General Overview of Code of Regulations 21 Part 58 Good Laboratory Practices

1. General Overview of Code of Regulations 21 Part 58 Good Laboratory Practices

2. Why GLP regulations ?

3. SAFETY • Non-clinical safety studies are to protect the safety of the participants in clinical studies • By assuring that non-clinical data is in a accordance with the GLP regulations 21 CFR 58

4. Chapter 1, Title 21 CFR 58 Subpart A: General Provisions Subpart B: Organization/Personnel Subpart C: Facilities Subpart D: Equipment Subpart E: Testing Facilities Operation Subpart F: Test and Control Articles Subpart G: Protocol for and Conduct of a nonclinical Laboratory Study Subpart J: Records and Reports Subpart K: Disqualification of Testing Facilities

5. Summary of Regulations 21 CFR 58 Subpart A: General Provisions 58. 1 Scope [a] This part prescribes good laboratory practices for conducting nonclinical laboratory [in vivo or in vitro] studies that support, or are intended to support, applications for research or marketing permits for products regulated by FDA including:

6. Subpart A: General Provisions • 58. 1 Scope…. Continuation . . . • food and color additives • animal food additives • human and animal drugs • medical devices for human use • biological products

7. Subpart A: General Provisions 58.3 GLP Definitions Sponsor: The entity that pays the bills and holds registration. Management [UA Office of the Vice President for Research]: Appoints Study Director and assures that the testing facility is in compliance. Study Director: Legally responsible for the conduct of the study. Quality Assurance: Designated by management to perform the duties relating to quality assurance of the study.

8. Subpart A: General Provisions • 58.3 Study: • Any experiment at one or more test sites, in which a test substance is studied in a test system under laboratory conditions or in the environment to determine or help predict its effects: • metabolism • product performance • environmental and chemical fate • persistence and residue • or other characteristics in humans, other living organisms or media.

9. Subpart A: General Provisions 58.3 Protocol: Approved, written document that clearly indicates objectives, study design and all methods to be used in conducting the study Standard operating procedures: Written, approved procedures that describe in detail standard and repetitive actions including policies Test system: the entity that the test substance is tested in or added to

10. Subpart A: General Provisions 58.3 Test Article: Any material or device administered to a test system Control Article: Any chemical substance or mixture, analytical standard, or material, other than a test substance, feed, or water, administered to or used in analyzing the test system to establish bases for comparison…commonly referred to as positive control or an analytical standard

11. Subpart A: General Provisions 58.3 Study Dates Study Initiation Date: date protocol is signed by the Study Director Study Completion Date: date final report is signed by the Study Director Experimental Start Date: first date the test substance is administered/ applied to the test system Experimental Completion Date: lastdaydata are collected for the study

12. Subpart A: General Provisions 58.3 Specimen: any material derived from a test system for examination or analysis Sample: a portion of the test, control or reference material Batch: a specific quantity or lot of a test, control or reference material Vehicle: an agent which facilitates the mixture, dispersion or solubilization of a test substance with a carrier Carrier: the material with which the test substance is combined for administration to the test system

13. Subpart A: General Provisions 58.3 Archives: Area used for the orderly storage and expedient removal of all raw data, documentation, protocols, specimens, and interim and final reports.

14. Subpart A: General Provisions 58.3 Raw Data: Any laboratory worksheets, records, memoranda, notes, or exact copies, that are the result of original observations and activities of a study and are necessary for the reconstruction and evaluation of the report of study

15. Subpart A: General Provisions 58.10 Applicability to studies performed under grants and contracts: When a sponsor conducting a nonclinical laboratory study intended to be submitted to or reviewed by the FDA……it shall notify the consulting laboratory, contractor or grantee that the service is part of a nonclinical laboratory study that must be conducted in compliance with section 58.15….

16. Subpart A: General Provisions 58.15 Applicability to studies performed under grants and contracts: (a) A testing facility shall permit an authorized employee of the FDA, at reasonable times in a reasonable manner to inspect to copy records …..regarding the studies with in the scope of part 58

17. Subpart A: General Provisions 58.15 Applicability to studies performed under grants and contracts: (b) The FDA will not consider a non-clinical laboratory study in support of an application for research or marketing permit if the testing facility refuses to permit inspection.

18. Subpart B Organization/Personnel58.29 Personnel • Each individual engaged in the conduct of or responsible for the supervision of a nonclinical laboratory study shall have education, training, and experience, or combination thereof, to enable that individual to perform the assigned functions. • Training Records

19. Subpart B Organization/Personnel58.29 Personnel • (b) Each testing facility shall maintain a current summary of training and experience and job descriptions for each individual engaged in or supervising the conduct of a nonclincal laboratory study. • Maintain Training Records and Job Descriptions

20. Training Records CV/Education summary GLP training certificates Professional meetings attended Campus/industry certificates Chemical safely Animal Care Radiation Safety Proficiency on methods required by protocol and SOPs

22. Subpart B Organization/Personnel58.29 Personnel • (c) There shall be a sufficient number of personnel for the timely and proper conduct of the study according to the protocol. • (d) Personnel shall take necessary personal sanitation and health precautions designed to avoid contamination of test and control articles and test systems. • (e) Personnel engaged in a nonclinical laboratory study shall wear clothing appropriate for the duties they perform. Such clothing shall be changed as often as necessary to prevent microbiological, radiological, or chemical contamination of test systems and test and control articles.

23. Subpart B Organization/Personnel58.29 Personnel • (f) Any individual found at any time to have an illness that may adversely affect the quality and integrity of the nonclinical laboratory study shall be excluded from direct contact with the test systems, test and control articles and other operations or function that may adversely affect the study until the condition is corrected. All personnel shall be instructed to report to their immediate supervisors any health or medical conditions that may reasonably be considered to have an adverse effect on a nonclinical laboratory study.

24. Subpart B: Organization and Personnel 58. 31 Testing Facility Management For each nonclinical laboratory study management [OVPR] shall: (a) Designate a study director before the study is initiated (b) Replace the study director promptly if it becomes necessary to do so during the study (c) Assure that there is a quality assuranceunit (d) Assure that personnel, resources, facilities, equipment, materials and methods are available

25. Subpart B: Organization and Personnel 58. 31 ….Continuation… (f) Assure that personnel clearly understand the functions they are to perform (g) Assure that any deviations from these regulation reported by the quality assurance unit are communicated to the study director and corrective actions are taken and documented

26. Management Organizational Chart, University of Arizona 21 CFR 58 Compliance

27. Subpart B Organization/Personnel58.33 Study director • For each nonclincal laboratoty study, a scientist or other professional of appropriate education,training, and experience, or combination thereof, shall be identified as the study director. The study director has overall responsibility for: • the technical conduct of the study • interpretation • analysis • documentation • reporting of results ……

28. Subpart B Organization/Personnel58.33 Study director • …….represents the single point of study control • The study director shall assure that: • (a) The protocol, including any change, is approved • (b) All experimental data, including observations of unanticipated responses of the test system are accurately recorded and verified.

29. Subpart B Organization/Personnel58.33 Study director • (c) Unforeseen circumstances that may affect the quality and integrity of the nonclinical laboratory study are noted when they occur, and corrective action is taken and documented. • (d) Test systems are as specified in the protocol. • (e) All raw data, documentation, protocols, specimens, and final reports are transferred to the archives during or at the close of the study

30. Subpart B Organization/Personnel58.35Quality Assurance Unit • Responsible for monitoringeachGLPstudy to assure management that the following: • facilities • equipment • personnel • methods • practices • records • controls • are in conformance with the regulation in 21 CFR 58 and 40 CFR 160.

31. Subpart B Organization/Personnel58.35Quality Assurance Unit • Quality Assurance Officer is responsible to: • Maintain a copy of the Master Schedule of all studies conducted at the testing facility • Maintain copies of all protocols • Inspect each study at intervals to assure the integrity of the study • Immediately report any problems likely to affect study integrity to management and study director

32. Subpart B Organization/Personnel58.35Quality Assurance Unit • Quality Assurance Officer is responsible to: • Maintain written and properly signed records of each periodic Inspection • Date of Inspection • Study inspected • Phase or segment inspected • Findings and problems • Action recommended and taken to resolve existing problems • Scheduled date for re-inspection

33. Subpart B Organization/Personnel58.35Quality Assurance Unit • Quality Assurance Officer is responsible to: • Review the final study report to assure that such report accurately: • describes the methods and SOPs • and that the reported results accurately reflect the raw data • Prepare and sign a statement to be included with the final study report which shall specify the dates inspections were made

34. Examples of Quality Assurance • Assuring protocols are followed • Assuring SOPs are followed • Assuring deviations are documented and reported • Assuring personnel are properly trained • Assuring equipment calibration meets SOP requirements and documented • Assuring that equipment is as specified in the protocol.

35. Examples of Quality Assurance • Assuring dosing/application rates as specified • Assuring problems are reported to management and study director immediately • Assuring study events are adequately documented • Assuring management that systems are functioning as intended

36. Everyone bears responsibility for compliance • Management • Study Director • Study Facilitates • Quality Assurance

37. Subpart C: Facilities • 58.43 Animal Care Facilities • (a) A testing facility shall have a sufficient number of animal rooms or areas, as needed, to assure proper: • isolation of individual projects • quarantine of animals and • routine or specialized housing of animals • separation of species or test systems

38. Subpart C: Facilities • 58.43 Animal Care Facilities • (b) A testing facility shall have a number of animal rooms or areas or areas separate to ensure isolation of studies being done with test systems or test and control articles known to be bio-hazardous, including volatile substances, aerosols, radioactive materials, and infectious agents.

39. Subpart C: Facilities 58.43 Animal Care Facilities (c) Separate areas shall be provided, as appropriate for the diagnosis, treatment, and control of laboratory animal diseases. These areas shall provide effective isolation for the housing of animals either known or suspected of being diseased, or of being carriers of disease, from other animals.

40. Subpart C: Facilities 58.43Animal Care Facilities (d) When animals are housed, facilities shall exist for the collection and disposal of all animal waste and refuse or for safe sanitary storage of waste before removal from the testing facility. Disposal facilities shall be so provided and operated as to minimize vermin infestation, odors, disease hazards, and environmentalcontamination.

41. Subpart C: Facilities • 58.47Facilities for handling test and control articles • (a) Separate areas for: • Receipt and storage of the test and control articles • Mixing of the test and control articles with a carrier • Storage of the test and control article mixtures

43. Subpart C: Facilities 58.47Facilities for handling test and control articles (b) Storage areas for the test and/or control articles and test and control mixtures shall be separate from housing the test systems and shall be adequate to preserve the identity, strength, purity, and stability of the articles and mixtures

44. Subpart C: Facilities 58.49Laboratory Operation Areas Separate laboratory space shall be provided for the performance of the routine and specialized procedures required by nonclincal laboratory studies

45. Subpart C: Facilities 58.51Specimen and Data Storage Space shall be provided for archives, limited access by authorized personnel, for the storage and retrieval of all raw data and specimens from completed studies

46. Subpart D: Equipment 58.61 Equipment design Equipment used in the generation, measurement, or assessment of data and equipment used for facility environmental control shall be of appropriate design and adequate capacity to function according to the protocol and shall be suitably located for operation, inspection, cleaning and maintenance.

47. Subpart D:Equipment • 58.63 Maintenance and calibration of equipment • Equipment shall be adequately inspected, cleaned and maintained. Equipment used for the generation, measurement, or assessment of data shall be adequately tested, calibrated and or standardized. • SOPs shall describe methods, materials and schedules to be used in the routine inspection, cleaning, maintenance, testing, calibration …and designate the person responsible for the performance of each operation

48. Subpart D:Equipment 58.63 Maintenance and calibration of equipment (c) Written records shall be maintainedof all inspection, maintenance, testing, calibration, and/or standardizing operations.

49. Subpart E: Testing Facilities Section 58.81 Standard Operating Procedures [SOPs]

50. Subpart E: Testing Facilities • Section 58.81 • Standard Operating Procedures [SOPs] • (a) A testing facility shall have standard operating procedures in writing setting forth nonclinical laboratory study methods that management is satisfied are adequate to insure the quality and integrity of the data generated in the course of study. • All deviations in a study from the SOPs shall be authorized by the study director and shall be documented in the raw data. • Significant changes in established SOPs shall be properly authorized in writing by the management.