FDA Drug Compliance. Pepe Rodriguez-Perez, PhD Business Excellence Consulting Inc / BEC Spain SL.

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1 FDA Drug Compliance Presented by Pepe Rodriguez-Perez, PhD Business Excellence Consulting Inc / BEC Spain SL pepe@calidadpr.com

2 Agenda 1. FDA s Strategic Priorities CDER s Office of Pharmaceutical Quality 3. Quality Metrics 4. Generic Drug Review Dashboard 5. Data Integrity 6. Field Alert Report / Complaint Investigation 7. FY 2015 Drug Inspection Observations 2

Center for Veterinary Medicine (CVM) Center fortobacco Products (CTP) Office of Regulatory Affairs (ORA HQ) Field Regions (SER,

3 FDA Overview US Department of Health & Human Services US Food and Drug Administration Centers for: Food Safety and Nutrition (CFSAN) Drug Evaluation and Research (CDER) Biologics Evaluation and Research (CBER) Devices and Radiological Health (CDRH) Center for Veterinary Medicine (CVM) Center fortobacco Products (CTP) Office of Regulatory Affairs (ORA HQ) Field Regions (SER, SWR, PAR, NER, CER)» District Offices San Juan District Office (SJN-DO) SJN, MRP, PON, USVI FY 2016= $4900 millones 13,000 BEC - QSR 3

4 FDA Strategic Priorities Regulatory Science 2. Globalization 3. Safety and Quality 4. Smart Regulation 5. Stewardship 4

5 FDA Core Mission Goals and Objectives 5

6 Office of Pharmaceutical Quality (OPQ) OPQ will establish a uniform approach to pharmaceutical quality across all manufacturing facilities, whether domestic or foreign, and across all drug product areas new drugs, generic drugs, and overthe-counter drugs. 6

7 OPQ Objectives 1. Assure that all human drugs meet the same quality standards to safeguard clinical performance; 2. Enhance science- and risk-based regulatory approaches; 3. Transform product quality oversight from a qualitative to a quantitative and expertise-based assessment; 4. Provide seamless integration of review, inspection, surveillance, policy, and research across the product life cycle; and 5. Encourage development and adoption of emerging pharmaceutical technology 7

8 Office of Pharmaceutical Quality 8

9 Quality Metrics Under Title VII of the Food and Drug Administration Safety and Innovation Act (FDASIA) Public Law No , FDA may require the submission of any records or other information that FDA may inspect under section 704 of the FD&C Act, in advance or in lieu of an inspection, by requesting the records or information from a person that owns or operates an establishment that is engaged in the manufacture, preparation, propagation, compounding, or processing of a drug. 9

10 Quality Metrics: Data 1) The number of lots attempted of the product; 2) The number of specification-related rejected lots of the product, whether rejected during or after manufacturing; 3) The number of attempted lots pending disposition for more than 30 days; 4) The number of OOS results for the product, including stability testing; 5) The number of lot release and stability tests conducted for the product; 6) The number of OOS results for lot release and stability tests for the product that are invalidated because of a lab error; 7) The number of quality complaints received for the product; 8) The number of lots attempted that are released for distribution or for next stage of manufacturing; 9) Whether the associated annual product review or product quality review were completed within 30 days of their annual due date; and 10) The number of APRs or PQRs required for the product. 10

11 Four Quality Metrics Lot Acceptance Rate = 1 x (x = the number of specification-related rejected lots in a timeframe divided by the number of lots attempted by the same establishment in the same timeframe). Product Quality Complaint Rate = the number of product quality complaints received for the product divided by the total number of lots of the product released in the same timeframe. Invalidated Out-of-Specification (OOS) Rate = the number of OOS test results for the finished product invalidated by the establishment divided by the total number of OOS test results divided by the total number of tests performed by the establishment in the same timeframe. Annual Product Review (APR) or Product Quality Review (PQR) on Time Rate = the number of APRs or PQRs completed within 30 days of annual due date at the establishment divided by the number of products produced at the establishment. 11

12 Two Optional Quality Metrics for Quality Culture A. Senior Management Engagement Was each APR/PQR reviewed and approved by 1. the head of quality unit 2. The head of he operations unit 3. Both 4. Neither B. CAPA Effectiveness 1. What percentage of your CA involved re-training of personnel? 12

13 One Optional Quality Metric for Process Capability/Performance A yes or no value of whether the establishment s management calculated a process capability or performance index for each critical quality attribute (CQA) as part of that product s APR or PQR. A yes or no value of whether the establishment s management has a policy of requiring a corrective action or preventive action (CAPA) at some lower process capability or performance index. If yes to the above question what is the process capability or performance index that triggers a CAPA? If no to the above question please do not respond. 13

14 Quality Metrics: Effects of Non-Reporting The failure to report requested quality data may elevate an establishment s predicted risk in FDA s prioritization of inspections and may lead to an earlier inspection. In addition, products associated with an establishment that does not report as required under section 704(a)(4)(A) may be deemed adulterated under section 501 and subject to enforcement action. 14

15 Generic Drug Review Dashboard As of January 2016= 4105 ANDAs 2962 ANDAs pending FDA review 1143 ANDAs pending response from Industry FY2016= 15 months to respond FY2017= 10 months to respond Since October 2012: 6352 ANDAs 1499 ANDAs approved 172 ANDAS Refusal to Receive 573 ANDAs Withdrawals 4105 ANDAs In-process 15

16 Original ANDAs CY

17 Data Integrity: Information that is accurate, complete and truthful Data integrity, data manipulation and fraud appears to be increasing It s occuring in early stages of drug development (i.e., clinical studies), during commercial manufacturing and in various FDA regulated products The FD&C Act is a strict liability statute FDA takes the position that corporations act through the actions of individuals Part of an FDA Investigator s job is to document individual responsibility for violations noted during inspections 17

18 Data Integrity and Quality FDA needs to be able to verify the quality and integrity of the data during inspections. Data needs to meet ALCOA elements of quality Attributable data are identified with a specific subject and a specific observer and recorder. (Password, audit trail and e-signature) Legible data are readable and understandable by humans (reports, tables, and listings) Contemporaneous - data are recorded at the time they are generated or observed. (Time stamps and time-limited entry) Original data are recorded for the first time. (Source data) Accurate data are correct (Calculations, algorithms, analyses) 18

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23 FDA Warns India-based Ipca Laboratorios of Data Integrity Violations at Three Plants 23

24 FAR (Field Alert Reporting)

25 FAR Observation 25

26 Field Alert Program Quickly identify drug products that could pose a potential health hazard to the public. Regulatory reporting requirements (effective 5/1985) that all holders/applicants with approved New Drug Applications (NDAs) and Abbreviated New Drug Applications (ANDAs) are required to submit Field Alert Reports (FARs) to the jurisdictional FDA district office, as specified in 21 CFR (b). 26

27 NDA Field Alert Report The applicant shall submit information of the following kinds about distributed drug products (i) Information concerning any incident that causes the drug product or its labeling to be mistaken for, or applied to, another article. (ii) Information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug product, or any failure of one or more distributed batches of the drug product to meet the specifications established for it in the application. 27

28 Field Alert Program FARs must be submitted to the FDA DO that is responsible for the facility where problem occurred within 3 working days by the applicant. The facility where problem occurred may not be in the same district as the applicant (i.e. contract manufacturer, contract labeler/repacker, etc). The 3 working days begins when the applicant becomes aware of a reported problem (complaint or internal testing); not the day the applicant confirms or invalidates a problem. If the problem is appropriately invalidated within 3 working days, then no FAR. The information may be provided by telephone or other rapid communication means, with prompt written followup. The report and its mailing cover should be plainly marked: ``NDA- - Alert Report.'' 28

29 Regulatory Guidance: CP Drug Quality Reporting System NDA Field Alert Report 29

30 What To Report Any incident that causes the drug product or its labeling to be mistaken for, or applied to, another article Bacterial contamination Significant chemical, physical or other changes Product deterioration Failure of one or more distributed batches of drug products to meet the specification established in the application. 30

31 What To Report Mislabeling, missing label, obscured label Matters involving dissolution failures, impurity levels, sub/super potency OOS results obtained during stability testing If cannot appropriately invalidate within 3 days then >report If product is at expiry may still need to report as the stability sample is representative of all marketed product of that application OOS results obtained from reserve samples appearance, particulates Complaints for distributed product which are deemed significant 31

32 During Inspection FDA will look to 1. Ensure that applicant holders are submitting FARs as required by 21 CFR (b)(1)(i) and (ii). 2. As part of the preparation for inspections, review any FARS (and relevant DQRS reports) to be covered while on inspection. Two weeks prior to the inspection, the inspector should request through CDER DQRS Reports the FAR history associated for a specified firm and drug product(s). 3. For investigations which involve OOS results for finished marketed products, the inspector should ask if the firm submitted any FARs to the Agency. 32

33 During Inspection FDA will look to 4. For FARs that affect more than one product, firms should submit one FAR per NDA/ANDA of distributed product. Multiple lots of the same product may be submitted on one form. 5. When reviewing Standard Operating Procedures (SOPs) during inspections, note the firm s handling and reporting of NDA FARs to ensure their compliance with 21 CFR (b)(1)(i) and (ii). 33

34 During Inspection FDA will look to 6. Failure of a firm to submit an NDA/ANDA FAR for distributed violative product is reportable as a FDA- 483 observation. 7. Investigators, in conjunction with Field Alert Monitors, should attempt to determine if the firm s root cause analysis, as stated in any FAR has been thoroughly investigated. The firm s investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. They should also determine if the corrective and preventive actions (CAPA) are adequate to mitigate risk. 34

35 Complaint Handling System

36 Effective Complaint Handling System Any complaint received on a product must be evaluated and IF NECESSARY Investigated and analyzed? Corrective action taken? Was the complaint valid? What was the cause(s) of the complaint? Action(s) necessary to prevent further occurrences? Complaints can not be ignored!!!!! 36

37 Effective Complaint Handling System Manufacturers shall: document, review, evaluate, and file all complaints; formally designate a unit or individual to perform these activities; determine if an investigation is necessary; record the reason if no investigation is made; assign responsibility for deciding when not to investigate; and, Determine if the complaint requires an Field Alert Report. 37

Effective Complaint Handling System Complaint investigation must be completed within a standard timeframe, generally 30-45 calendar days, from the date the company received the complaint.

38 Effective Complaint Handling System Complaint investigation must be completed within a standard timeframe, generally calendar days, from the date the company received the complaint. Some complaints, such as those involving third-party manufacturers, may require longer timelines. If the investigation cannot be completed on time, an interim report approved by the Quality Unit should be issued 38

39 Top Observations Drug Inspections FY 2015 (678 Forms 483s, 3506 observations) 39

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42 Top Observations Device Inspections FY 2015 (1008 Forms 483s, 3599 observations) 42

43 Devices - Drugs FDA Inspections Comparison Device Inspection International (FY : 3083) Device Inspection US (FY : 19102) VAI, 1182, 38% OAI, 487, 16% NAI, 1414, 46% OAI, 1126, 6% VAI, 6811, 36% NAI, 11165, 58% Drug Inspections International (FY : 3648) Drug Inspections US (FY : 9220) VAI, 2008, 55% NAI, 1497, 41% VAI, 4232, 46% NAI, 4508, 49% OAI, 143, 4% OAI, 480, 5%

44 Devices - Drugs FDA Inspections Comparison Drug Inspection Spain (FY : 113) Device Inspection Spain (FY : 18) VAI, 63, 56% NAI, 46, 41% VAI, 8, 45% NAI, 6, 33% OAI, 4, 22% OAI, 4, 3% Drug Inspection Germany (FY : 323) Device Inspection Germany (FY : 471) VAI, 170, 53% NAI, 147, 45% VAI, 187, 40% NAI, 222, 47% OAI, 6, 2% OAI, 62, 13% 44

45 FDA Revokes Approval for Sun Pharma Drug over GMP Issues 45

46 Sun Pharma May Ask for US FDA Reinspection 46

47 GMP Status of R&D Laboratories 47

48 Pest (lack of) Control 48

49 More about Pan Drugs Limited 49

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51 Import Alert Examples 51

129 sites on Import Alert 66-40 as of February 18, 2016 42 China (33%) 42

52 129 sites on Import Alert as of February 18, China (33%) 42 India (33%) 7 Canada 5 Hong Kong 4 Denmark 3 Mexico 3 UK 3 France 2 Spain 52

53 FDA ONLINE Resources 53

54 Gracias

IVT Laboratory Week Jerry Lanese. Ph.D. The Lanese Group, Inc The Lanese Group, Inc.

IVT Laboratory Week Jerry Lanese. Ph.D. The Lanese Group, Inc The Lanese Group, Inc. IVT Laboratory Week-2015 Jerry Lanese Ph.D. The Lanese Group, Inc. 1 Name Job What brought you here. 2 FDA interest in Quality Metrics What are Quality Metrics Quality metrics FDA will request The impact