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

3. FDA Strategic Priorities 2011-2015
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 3

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. Pathway to Global Product Safety and Quality
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% 5

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Distinction between domestic and imported products is obsolete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 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
Pre-approval
“For-cause” or directed
Post-marketing adverse drug event
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. FDA Foreign Inspections since 2008
135%

17. FDA’s Foreign Inspection Accomplishments
This slide, showing data from the international part of ORA shows the recent trend of foreign inspections by regulated product. Since 2008, foreign inspections have increased almost 130 percent and in both 2009 and 2010 FDA accomplished more than any previous year. It appears that again, we will exceed the 1422 number this year too – and that’s because we’re getting more pressure from our Congress to conduct foreign inspections, we have more qualified inspectors traveling now too.

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
Foods - 84%
Drugs - 63 % 18

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 - 472
Foods - 994
CVM - 88
Biologics - 42
TOTAL – 2825* 21

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 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

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, Inspectional Observations 39

40. FY 2009 cGMP deficiencies systems cited40

41. FY 2011 cGMP deficiencies systems cited41

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
Here are the top 10 citations listed on the 483s issued when our inspectors visited drug manufacturing facilities around the world last fiscal year.

43. cGMP deficiency observations for international inspections

44. FY 2010 cGMP deficiencies cited in India44

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
This slide lists the top 10 cGMP deficiencies found by FDA inspectors in Indian drug manufacturing facilities.
In our analysis – we note that there is a difference between India’s schedule M – their GMPs – and those in the United States which may explain why the high number of the top five findings. Firms may have begun with a domestic market focus first and as they shifted to manufacturing for the U.S. market, may not have paid as close attention to the need to validate processes, to demonstrate the control of their manufacturing process and to document all the changes made in a process as they seek to assure specifications are met.

46. Comparing cGMP deficiencies (Europe, China & India)
This slide compares the percentage of cGMP deficiencies found by system in China, Europe and India.
When we look at the common top deficiencies across these regions
Documentation Issues
Deficient records and reports
Lack of or inadequate procedures
QA Systems
Inadequate Lab Controls
And the differences:
China: Control of Components,
Intermediates and Raw Materials
India: Buildings and Facilities, Equipment
Cleaning and Maintenance
Europe: Production and Process Controls

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 - 2005 to 2010
The increase in regulatory actions can be related to many factors: increase in the # of inspections conducted by FDA, better and more focused inspections, DDC, more and more intelligence, industry moving to countries with less develop GMP cultures.
54% of the WLs issued during FY 09 (7 of 13) contain citations related to OOS investigations
46% of the WLs (6 of 13), issued during FY’2009, contain at least 1 violation related to data integrity or the failure to maintain records detected during an inspection
Source CDER ICB 48

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

51. Key Initiatives Set post-inspection deadlines
Take responsible steps to speed the warning letter process
Work more closely with FDA’s regulatory partners.
1. Business-day timeframe of 15 days for firms to provide a response to significant FDA 483 observations, before the agency issues a WL or take another enforcement action. Effective August 11, 2009.
2. The FDA will streamline the warning letter process by limiting review of WL and UL by the Office of Chief Counsel to those that present significant legal issues. Effective August 6, 2009 51

52. Key Initiatives
Swift, appropriate enforcement action with prioritizing on follow-up.
Be prepared to take immediate action in response to public health risks
Develop and implement a formal warning letter “close-out” process
4. The FDA will work quickly to assess and follow up on corrective actions taken by industry after a warning letter is issued or major product recall occurs.
Because not all WLs result on an IA, FDA needs to reinspect sites to which a WL has been issued in a timely manner to determine if the appropriate corrective actions have been implemented.
5. To better protect the public health, the agency is prepared to act more quickly
and aggressively to deal with significant public health concerns and violations.
Such actions may occur before a formal warning letter is issued.
6. If the agency can determine that a firm has fully corrected violations raised in a warning letter the agency will issue an official “close-out” notice and post this information on the FDA Web site. This will be an important motivator for corrective action by manufacturers. 52

53. 53

54. Questions?

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