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

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Presentation on theme: "FDA Foreign Priorities, Inspections and Compliance Bruce Ross, M.A. M.P.H. Director, India Office."— Presentation transcript:

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

2 Agenda Priorities Challenges of globalization cGMP deficiencies Comparison Post inspection regulatory actions 2

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

4 1.Modernize Toxicology 2.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 Advancing Regulatory Science 4

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 ulatoryOperationsandPolicy/GlobalProductPathway/default.htm 5

6 Four Pillars of the Strategy 1.Create global coalitions of regulators 2.Build global data-information systems and networks and proactively share data with peers 3.Expand intelligence-gathering, with an increased focus on risk analytics 4.Effectively allocate agency resources based on risk, and leveraging government, industry and public and private third parties 6

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Challenges  Explosion of production of FDA-regulated goods  Distinction between domestic and imported products is obsolete  Supply chain more complex, oversight much more difficult  FDA-regulated products originate from more than 150 countries and pass through 300 ports of entry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 7

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 8

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

10 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 11

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 12

13 Major Inspection Types 1.Pre-approval 2.“For-cause” or directed 3.Post-marketing adverse drug event 4.CGMP surveillance (routine) 13

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 14

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 15

16 16 FDA Foreign Inspections since %

17 FDA’s Foreign Inspection Accomplishments 17

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

19 19 FDA Foreign GMP Inspections

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

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

22 India inspections (FY ) 22

23 Drug Inspections in India 23

24 FDA inspection process 24

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

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 29

30 CGMP Inspection Programs (Compliance Program Guidance Manuals) Pre-approval:  / , Pre-Approval Inspections/Investigations Post-Approval/Surveillance:  , 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: 30

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

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

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 33

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 34

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

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

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

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

39 Conclusion of an inspection  Formal close out  May include: Sample collections Issuance of FDA 483, Inspectional Observations 39

40 FY 2009 cGMP deficiencies systems cited 40

41 FY 2011 cGMP deficiencies systems cited 41

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 42

43 cGMP deficiency observations for international inspections 43

44 FY 2010 cGMP deficiencies cited in India 44

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 45

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

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.) 47

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

49 International Warning Letters issued 2009 &

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

51 Key Initiatives 1.Set post-inspection deadlines 2.Take responsible steps to speed the warning letter process 3.Work more closely with FDA’s regulatory partners. 51

52 Key Initiatives 4.Swift, appropriate enforcement action with prioritizing on follow-up. 5.Be prepared to take immediate action in response to public health risks 6.Develop and implement a formal warning letter “close-out” process 52


54 Questions? 54

55 Bruce Ross, M.A., M.P.H. Country Director, India

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