate stability program • Lack of written procedures or inadequate SOPs • Inadequate controls of components, intermediates, and raw materials • Inadequate validation of equipment cleaning and maintenance cleaning

46. Comparing cGMP deficiencies (Europe, China & India)

47. After the inspection • Write the Establishment Inspection Report (EIR) • Must be done in a timely manner • Submit recommendation • EIR reviewed by GMP product experts • Final classification of inspection (acceptable, unacceptable: Warning Letter, Untitled Letter, Import Alert etc.)

48. Warning and Untitled Letters drug sites - 2005 to 2010 Source CDER ICB

49. International Warning Letters issued 2009 & 2010

50. Global marketplace Ensuring safe, effective and quality foods and drugs for the citizens of India, the United States and the world