GLP Training

1. GLP Training Daniel W. Sved, PhD Director, Metabolism and Analytical Chemistry Lori A. Rush, BS, LAT, RQAP-GLP Sponsor Specialist, Quality Assurance

2. Terms to Know • GLP Good Laboratory Practice • GMP Good Manufacturing Practice • GCP Good Clinical Practice

3. Terms to Know • Protocol • A document which clearly indicates the objectives and methods for the conduct of the study • SOP • Standard operating procedure

4. Terms to Know • Electronic Record/Signature Regulations • Part 11 (21 CFR Part 11) • CROMERR (40 CFR Part 3)

5. Definitions • Good Laboratory Practice • Good Laboratory Practice (GLP) is a quality system with the organizational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported. • ENV/MC/CHEM(98)17 2.1.1

6. Definitions • Master Schedule • A compilation of information to assist in the assessment of workload and for the tracking of studies at a test facility • ENV/MC/CHEM(98)17 2.2.10

7. Definitions • Nonclinical laboratory study • In vivo or in vitro experiments in which test articles are studied prospectively in test systems under laboratory conditions to determine their safety. The term does not include studies utilizing human subjects or clinical studies or field trials in animals. The term does not include basic exploratory studies carried out to determine whether a test article has any potential utility or to determine physical or chemical characteristics of a test article. • 21 CFR Part 58.3(d)

8. Definitions • Sponsor • A person who initiates and supports, by provision of financial or other resources, a nonclinical laboratory study; • A person who submits a nonclinical study to the FDA in support of an application for a research or marketing permit; or • A testing facility, if it both initiates and actually conducts the study. • 21 CFR Part 58.3(f)(1)(2)(3)

9. Definitions • Testing Facility • A person who actually conducts a nonclinical laboratory study, i.e., actually uses the test article in a test system. • 21 CFR Part 58.3(g)

10. Definitions • Quality Assurance Unit • Any person or organizational element, except the study director, designated by testing facility management to perform the duties relating to quality assurance of nonclinical laboratory studies. • 21 CFR Part 58.3(l)

11. Definitions • Standard Operating Procedures • Documented procedures which describe how to perform tests or activities normally not specified in detail in study plans or test guidelines • ENV/MC/CHEM(98)17 2.2.9

12. Definitions • Study Director • The individual responsible for the overall conduct of a nonclinical laboratory study. • 21 CFR Part 58.3(m)

13. Definitions • Study initiation date • The date the protocol is signed by the study director • Term defined in FDA, EPA FIFRA, EPA TSCA, OECD GLPs

14. Definitions • Study completion date • The date the final report is signed by the study director • Term defined in FDA, EPA FIFRA, EPA TSCA, OECD GLPs

15. Definitions • Experimental start date • The first date the test substance is applied to the test system. • Term defined in EPA FIFRA, EPA TSCA GLPs

16. Definitions • Experimental termination date • The last date on which data are collected directly from the study • Term defined in EPA TSCA, EPA FIFRA GLPs • Experimental completion date • The last date on which data are collected from the study • Term defined in OECD GLPs

17. Definitions • Experimental starting date • The date on which the first study specific data are collected. • Term defined in OECD GLPs

18. What are GLPs? • GLPs are regulations that are intended to ensure the quality and integrity of the data in a nonclinical laboratory study.

19. GLPs are the LAW • They are NOT ideas • They are NOT governmental philosophy • They are NOT guidelines

20. Basic information • GLPs deal with: • Planning • Performance • Monitoring • Recording • Reporting • GLPs do not: • Attempt to regulate science • Ensure “good science”

21. Basic information • Responsibility for establishing the safety and efficacy of human and veterinary drugs and devices, and the safety of food and color additives is placed on the sponsor (manufacturer) of the regulated product.

22. Basic information • Public agencies (FDA, EPA, OECD, etc) are responsible for reviewing the sponsor’s test results and determine if they demonstrate the product’s safety and efficacy. • Only when the agencies are satisfied that safety and efficacy have been established adequately is the marketing of the product permitted.

23. Nonclinical laboratory studies

24. Do other countries follow GLPs? United States Japan 30 member nations of the OECD UK Canada Australia Many other countries

25. Governmental Agencies - US

26. Scope of US agency GLPs EPA TSCA • All studies relating to health effects, environmental effects and chemical fate testing • Data required by testing consent agreements and test rules

27. Scope of US agency GLPs EPA FIFRA • Studies that support applications for research or marketing permits for pesticide products regulated by EPA

28. Scope of US agency GLPs FDA FFDCA • Nonclinical laboratory studies that support applications for research or marketing permits for products regulated by FDA • Includes food and color additives, animal food additives, human and animal drugs, medical devices for humans, biological products and electronic products

29. Governmental Agencies - Japan

30. International GLPs • Generally studies at WIL are conducted under GLPs from US, Japan and/or OECD • Many protocols list all three • Formal claims of compliance with other national regulations should be avoided, if possible

31. International GLPs • Key areas of difference • QA responsibilities • Management responsibilities • Study director responsibilities • Test article characterization • Multi-site Studies

32. Historical Perspectives

33. Historical Perspectives • Underlying assumption at the FDA • Reports submitted by the sponsors accurately described study conduct and precisely reported the study data.

34. Historical Perspectives • Mid-1970s • FDA suspicion during review of studies submitted by a major pharmaceutical manufacturer (G.D. Searle & Co.) in support of New Drug Applications (NDAs) for two important therapeutic products. • Data inconsistent • Unacceptable laboratory practices • Deliberately tried to minimize chance of toxic results • Impossible to draw conclusions regarding toxic potential of tested products

35. Historical Perspectives • FDA requested a “for cause” inspection of the manufacturer’s laboratories to determine the cause and extent for the discrepancies • Revealed defects in design, conduct and reporting of the studies • Further inspections at other sites revealed similar problems.

36. FDA’s Reaction • Alarm that many of the studies on which proof of safety had been based could be invalid. • Task forces formed quickly • FDA GLPs proposed Nov. 19, 1976 • FDA GLPs finalized 1979

37. EPA follows suit • EPA issued almost identical regulations in 1983. • EPA GLPs extensively amended in 1989 to encompass all pesticide research data.

38. Too Abstract and Historical? Aspartame What product tested at Searle have most of us consumed?

39. Why comply? • Compliance with GLPs promotes the quality and integrity of test data • An inspector must be able to easily determine • Why, how and by whom the work was done • Who was in control • What equipment was used • Results obtained • Any problems and how they were overcome

40. Research Misconduct …fabrication, falsification or plagiarism in proposing, performing or reviewing research, or in reporting research results…does not include honest error or differences of opinion. Federal Policy on Research Misconduct Office of Science Technology and Policy Executive Office of the President December 6, 2000

41. Basic GLP Principles

42. Integrity Affects…. Data points Each non-clinical study The regulatory submission The work/career of an investigator All of the research conducted at a laboratory Public health, safety and confidence in scientific research

43. Flexibility vs Requirements GLPs do not specify exactly how everything is to be done

44. Flexible • SOPs shall set forth in sufficient detail... • Equipment shall be adequately inspected, cleaned and maintained • Animal cages…shall be cleaned and sanitized at appropriate intervals • QAU shall inspect each study at intervals adequate to assure the integrity of the study

45. Required • SOP deviations shall be documented… • Written recordsshall be maintained for all inspection, maintenance, testing… • Use of pest control materials shall be documented • Maintain a current summary of training and experience and job description for each individual...

46. Protocol

47. Protocol • Every study needs an approved protocol that contains at least: • Descriptive title and purpose of the study • ID of test, control and reference substance • Name and address of the sponsor and testing facility • Appropriate dates • Justification for selection of test system

48. Protocol • The number, body weight, sex, source of supply, species, strain, substrain and age of the test system • Procedure for ID of the test system • Description of the experimental design, including control of bias • A description of the diet, including acceptable levels of contaminants, if applicable • Route of administration and the reason for its choice

49. Protocol • Each dosage level in appropriate units and the method and frequency of administration • Type and frequency of tests, analyses and measurements • Records to be maintained • Date of protocol approval by the sponsor and the dated signature of the study director • Proposed statistics

50. Protocol • Changes or revisions of an approved protocol and the reasons therefore shall be documented, signed by the study director, dated and maintained with the protocol