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

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

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

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

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% http://www.fda.gov/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/GlobalProductPathway/default.htm 5

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

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Challenges Explosion of production of FDA-regulated goods Distinction between domestic and imported products is obsolete Supply chain more complex, oversight much more difficult FDA-regulated products originate from more than 150 countries and pass through 300 ports of entry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

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

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

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.

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

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

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

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

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

FDA Foreign Inspections since 2008 135%

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.

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

FDA Foreign GMP Inspections

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

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

India inspections (FY 2008-2012)

Drug Inspections in India

FDA inspection process

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

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.

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

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)

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

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 30

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

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

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

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

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

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

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

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

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

FY 2009 cGMP deficiencies systems cited 40

FY 2011 cGMP deficiencies systems cited 41

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.

cGMP deficiency observations for international inspections

FY 2010 cGMP deficiencies cited in India 44

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.

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

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

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

International Warning Letters issued 2009 & 2010

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

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

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

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Questions? NDBoxFDAIndiaOffice@state.gov Bruce.Ross@fda.hhs.gov

Bruce Ross, M.A., M.P.H. Country Director, India Bruce.Ross@fda.hhs.gov