Global Regulatory Update FDA, USP, EP and ICH Standards for Test Method Validation. Jane Weitzel

Transcription

1 Global Regulatory Update FDA, USP, EP and ICH Standards for Test Method Validation Jane Weitzel

2 Jane Weitzel Biosketch Jane Weitzel has been working in analytical chemistry for over 35 years for mining and pharmaceutical companies with the last 5 years at the director/associate director level. She is currently a consultant, auditor, and trainer. Jane has applied Quality Systems and statistical techniques, including the estimation and use of measurement uncertainty, in a wide variety of technical and scientific businesses. She has obtained the American Society for Quality Certification for both Quality Engineer and Quality Manager. She was pointed to the Chinese National Drug Reference Standards Committee and attended their inaugural meeting in Beijing for 2013 to 2016 For the cycle, Jane is a member of the USP Statistics Expert Committee and Expert Panel on Method Validation and Verification. mljweitzel@msn.com 2

3 Disclaimer This presentation reflects the speaker s perspective on this topic and does not necessarily represent the views of USP or any other organization. mljweitzel@msn.com 3

4 Abstract The ICH, USP and other global organizations, such as Eurachem, have provided guidances on method validation for many years. Understand the history of these guidances Learn how their similarities and differences Hear about the coming changes See how tools such as measurement uncertainty and QbD can be used today Look at Warning Letter Examples Prepare now for these changes 4

5 History of Method Validation Before 1970s, not much Errors, accuracy, precision 1970s papers published 1971 FDA approached (accuracy & precision) 1990s conferences and workshops EPA, AOAC, Eurachem 1995 USP <1225> 1999 release of standard ISO/IEC 17025: , 1996 & 2005 ICH A good discussion of history: Analytical Separation Science, Jared Anderson, Alain Berthod, Veronica Pino, Apryll M. Stalcup, mljweitzel@msn.com 5

6 Similarities & Differences Terminology Accuracy & trueness is a good example We need to define the terms we use and understand the differences Statistical approaches ISO, AOAC, USP, EP, IUPAC, FDA The good news: Becoming standardized mljweitzel@msn.com 6

7 Coming Changes Focus on good science Quality by Design Lifecycle approaches Statistical Techniques Bayesian Statistics Link to fitness for purpose Target Measurement Uncertainty Decision Rules 7

8 Good Science There are many types of pharmaceutical materials There are many types of analytical procedures There are many guidances There are many regulatory bodies Recent developments for analytical procedures include Good Science 8

9 Good Science Includes What Science Is and How and Why it Works Science power to probe and understand the behavior of nature on a level that allows us to predict with accuracy, if not control, the outcomes of events in the natural world. Science especially enhances our health, mljweitzel@msn.com 9

10 Scientific Method The scientific method, which underpins these achievements, can be summarized in one sentence, which is all about objectivity: Do whatever it takes to avoid fooling yourself into thinking something is true that is not, or that something is not true that is. 10

11 LOOK AT PHARMACEUTICAL INDUSTRY 11

12 Relevance of People & Concepts 12

13 Deming 13

14 Quality Total Quality Management Statistical Process Control Deming Juran Quality Control Quality Assurance American Society for Quality 14

15 Quality Revolution the Deming principle 8. Drive out fear, so that everyone may work effectively for the company the FDA is changing its regulatory approach to drive out fear Watch the Deming videos 15

16 EMA Mentions Deming 16

17 Sound Science Metrological approach to measurements Measurement uncertainty Target measurement uncertainty Completely characterises the variability 17

18 Scientifically Sound and Appropriate Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures CFR has always required use of sound science: Decision rules, measurement uncertainty, risk and probability have been used in many scientific areas for many years. 18

19 21 CFR (d) (d) Acceptance criteria for the sampling and testing conducted by the quality control unit shall be adequate to assure that batches of drug products meet each appropriate specification and appropriate statistical quality control criteria as a condition for their approval and release. The statistical quality control criteria shall include appropriate acceptance levels and/or appropriate rejection levels. Decision Rule mljweitzel@msn.com 19

20 FDA Guidance The FDA Guidance discusses the role of the analytical procedure in the lifecycle of the product To meet its requirements Good science Metrology 20

21 Japan and QbD Pharmaceutical and Medical Devices Agency (PDMA) 21

22 Japan More sophisticated guidelines will be created Discusses the role of ICH in managing expectations for its responsibilities How ICH will remain relevant Will there be more emphasis on training? 22

23 Japan & ATP PF Article Translating the article on ATP 23

24 QbD The recognition that the current pharmaceutical industry's manufacturing performance was not as state of the art as other industries has been a key driver behind the increasing adoption of quality-by-design (QbD) concepts. The Role of Analytical Science in Implementing Quality by Design Mar 02, 2013 By Lucinda Buhse, Graham Cook, Moheb Nasr, Phil Nethercote, Siegfried Schmitt Pharmaceutical Technology Volume 37, Issue 3 mljweitzel@msn.com 24

25 ICH (International Council for Harmonization) 25

26 ICH Organizational Changes Held inaugural meeting Oct 27, 2015 The International Council for Harmonization (ICH) formerly the International Conference on Harmonization to establish a more stable operating structure. The committee is also now a legal entity under Swiss law. mljweitzel@msn.com 26

27 Global & Regulators The reforms will mean that ICH is a truly global initiative, expanding beyond the current ICH members. More involvement from regulators around the world is welcomed and expected, as they will be invited to join counterparts from Europe, Japan, USA, Canada and Switzerland as ICH regulatory members. mljweitzel@msn.com 27

28 Q12 EWG Q12 EWG Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management 28

29 Adoption of Step 4 Document 2Q 2017 mljweitzel@msn.com 29

30 ICH Q12 & Analytical Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management Enable control strategy lifecycle (e.g., model maintenance, analytical lifecycle) 30

31 Q12 - Control & analytical Q12 will Support continual improvement of the manufacturing process and the control strategy which can result in decreased product variability and increased manufacturing efficiency mljweitzel@msn.com 31

32 ICH Q12 The efforts of the EWG are focused on lifecycle of the product from the perspective of the introduction of post-approval manufacturing changes. There is no specific focus on "lifecycle of methods" but up-to-date methodology is always encouraged; and so it would be desirable to lower the regulatory burden associated with making changes to methods during the product lifecycle. 32

33 ICH Q12 cont d. There has been discussion on which types of methods, and what aspects of methods, are part of the "established conditions" for the product approval; i.e., for what changes to methods used to analyse the product does one need to communicate directly with the regulatory agency (either requesting or notifying). There is some consideration that if the description of the analytical method can justifiably focus on the outcomes for the product, then many types of method changes would not need to be reported so long as the "outcome" does not change. The EWG is considering ways to try to illustrate this issue with examples of specific method parameters. 33

34 Q12 Point 1 1) for what changes to methods used to analyse the product does one need to communicate directly with the regulatory agency Briefly, what we are looking at is the use and estimate of measurement uncertainty which is extremely helpful in identifying these changes mljweitzel@msn.com 34

35 Q12 Point 2 2) There is some consideration that if the description of the analytical method can justifiably focus on the outcomes for the product, What we are looking at is the Target Measurement Uncertainty which clearly defines the link between the performance of the analytical procedure and its "fitness for purpose" which is the outcome for the product. mljweitzel@msn.com 35

36 Q2 Analytical Procedure Development and Revision of Q2 (R1) Analytical Validation Proposed 3 year timeline to review Include lifecycle Aligned with ICH Q8-Q12 mljweitzel@msn.com 36

37 ICH Future Proposed to address analytical requirements in detail about

38 Scientific Journals Fit for Intended Purpose Assays must therefore be suitable for the purpose of their respective applications. Harmonizing Best Practices in Bioanalytical Methods Citation: Tutunji L (2015) Harmonizing Best Practices in Bioanalytical Methods. MOJ Bioequiv Availab 1(1): DOI: / mojbb mljweitzel@msn.com 38

39 History Eurachem Eurachem was founded in 1989, and on the occasion of the tenth General Assembly, Alex Williams, the convenor of the initial meetings set up to consider establishing a forum for traceability in analytical chemistry in Europe. mljweitzel@msn.com 39

40 Eurachem Guides 40

41 Many Useful Guidelines Setting Target Measurement Uncertainty 41

42 New: Setting TMU Fit for Purpose is in the title 42

43 ISO Meeting internationally accepted criteria for validation and measurements of uncertainty as defined in ISO standards 9000 and will increase the likelihood of acceptance by international and national regulatory agencies. Validating Immunoassays Using the Fluorescence Polarization Assay for the Diagnosis of Brucellosis An Example and as an Application to ISO Standards 9000 and By David Gall and Klaus Nielsen 43

44 ISO Revision Includes: Decision rule TMU Risk Sampling Expected early

45 FDA Lab Quality Manual ORA labs have been accredited to ISO Recently added training information to the website Expanding to other FDA and State labs Food initiative, FSMA 45

46 FDA Policies and SOPs Includes Measurement Uncertainty (MU) 46

47 4. Background Every measurement or test has an error of measurement. If repeated, a test or measurement often gives a different result, even though it usually is very similar to the original result. Therefore, a test or measurement gives only an approximation of the true value of the quantity to be measured. A measurement or test is only complete if it includes the measurement uncertainty of the test. This can be thought of as a quantitative indication of the quality of the result. mljweitzel@msn.com 47

48 Added Training Useful reference on training in a laboratory mljweitzel@msn.com 48

49 Statistics 49

50 USP <1210> New proposed USP General Chapter <1210> Statistical Tools for Method Validation. This new proposed chapter, which was published in PF 42(5) [Sept-Oct 2016], will be a statistical companion chapter for USP General Chapter <1225> Validation of Compendial Procedures. mljweitzel@msn.com 50

51 USP PF The USP Pharmacopeia Forum (PF) Stimuli Articles and Proposed new general chapters articles are freely available from the USP.org website under the Pharmacopeia Forum (PF). You have to register once, but there is no charge 51

52 USP Stimuli Articles - USP.org Proposed New USP General Chapter: The Analytical Procedure Lifecycle <1220>;USP PF 42(6) Fitness for Use: Decision Rules and Target Measurement Uncertainty; USP PF 42(2) Analytical Target Profile: Structure and Application Throughout the Analytical Lifecycle; USP PF 42(5) Analytical Control Strategy; USP 42(5) Proposed new USP General Chapter <1210> Statistical Tools for Method Validation. This new proposed chapter, which was published in PF 42(5) [Sept-Oct 2016], will be a statistical companion chapter for USP General Chapter <1225>Validation of Compendial Procedures. Proposed New USP General Chapter: The Analytical Procedure Lifecycle 1220 USP PF 43(1) mljweitzel@msn.com 52

53 Law This bill requires the Food and Drug Administration to issue guidance that addresses using alternative statistical methods, including adaptive trial design and Bayesian methods, in clinical trials and in the development and review of drugs and biological products. 53

54 u definition Measurement uncertainty - The measurement of uncertainty is the parameter associated with the result of a measurement that characterized the dispersion of the values that could be reasonably attributed to the measurand. GUM & BIPM mljweitzel@msn.com 54

55 BIPM.org 55

56 Setting TMU This document discusses how to set a maximum admissible uncertainty, defined in the third edition of the International Vocabulary of Metrology as the target uncertainty, to check whether measurement quality quantified by the measurement uncertainty is fit for the intended purpose. mljweitzel@msn.com 56

57 Let s Look at FDA Guidance The FDA Guidance discusses the role of the analytical procedure in the lifecycle of the product To meet its requirements Good science Metrology mljweitzel@msn.com 57

58 Life Cycle Used 6 times Refers to the life cycle of the product Once an analytical procedure (including compendial methods) is successfully validated (or verified) and implemented, the procedure should be followed during the life cycle of the product to continually assure that it remains fit for its intended purpose. mljweitzel@msn.com 58

59 Continued Verification Over the life cycle of a product, new information and risk assessments (e.g., a better understanding of product CQAs or awareness of a new impurity) may warrant the development and validation of a new or alternative analytical method. mljweitzel@msn.com 59

60 Improvements in analytics In anticipation of life cycle changes in analytics, an appropriate number of retention samples should be maintained to allow for comparative studies. 60

61 Intended Purpose Intended purpose is mentioned 5 times Data must be available to establish that the analytical procedures used in testing meet proper standards of accuracy, sensitivity, specificity, and reproducibility and are suitable for their intended purpose. mljweitzel@msn.com 61

62 Stage 1, Design & Development Early in the development of a new analytical procedure, the choice of analytical instrumentation and methodology should be selected based on the intended purpose and scope of the analytical method. mljweitzel@msn.com 62

63 Stage 2 Analytical Procedure Qualification Analytical method validation is the process of demonstrating that an analytical procedure is suitable for its intended purpose. mljweitzel@msn.com 63

64 Stage 3 Continued Verification the procedure should be followed during the life cycle of the product to continually assure that it remains fit for its intended purpose. Trend analysis on method performance should be performed at regular intervals to evaluate the need to optimize the analytical procedure or to revalidate all or a part of the analytical procedure. mljweitzel@msn.com 64

65 Change The new method coupled with any additional control measures is equivalent or superior to the original method for the intended purpose. 65

66 Warning Letters 1 3. Your firm does not have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient and freedom from objectionable microorganisms, prior to release (21 CFR (a), (b)). mljweitzel@msn.com 66

67 Warning Letter 2 In your response to this letter, include: a list of the current quality control criteria and test methods you currently use to test each drug product batch prior to release. a thorough assessment to determine insufficiencies in chemical, physical, and microbiological specifications and analytical methods established for each of your drug products. Include a full remediation plan with appropriate specifications and analytical methods to be used for testing each batch of drug product. mljweitzel@msn.com 67

68 Warning Letter 3 1. Failure to ensure that test procedures are scientifically sound and appropriate to ensure that your API conform to established standards of quality and/or purity. mljweitzel@msn.com 68

69 Warning Letter 4 You have not shown how you will ensure that your test methods are appropriate to determine whether your API conform to established standards and specifications. Consequently, the summary data you provided does not demonstrate that previously released lots do not contain excessive levels of unknown impurities. mljweitzel@msn.com 69

70 Good Science The methodology and objective of the analytical procedures should be clearly defined and understood before initiating validation studies. This understanding is obtained from scientifically-based method development and optimization studies. 70

71 Lifecycle of Analytical Procedure Stage 1 Design Development & Understanding Stage 2 Performance Qualification Stage 3 Continued Performance Verification Session 1 Analytical Procedures and Method Validation Develop a Quality by Design (QbD) Approach for Analytical Method Development Session 6 Analytical Procedures and Method Validation Method Validation Characteristics through Statistical Analysis Approaches Session 8 - Investigating Laboratory OOS Test Results Manage Risk and Improve Efficiency in the Laboratory mljweitzel@msn.com 71

72 Career search Job descriptions are starting to include the knowledge and understanding of QbD, Life Cycle, and uncertainty. Proficiency with Quality by Design (QbD) concepts, statistical process control (SPC) and complex data analysis 72

73 Conclusion History we have come a long way New concepts meet the need MU, TMU, QbD, Life Cycle Regulatory bodies have adopted and continue to adopt these useful concepts Because They are based on sound science mljweitzel@msn.com 73

74 Trueness 74