3FDA 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 productsStrengthen the safety and integrity of the global supply chainA paradigm shift is required to meet this challenge: focus on prevention of threatsInnovative analytical toolsInternational capacity building3
4Advancing Regulatory Science Modernize ToxicologyStimulate Innovation in Clinical Evaluations3. Support New Approaches to Improve Product Manufacturing and Quality4. Ensure FDA Readiness to Evaluate Innovative Emerging Technologies5. Harness Diverse Data through Information Sciences6. Implement a New Prevention-Focused Food Safety System to Protect Public Health7. Facilitate Development of Medical Countermeasures8. Strengthen Social and Behavioral Science - Make Informed Decisions about Regulated Products
5Pathway 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 consumed30% of drugs by value80% of API used in US50% of medical devicesExpected annual growth 5-15%5
6Four Pillars of the Strategy Create global coalitions of regulatorsBuild global data-information systems and networks and proactively share data with peersExpand intelligence-gathering, with an increased focus on risk analyticsEffectively allocate agency resources based on risk, and leveraging government, industry and public and private third parties
7Globalization Challenges Explosion of production of FDA-regulated goodsDistinction between domestic and imported products is obsoleteSupply chain more complex, oversight much more difficultFDA-regulated products originate from more than 150 countries and pass through 300 ports of entry130,000 importers300,000 foreign facilitiesIncrease in variety and complexity of imported medical productsGrowing demand, yet constrained supply
8Understanding FDA’s Approach and Expectations CommunicateLeverage ResourcesEstablish and use new “tools”Secure supply chainBecome a global agencyStop distinguishing between foreign and domestic procedures, policies, and expectations
10Objectives 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; andIncrease capacity to perform more timely FDA overseas inspections, especially of high risk products.
11FDA’s Enforcement Priorities Drug quality in OTCsAssure investigations (complaints, rejects) are prompt and root causes correctedData integrity and quality systemsSupply chain security Contract manufacturersRaw material/excipient vendor qualification programs11
13Major Inspection Types Pre-approval“For-cause” or directedPost-marketing adverse drug eventCGMP surveillance (routine)13
14Foreign establishments routinely inspected Manufacturers of drugs, includingAPI and dosage formhuman and animalbiotech, vaccine, etc. (biologicals)Re-packagers/re-labelersIndependent sterilizersIndependent laboratories14
15FDA’s Inspectorate1,700 investigators in our field offices conducting domestic inspectionsAbout 400 investigators and 150 analysts qualified to conduct foreign inspections (all commodities)Dedicated Foreign CadresDrugsFoodsMedical devices15
17FDA’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.
18FDA Foreign Inspections types & numbers Factors which result in inspectionsPre-Approval Submissions (PEPFAR)Routine surveillanceFollow - upFood assessmentsMOUs/international agreementsImport issuesEmergenciesFoods - 84%Drugs - 63 %18
25Inspections… Are fact finding Require evidence Require organization and time managementAre regulatory25
26Purpose of GMP AuditsTo 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.
27System 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 SystemFacilities and Equipment SystemMaterials SystemProduction SystemLaboratory SystemPackaging and Labeling System
28Product 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 identificationSeverity rankingProbability ranking (with cause identification)Assessment of risk level for each identified hazard (risk matrix)
29Inspection objectives Conduct inspection in accordance with FDA law and regulations Current Good Manufacturing PracticeAccomplish what is necessary per established inspection procedures (“Compliance Programs”)Follow-up on additional questions/ concerns in inspection assignment29
30CGMP Inspection Programs (Compliance Program Guidance Manuals) Pre-approval:/ , Pre-Approval Inspections/InvestigationsPost-Approval/Surveillance:, Drug Process InspectionsSterile Drug Process InspectionsDrug Repackers and relabelersRadioactive DrugsCompressed Medical GasesActive Pharmaceutical Ingredients Process InspectionsInspections of Licensed Biological Therapeutic Drug ProductsRefer to:30
33Conduct of an inspection QualityAnnual Product ReviewsList of non-conformance reportsOut-of-specification resultsComplaintsRejected/Aborted/Destroyed batchesField Alerts (defect reports)Corrective actions since previous inspection33
34Conduct of an inspection Materials Management (ingredients & packaging)Separation and control of materialsIdentification of materialsLabeling practicesSampling of incoming materialsInventory control systems34
35Conduct of an inspection ProductionPersonnel practicesContemporaneous completion of documentsWritten proceduresCalibration stickers for critical equipmentCondition of equipment35
36Conduct of an inspection Facilities & EquipmentEquipment designHeating/Ventilation/Cooling systemsWater systems36
37Conduct of an inspection Packaging and LabelingAppropriate controlsLine clearance proceduresVisual inspection procedures (sterile products)Label issuance and reconciliation documents
38Conduct of an inspection Laboratory controlRaw data practicesSample flowSample/standard identificationStatus of the instrumentsStabilityMethods in use
39Conclusion of an inspection Formal close outMay include:Sample collectionsIssuance of FDA 483, Inspectional Observations39
42Top 10 deficiencies cited 2011 international inspections Inadequate Quality SystemsLack of investigations of batches that fail to meet specificationsLack of written procedures or inadequate SOPsInadequate laboratory controlsUn-validated test methodsInadequate stability programInadequate process validation or no process validationLack of process controls that validate the performance of manufacturing processInadequate validation of equipment cleaning and maintenance cleaningInadequate controls of components, intermediates, and raw materialsHere are the top 10 citations listed on the 483s issued when our inspectors visited drug manufacturing facilities around the world last fiscal year.
43cGMP deficiency observations for international inspections
45Top 10 deficiencies cited in 2011 in India Inadequate Quality SystemsLack of investigations of batches that fail to meet specificationsDeficient records and reportsInadequate process validation or no process validationLack of process controls that validate the performance of manufacturing processInadequate laboratory controlsInadequate stability programLack of written procedures or inadequate SOPsInadequate controls of components, intermediates, and raw materialsInadequate validation of equipment cleaning and maintenance cleaningThis 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.
46Comparing 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 regionsDocumentation IssuesDeficient records and reportsLack of or inadequate proceduresQA SystemsInadequate Lab ControlsAnd the differences:China: Control of Components,Intermediates and Raw MaterialsIndia: Buildings and Facilities, EquipmentCleaning and MaintenanceEurope: Production and Process Controls
47After the inspection Write the Establishment Inspection Report (EIR) Must be done in a timely mannerSubmit recommendationEIR reviewed by GMP product expertsFinal classification of inspection (acceptable, unacceptable: Warning Letter, Untitled Letter, Import Alert etc.)47
48Warning 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 investigations46% 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 inspectionSource CDER ICB48
50Global marketplaceEnsuring safe, effective and quality foods and drugs for the citizens of India, the United States and the world
51Key Initiatives Set post-inspection deadlines Take responsible steps to speed the warning letter processWork 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, 200951
52Key InitiativesSwift, appropriate enforcement action with prioritizing on follow-up.Be prepared to take immediate action in response to public health risksDevelop and implement a formal warning letter “close-out” process4. 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 quicklyand 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