Good Laboratory Practices

1. Good Laboratory Practices Prof C V Raghuveer. Session-1 on GLP for 2013 PhD Batch. May 2013. 1

2. Do you want to be like this ?

3. Do you want to be this ?

4. GOOD LABORATORY PRACTICE- GLP GLP- FDA regulation. Definition: GLP embodies a set of principles providing a framework within which laboratory studies are Planned, Performed, Monitored, Recorded, Reported & Archived. GLP is sometimes confused with the standards of laboratory safety like wearing safety goggles.

5. GOOD LABORATORY PRACTICE • GLP applies to nonclinical studies conducted for the assessment of the safety or efficacy of chemicals (including pharmaceuticals). • GLP helps assure regulatory authorities that the data submitted are true.

6. HISTORY • The formal regulatory concept of GLP originated in the US in the 70’s. • The FDA’s Proposed Regulations on GLP came in 1976 & the Final Rule in June 1979 (21 CFR 58). • In 1981,OECDproduced GLP principles that are international standard.

7. WHY WAS GLP CREATED? Early 70’s FDA became aware of cases of poor laboratory practice PLP all over the US. FDA conducted an in-depth investigation on 40 toxicology labs. Many fraudulent activities & PLPs came to light For e.g, Equipment not calibrated to standard form giving wrong measurements. Incorrect/inaccurate accounts of study Inadequate planning

8. FAMOUS EXAMPLE One such Lab was Industrial Bio Test-a big lab that ran tests for big companies such as P & G • It was discovered that mice that they had used to test lotion and deodorants had developed cancer and died. • This “big lab” threw the dead mice, hushed up results deeming products good for human use.

9. Those involved in production, distribution & sales for IBT eventually served jail term.

10. OBJECTIVES OF GLP GLP makes sure that the data submitted are a true reflection of the results that are obtained during the study. GLP also makes sure that data is traceable. Promotes international acceptance of tests.

11. MISSION OF GLP Test systems Apparatus, material and reagent facilities. Performance of the study. Reporting of study results. Standard operating procedures (SOP) Archiving of records Quality assurance programs.

12. 21 CFR Part 58: Non-Clinical Laboratory Studies Subpart A: General Provisions Subpart B: Organization & Personnel Subpart C: Facilities Subpart D: Equipment Subpart E: Testing Facilities Operation Subpart F: Test & Control Articles Subpart G: Protocol for & Conduct of Non-Clinical Laboratory Study Subpart J: Records & Reports Subpart K: Disqualification of Testing Facilities

13. GLP Regulations (Rules)‏ Documentation (Tools)‏ ORGANIZATION & PERSONNEL Training records, CVs, GLP training FACILITIES Maintain adequate space/separation of chemicals from office areas EQUIPMENT Calibration, logbooks of use, repair, & maintenance FACILITY OPERATION SOPs TEST, CONTROL, & REFERENCE SUBSTANCES Chemical & sample inventory, expiry dates RECORDS & REPORTS Timely reporting, storage of raw data & reports GLP Regulations: Rules and Tools

14. Organization and Personnel 58.29 Personnel (a)“Each individual engaged in the conduct of or responsible for the supervision of a nonclinical laboratory study shall have education, training, and experience, to enable him/her to “perform the assigned functions.” (b)“Each testing facility shall maintain a current summary of training, experience & job description for each individual engaged in or supervising the conduct of the study.”

15. Organization and Personnel 58.33 Study Director 58.35 Quality Assurance Unit “A testing facility shall have a QAU responsible for monitoring the study to ensure that facilities, equipment, personnel, methods, practices, records & controls are in conformancewith regulations. For any given study, QAU shall be entirely separate from & independent of the personnel engaged in direction & conduct of that study.” “For each study, a scientist (professional)of appropriate education, training, and experience, shall be identified as Study Director with responsibilityfor the technical conduct of the study,as well as for interpretation, analysis, documentation & reporting of results & represents the singlepointofstudycontrol.”

16. Facilities 58.41 General “Each testing facility shall be of suitable size &construction to facilitate proper conduct of studies. It shall be designed so that there is a degree of separation to prevent any function or activity from having an adverse effect on the study.” Facilities include: Animal care facilities Animal supply facilities Facilities for handling test & control articles • Laboratory operation areas • Specimen and data storage facilities

17. Equipment 58.61 Equipment Design “Equipment used in ... shall be of appropriate design and adequate capacity” 58.63 Maintenance and Calibration (a) “Written S O P ...” (b) “Written records shall be maintained ...” • Log book • Fit for use • Not for GLP use.

18. Equipment Verification • Verification (Testing):External check of equipment accuracy (e.g. check balance accuracy against weights at laboratory- no adjustment)‏ • Calibration: Equipment adjusted based on comparison to certified or known reference materials (e.g. balance adjusted after comparison to certified weights by trained professional)‏ • Standardization:Comparison with similar equipment (e.g.usetwo thermometers of similar design to compare readings)‏ Calibration Standardization

19. Protocol , Reports & Records 58.120 Protocol “Each study shall have an approved written protocol that clearly indicate objectives & methods for the conduct of the study.” 58.130 Conduct of a Non-clinical Laboratory Study “The study shall be conducted in accordance with protocol” 58.185 Reporting of Non-clinical Laboratory Study Results “A final report shall be prepared for each study ” 58.190 Storage and Retrieval of Records and Data “All raw data, documentation, protocols, final reports, & specimens shall be retained.”

20. Raw Data Raw data- “Laboratory worksheets,records,memoranda,notes,orexact copies thereof, that are the result of original observations & activities of a study & are necessary for the reconstruction & evaluation of report of that study.” If anyone scribbles some notes on a scrap of paper, even they are considered raw data

21. Raw Data Question: What happens if you make a mistake? E.g, of raw data:- • Logbooks • To record temperatures, equipment use, repair, maintenance. • Field or laboratory notebooks • Forms • For field or laboratory observations, chain-of-custody, sample or chemical receipt‏. • Training reports • Computer printouts • Recorded data from automated instruments

22. Standard Operating Procedures (SOP) 40 CFR Part 160 (EPA GLP regulations)‏ “Section 160.81 SOPs. (a) A testing facility shall have SOPs in writing setting forth study methods that management is satisfied are adequate to insure the quality and integrity of the data generated in the course of a study.” Written procedures for a laboratories program. They define how to carry out protocol-specified activities. Most often written in a chronological listing of action steps. They are written to explain how the procedures are suppose to work Standard Operating Procedures (SOP)

23. SOPs SOPs should accurately reflect how routine tasks are performed Routine inspection, cleaning, maintenance, testing and calibration. Actions to be taken in response to equipment failure. Reviewed on regular basis.

24. What happens if a laboratory fails to comply with federal G L P standards?

25. Possible Violations Falsifying information for permit, registration or any required records Falsifying information related to testing~ protocols, ingredients, observations, data equipment, etc. Failure to prepare, retain, or submit written records required by law.

26. Consequences of Non-compliance FDA states following for non-compliance: The commissioner will send a written proposal of disqualification to the testing facility A regulatory hearing on the disqualification will be scheduled If the commissioner finds that after the hearing, the facility has complied, then a written statement with an explanation of termination of disqualification will be sent to the facility Thus, if it can be shown that such disqualifications did not affect the integrity and outcome of the study itself, or did not occur at all, then the study may be reinstated.

27. Upon Disqualification… If the commissioner finds that the facility showed a noncompliance, any of the grounds after the hearing, then a final order of noncompliance will be sent to the facility with explanations If a testing facility has been disqualified, any studies done before or after the disqualification will need to be determined as essential to a decision (acceptable or not) If the study is determined unacceptable, then the facility itself may need to show that the study was not affected by the noncompliance that led to the disqualification Once finally disqualified, the facility may not receive or be considered for a research or marketing permit and the study is rejected.

28. Upon Disqualification… The commissioner may notify the public and all interested persons, including other federal agencies the facility may have contacted The FDA may ask the other agencies to consider whether to support the facility or not under the disqualification Civil or criminal proceedings may occur at the discretion of the commissioner Fines of up to $50,000 if one knowingly commits crime and/or 1 year imprisonment~ for registration applicants and producers Fines up to $5,000 all others~ civil penalty after failing to improve after a minor violation warning was issued~ only those involved in testing will be given civil penalties Those involved in the distribution or sales will be assessed more heavy penalties, such as criminal penalties

29. Upon Disqualification… The FDA may turn it over to the federal, state or local law enforcement The facility’s sponsor may terminate or suspend the facility from doing any non- clinical study for a permit The sponsor is required to notify the FDA in writing within 15 working days that the facility is to be suspended or terminated and why

30. Reinstatement of a Disqualified Facility The commissioner will inspect the facility and determine if it shall be reinstated If it is reinstated, the commissioner is required to notify all persons that were notified of the disqualification including the facility itself

31. Thank you End of GLP Session-1

32. Good Clinical Practice

33. Contents • Glossary • Principles of GCP • IEC/IRB Responsibilities • Investigator Responsibilities • Sponsor Responsibilities • Protocols and Amendments • Investigator’s Brochure • Essential Documents

34. Glossary • Adverse drug reaction (ADR) • Serious Adverse Event (SAE) • Audit • Blinding/masking • Investigator • Protocol • Sponsor

35. History of Good Clinical Practice • Prior to an actual set of guidelines to follow for good clinical practice, clinical studies were dangerous and could result in serous disease, or possibly death. • The Nuremburg Code of 1947 • Experiments performed in Germany during WWII opened the eyes of the world for guidance for clinical testing on humans. • The code did set ethical guidelines, but it lacked legislation to back it up. • Declaration of Helsinki • In 1964, the World Medical Association established recommendations guiding medical doctors in biomedical research involving human subjects. These guidelines influenced national legislation, but there was no set standard between nations.

36. GOOD CLINICAL PRACTICE FDA ICH 21 CFR International • Electronic Docs. • Inf. Consent • Financial Disclosure • IRBs • IND regs. • glossary • principles • IRBs • Investigator • Sponsor • Essential Docs

37. ICH Guidelines • ICH Guidelines are divided into 4 main topics: • Quality Topics – relate to chemical and pharmaceutical quality assurance e.g. Q1 Stability Testing • Safety Topics – relate to preclinical studies e.g. S1 Carcinogenicity Testing • Multidisciplinary Topics – cross-cutting topics which don’t fit into one of the other categories e.g. M1 Medical Terminology • Efficacy Topics – relate to clinical studies in human subjects • e.g. E6 Good Clinical Practice; • e.g. E2A Clinical Safety Data Management: • e.g. E9 Statistical Principles for Clinical Trials

38. FDA Regulations • 21 C.F.R. Part 312, Subpart D (Duties of Sponsors, Investigators) • – 21 C.F.R. Part 50 (Informed Consent) • – 21 C.F.R. Part 56 (Institutional Review Boards) • – 21 C.F.R. Part 54 (Investigator Financial Disclosure)

39. What is GCP ? Good Clinical Practice (GCP) is defined as a ‘standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of trial subjects are protected’

40. GCP • Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human patients. • Compliance with this standard provides public assurance that the rights, safety and well-being of trial patients are protected and clinical trial data are credible.

41. GCP • Are mainly focused on the protection of human rights in clinical trial. • Provide assurance of the safety of the newly developed compounds. • Provide standards on how clinical trials should be conducted. • Define the roles and responsibilities of - • Clinical Sponsors, • Clinical Research Investigators, • Clinical Research Associates, And • Monitors.

42. Principles of ICH GCP • Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirements. • Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject & society. A trial should be initiated and continued only if the anticipated benefits justify the risks. Benefits RISKS

43. Principles of ICH GCP Continued • The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science & society. • The available non-clinical & clinical information on an investigational product should be adequate to support the proposed clinical trial. • Clinical trials should be scientifically sound, and describe in a clear, detailed protocol. • A trial should be conducted in compliance with the protocol that has received prior IRB (or IEC) approval.

44. Principles of ICH GCP Continued • The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist. • Each individual involved in conducting a trial should be qualified by education, training and experience to perform his or her respective tasks. • Freely given informed consent should be obtained from every subject prior to clinical trial participation.

45. Principles of ICH GCP Continued • All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification. • The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory compliance.

46. Principles of ICH GCP Continued 12. Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol 13.Systems with procedures that assure the quality of every aspects of the trial should be implemented.

47. Institutional Review Board (IRB),Independent Ethics Committee (IEC) • A formally designated group that oversees research involving human subjects. • Approves and disapproves human subject research. • According to the standards of the community or the institution, the IRB/IEC may require modifications to a protocol to ensure patient safety.

48. IRB Function • •The primary function of an IRB/IEC is to safe guard the rights ,safety ,and well being of all trial subjects. This is accomplished by initial, continuing and annual review. • •An IRB should consist of members who collectively have the qualifications and experience to review and evaluate the science , medical aspects, and ethics of the proposed trial.

49. IRB Members 1.A minimum of five (5) members. 2.One member whose concern is not scientific. 3.One member who has no personal or familial relationship to the institution or trial site. 4.Any member with a conflict of interest may not participate in any part of the review or vote (except to provide requested information). 5.Individuals with special expertise may be invited to assist with areas of unique or complex nature. These will not be voting members. 6.A list of IRB/IEC members and their qualifications should be maintained.

50. IRB/Ethics Committee • All studies must be approved prior to recruiting participants • IRB must review all documents given to participants • Reporting AEs and Deviations from protocol to the IRB • Maintenance of Records