FDA Quality Metrics, Data Integrity and Application of Statistics Throughout Process Validation in a Global Economy

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1 CBI Statistics in Validation FDA Quality Metrics, Data Integrity and Application of Statistics Throughout Process Validation in a Global Economy Jerry Lanese Ph.D. The Lanese Group, Inc The Lanese Group, Inc. 1

2 Pharmaceutical firms must operate in compliance with the drug GMPs The Lanese Group, Inc. 2

3 TITLE 21 FOOD AND DRUGS CHAPTER I FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES SUBCHAPTER C DRUGS: GENERAL Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals 2017 The Lanese Group, Inc. 3

4 Have you read 21cfr211? Have you read the parts of 21cfr211 that pertain to your job? 2017 The Lanese Group, Inc. 4

5 Why worry about, it is old? What is new? 2017 The Lanese Group, Inc. 5

6 In order to assure the consistent production of quality products the drug GMPs must reflect the current state of the industry. New GMPs or Interpretation 2017 The Lanese Group, Inc. 6

7 The regulations set forth in this part and in parts 211, 225, and 226 of this chapter contain the minimum current good manufacturing practice for methods to be used in, and the facilities or controls to be used for, the manufacture, processing, packing, or holding of a drug to assure that such drug meets the requirements of the act as to safety, and has the identity and strength and meets the quality and purity characteristics that it purports or is represented to possess. 21CFR210.1(a) 2017 The Lanese Group, Inc. 7

8 The failure to comply with any regulation set forth in this part and in parts 211, 225, and 226 of this chapter in the manufacture, processing, packing, or holding of a drug shall render such drug to be adulterated under section 501(a)(2)(B) of the act and such drug, as well as the person who is responsible for the failure to comply, shall be subject to regulatory action. 21CFR210.1(b) 2017 The Lanese Group, Inc. 8

9 Typical FDA Warning Letter Statement Because your methods, facilities, or controls for manufacturing, possessing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(2)(2)(B) of the Food Drug, and Cosmetic Act (FD&C Act, 21 U.S.C. 351(a)(2)(B) 2017 The Lanese Group, Inc. 9

10 The current interpretation 2017 The Lanese Group, Inc. 10

11 Have you read: FDA Process Validation Guidance CPG ICH Q8 ICH Q9 ICH Q10 ICH Q11 EU GMP Annex 15 Qualification and Validation Quality Metrics Guidance Data Integrity Guidance 2017 The Lanese Group, Inc. 11

12 CPG CFR211 EMA Guideline on Process Validation And Annex 15 FDA 2011 Process Validation Guidance ICH Q10 ICH Q8 ICH Q9 Guidance for the Industry Data Integrity ICH Q11 Guidance for the Industry Quality Metrics 2017 The Lanese Group, Inc. 12

13 2017 The Lanese Group, Inc. 13

14 What is the regulatory justification for requiring process validation? 2017 The Lanese Group, Inc. 14

15 CPG Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients The Lanese Group, Inc. 15

16 CPG CFR211 EU Annex 15 FDA 2011 Process Validation Guidance ICH Q10 ICH Q8 ICH Q9 ICH Q The Lanese Group, Inc. 16

17 Is validation enforceable? Validation of manufacturing processes is a requirement of the Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals (21 CFR and ), and is considered an enforceable element of current good manufacturing practice for active pharmaceutical ingredients (APIs) under the broader statutory CGMP provisions of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act. CPG The Lanese Group, Inc. 17

18 What is Process Validation? 2017 The Lanese Group, Inc. 18

19 Validation 1987 US Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre determined specifications and quality attributes PV Guidance 2017 The Lanese Group, Inc. 19

20 Industry paradigm (pre 2001) Process validation is the responsibility of operations Three production runs before product is distributed constitutes validation. Validation was a one time activity 2017 The Lanese Group, Inc. 20

21 The proof of validation is obtained through rational experimental design and the evaluation of data, preferably beginning from the process development phase and continuing through the commercial production phase. CPG The Lanese Group, Inc. 21

22 Before commercial distribution begins, a manufacturer is expected to have accumulated enough data and knowledge about the commercial production process to support postapproval product distribution. Normally, this is achieved after satisfactory product and process development, scale up studies, equipment and system qualification, and the successful completion of the initial conformance batches CPG The Lanese Group, Inc. 22

23 Quality should be built into the product Testing alone cannot be relied on to ensure product quality FDA QS Guidance 2017 The Lanese Group, Inc. 23

24 CPG CFR211 EMA Guideline on Process Validation FDA 2011 Process Validation Guidance ICH Q10 ICH Q8 ICH Q9 ICH Q The Lanese Group, Inc. 24

25 2017 The Lanese Group, Inc. 25

26 Process Validation The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products 2011 FDA PV Guidance 2017 The Lanese Group, Inc. 26

27 Process Validation FDA 2011 This guidance describes process validation activities in three stages The Lanese Group, Inc. 27

28 Stage 1 Process Design: The commercial process is defined during this stage based on knowledge gained through development and scale up activities. Stage 2 Process Qualification: During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing. Stage 3 Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control. FDA 2011 Process Validation Guidance 2017 The Lanese Group, Inc. 28

29 This guidance aligns process validation activities with a product lifecycle concept and with existing FDA guidance, including the FDA/International Conference on Harmonisation (ICH) guidances for industry, Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System.2 Although this guidance does not repeat the concepts and principles explained in those guidances, FDA encourages the use of modern pharmaceutical development concepts, quality risk management, and quality systems at all stages of the manufacturing process lifecycle. FDA Process Validation Guidance 2017 The Lanese Group, Inc. 29

30 CPG CFR211 EMA Guideline on Process Validation FDA 2011 Process Validation Guidance ICH Q10 ICH Q8 ICH Q9 ICH Q The Lanese Group, Inc. 30

31 Accordingly, in process material should be controlled to assure that the final drug product will meet its quality requirements. The second principle in this regulation (CFR (b) further requires that in process specifications... shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate. FDA PV Guidance 2017 The Lanese Group, Inc. 31

32 An ongoing program to collect and analyze product and process data that relate to product quality must be established ( (e)). The data collected should include relevant process trends and quality of incoming materials or components, in process material, and finished products. The data should be statistically trended and reviewed by trained personnel. The information collected should verify that the quality attributes are being appropriately controlled throughout the process. FDA PV Guidance 2017 The Lanese Group, Inc. 32

33 INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE PHARMACEUTICAL QUALITY SYSTEM Q10 Current Step 4 version dated 4 June 2008 This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA The Lanese Group, Inc. 33

34 ICH Q10 Pharmaceutical Quality System Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuance Investigational Products GMP Management Responsibilities PQS Elements Process Performance and Product Quality Monitoring System Corrective Action/Preventive Action (CAPA) System Change Management System Management Review Enablers Knowledge Management Quality Risk Management 2017 The Lanese Group, Inc The Lanese Group 34 ICH Q10 4 June 2008

35 Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuance Stage 1 Process Design: The commercial process is defined during this stage based on knowledge gained through development and scale up activities. Stage 2 Process Qualification: During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing. Stage 3 Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control. FDA 2011 Process Validation Guidance 2017 The Lanese Group, Inc. 35

36 ICH Q10 Pharmaceutical Quality System Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuance Investigational Products GMP Management Responsibilities PQS Elements Process Performance and Product Quality Monitoring System Corrective Action/Preventive Action (CAPA) System Change Management System Management Review Enablers Knowledge Management Quality Risk Management 2017 The Lanese Group, Inc The Lanese Group 36 ICH Q10 4 June 2008

37 ICH Q10 Pharmaceutical Quality System Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuance Investigational Products GMP Management Responsibilities PQS Elements Process Performance and Product Quality Monitoring System Corrective Action/Preventive Action (CAPA) System Change Management System Management Review Enablers Knowledge Management Quality Risk Management 2017 The Lanese Group, Inc The Lanese Group 37 ICH Q10 4 June 2008

38 INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE PHARMACEUTICAL DEVELOPMENT Q8 Current Step 4 version dated 10 November 2005 This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA The Lanese Group, Inc. 38

39 CPG CFR211 EMA Guideline on Process Validation FDA 2011 Process Validation Guidance Knowledge management ICH Q10 ICH Q8 ICH Q9 Design Design Space Pharmaceutical Development Studies ICH Q The Lanese Group, Inc. 39

40 Pharmaceutical Development A systematic approach to development (also defined as QbD) can include incorporation of prior knowledge results from studies using design of experiment, use of quality risk management, and use of knowledge management throughout the lifecycle of the product. Such can enhance the process to achieve quality The Lanese Group, Inc. ICH Q8 40

41 CPG CFR211 EU GMP Annex 15 FDA 2011 Process Validation Guidance ICH Q10 ICH Q8 ICH Q9 ICH Q The Lanese Group, Inc. 41

42 A quality risk management approach should be applied throughout the lifecycle of a medicinal product. As part of a quality risk management system, decisions on the scope and extent of validation and qualification should be based on a justified and documented risk assessment of the facilities, equipment, utilities and processes. EU GMP Annex The Lanese Group, Inc. 42

43 State of Control A condition in which the set of controls consistently provides assurance of continued process performance and product quality. ICH Q The Lanese Group, Inc. 43

44 ICH Q10 Pharmaceutical Quality System Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuance Investigational Products GMP Management Responsibilities PQS Elements Process Performance and Product Quality Monitoring System Corrective Action/Preventive Action (CAPA) System Change Management System Management Review Enablers Knowledge Management Quality Risk Management 2017 The Lanese Group, Inc The Lanese Group 44 ICH Q10 4 June 2008

45 Written records required by this part shall be maintained so that data therein can be used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures. 21CFR (e) 2017 The Lanese Group, Inc. 45

46 ICH Q10 Pharmaceutical Quality System Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuance Investigational Products GMP Management Responsibilities PQS Elements Process Performance and Product Quality Monitoring System Corrective Action/Preventive Action (CAPA) System Change Management System Management Review Enablers Knowledge Management Quality Risk Management 2017 The Lanese Group, Inc The Lanese Group 46 ICH Q10 4 June 2008

47 Request for Quality Metrics Guidance for Industry DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to Submit written comments to the Division of Dockets Management (HFA 305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document contact (CDER) Tara Gooen Bizjak at or (CBER) Office of Communication, Outreach and Development at or Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) July 2015 Pharmaceutical Quality/CMC Current Good Manufacturing Practices (CGMPs) 2017 The Lanese Group, Inc. 47

48 FDA is: (your interpretation) providing industry an incentive to requiring industry to proactively understand and measure quality, identify problem areas, and implement appropriate corrective and preventive actions The Lanese Group, Inc. 48

49 Quality Metrics will: Allow the FDA to monitor pharmaceutical operations throughout the world with its limited personnel resources. Focus on key issues. Increase the emphasis on an effective quality system. Increase the visibility of the involvement of senior management in the pharmaceutical quality system 2017 The Lanese Group, Inc. 49

50 Quality Metrics will: Increase the use of statistical tools to monitor and improve products and processes. Increase the application of quality metrics within the pharmaceutical firm. Force the implementation of effective quality system throughout the organization The Lanese Group, Inc. 50

51 Proposed Optional Metric 3: 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 The Lanese Group, Inc. 51

52 Proposed Optional Metric 3: Process capability Interpretation Must identify all critical quality attributes. An indicator of the use of process capability, or other statistical tools, to monitor processes and identify areas for improvement. Target: yes for all CQAs, yes, 1.33 Lagging 2017 The Lanese Group, Inc. 52

53 Proposed Optional Metric 3: Process capability Turn this into a proactive metric. Identify all critical quality attributes. Continuously trend each CQA. Identify a limit which the calculated CQA should not exceed. Initiate an investigation and CAPA if that limit is exceeded. Monitor for undesirable trends. Initiate an investigation and CAPA when an undesirable trend is observed The Lanese Group, Inc. 53

54 More quotes from the GMPs (b) Written production and process control procedures shall be followed in the execution of various production and process and control funct ions and shall be documented at the time of performance (a).The requirements in tis subpart shall be followed and documented at the time of performance The Lanese Group, Inc. 54

55 More quotes from the GMPs (b) Appropriate controls shall be exercised over computer or related systems to assure that changes in master production and control or records or other records are are instituted only by authorized personnel The Lanese Group, Inc. 55

56 Data Integrity and Compliance With CGMP Guidance for Industry DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to Submit written comments to the Division of Dockets Management (HFA 305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document, contact (CDER) Karen Takahashi ; (CBER) Office of Communication, Outreach and Development, or ; or (CVM) Jonathan Bray U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Veterinary Medicine (CVM) April 2016 Pharmaceutical Quality/Manufacturing Standards (CGMP) 2017 The Lanese Group, Inc. 56

57 Warning Letter Observation Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes on master production and control records, or other records (21CFR.68(b)). CHI The Lanese Group, Inc. 57

58 Warning Letter Observation Failure to record activities at the time they are performed, and destruction of original records. In your process development laboratory, our investigator found several unofficial notebooks recording sample preparation for OOS investigations, route of synthesis experiments, and scale up data. Our investigator found discrepancies between these unofficial notebooks and the official data retained by your quality unit The Lanese Group, Inc. 58

59 FDA 2011 Process Validation Guidance: Is tightly aligned with ICH Q8, Q9 and Q10. Presents a lifecycle approach to process validation. Is integrated with FDA s interest in Quality Metrics. Requires data integrity The Lanese Group, Inc. 59

60 ICH Q10 Pharmaceutical Quality System Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuance Investigational Products GMP Management Responsibilities PQS Elements Process Performance and Product Quality Monitoring System Corrective Action/Preventive Action (CAPA) System Change Management System Management Review Enablers Knowledge Management Quality Risk Management 2017 The Lanese Group, Inc The Lanese Group 60 ICH Q10 4 June 2008

61 CPG CFR211 EMA Guideline on Process Validation And Annex 15 FDA 2011 Process Validation Guidance ICH Q10 ICH Q8 ICH Q9 Guidance for the Industry Data Integrity ICH Q11 Guidance for the Industry Quality Metrics 2017 The Lanese Group, Inc. 61

62 Questions Discussion 2017 The Lanese Group, Inc. 62

63 CBI Statistics in Validation FDA Quality Metrics, Data Integrity and Application of Statistics Throughout Process Validation in a Global Economy Jerry Lanese Ph.D. The Lanese Group, Inc The Lanese Group, Inc. 63

64 Contact Information Catalina Leawood, Kansas Phone E mail jerry@lanesegroup.com The Lanese Group, Inc. 64