1. Catalyzing Collaboration January 13. 2011 WORKSHOP 2: Optimizing Academic Labs to Encourage Industry Relationships Ann V. LeFever, Ph.D. LeFever Consulting alefever1@hotmail.com 262-853-3538

2. Good Laboratory Practice for Nonclinical Laboratory StudiesTitle 21 Code of Federal Regulations Part 58 The goal is to demonstrate SAFETY of test article before use in humans Do controlled, well-documented laboratory studies Use prospective and approved protocols Document testing methods and findings Provide Quality Assurance review

3. Organization of GLPsTitle 21 Code of Federal Regulations Part 58http://www.21cfrpart11.com/files/library/pred_rules/mcdowall_glp_annotate.pdf GLP Subpart A –– GENERAL PROVISIONS GLP Subpart B –– ORGANIZATION AND PERSONNEL GLP Subpart C –– FACILITIES GLP Subpart D –– EQUIPMENT GLP Subpart E –– TESTING FACILITIES OPERATION GLP Subpart F –– TEST AND CONTROL ARTICLES GLP Subpart G –– PROTOCOL FOR AND CONDUCT OF STUDY GLP Subparts H-I –– [RESERVED] GLP Subpart J –– RECORDS AND REPORTS GLP Subpart K –– DISQUALIFICATION OF TESTING FACILITIES

4. The 10 Commandments of GLP Thou shalt appoint study directors and quality assurance Thou shalt be competent, as a result of education, training and experience Honor thy protocol and thy SOPs Thou shalt conduct studies in adequate and clean facilities Thou shalt identify test and control articles and document their use

5. The 10 Commandments of 6. Thou shalt maintain and calibrate equipment according to a specified schedule 7. Thou shalt document and correct all deviations 8. Thou shalt not commit fraud; all thy work thou shalt note, sign and date 9. Thou shalt have archives 10.Thou shalt not turn your back on the FDA

6. Fundamentals of GLP Resources: organization, personnel, facilities & equipment Rules: protocols and written procedures Characterization: test items & test systems Documentation: raw data, final report & archives Quality assurance unit

7. ResourcesOrganization & Personnel The structure of the research organization and the responsibilities of the research personnel must be clearly defined Staffing levels must be sufficient to perform the tasks required & the qualifications and training of staff must be defined and documented

8. Resources Facilities & Eequipment Facilities and equipment must be sufficient to perform the studies of the laboratory All equipment must be in working word & a strict program of qualification, calibration and maintenance must be enforced

9. RulesProtocols & Written Procedures The main steps of research studies must be described in the study plan or protocol The specific details on the activities required to achieve the data in the study plan is described in written standard operating procedures (SOPs). Techniques used should be standardized & validated

10. Characterization The materials used during the study should be fully characterized Material information including vendor, lot number, specification, certificate of analysis, expiration date, etc. must be documented in each research experiment conducted

11. Documentation If an activity is not documented --- it never happened!

12. Documentation Raw data: represents the basis for establishing results and drawing conclusions. Must reflect the procedures and conditions of the study Final Report: The contents of the report describe the study accurately and includes the study director’s interpretation of the results Archives: Storage of records must ensure safekeeping for many years together with ability for prompt retrieval

13. Quality Assurance A team of staff members charged with assuring management that GLP compliance has been attained within the laboratory QA staff operate independently of the operational staff and function as witnesses to the whole pre-clinical research process

14. GLP Principles Main Goal – to help scientists obtain reliable, repeatable, auditable results that can be recognized by scientists worldwide The purpose is not to assess the intrinsic value of a study GLP principles are a set of organizational requirements

15. Goals of GLP Ensure efficient use of resources Ensure high quality results Ensure comparability of results Promote mutual recognition of results

16. Managerial Organizational Concepts for GLP Studies Performed Recorded Reported Archived Monitored Planned

17. §58.35 Quality Assurance Unit Duties QAU monitors each study to assure management that all systems are in conformance with GLP regulations QAU shall be entirely independent of personnel conducting a particular study

18. §58.35 Quality Assurance Unit (cont.) Duties The quality assurance unit shall: Maintain a master schedule sheet of all studies, indexed by test article and listing these elements: test system, nature of study, study initiation date, current status, sponsor identity, and name of the study director

19. §58.35 Quality Assurance Unit (cont.) Duties Maintain copies of all GLP protocols Inspect each nonclinical laboratory study at adequate intervals; maintain written signed records of periodic inspections Bring to the attention of the study director and management immediately any problems found during an inspection that may affect study integrity

20. §58.35 Quality Assurance Unit (cont.) Duties Periodically submit to management and to the study director written status reports on each study, noting problems and corrective actions taken Determine that no deviations from approved protocols or standard operating procedures were made without authorization and documentation

21. §58.35 Quality Assurance Unit (cont.) Duties Review the final study report to assure accuracy in description of methods and Standard Operating Procedures, and that results accurately reflect the raw data of the study Prepare and sign a statement specifying dates of inspections and when findings were reported to management and study director

22. The QAU SOPs (and related) Topics: GLP Training QA training within the GLP environment Structure of the QAU, e.g. Inspection group, archiving group, validation group QA Reporting Systems, e.g. To respond to QA findings To report to management (including trend analysis)

23. The QAU SOPs (and related) Topics (continued): Good documentation practices “Inspection” of computer systems QA Master Schedule Archiving procedures (including off site archiving) Disaster recovery plan Data Audit

24. Good Documentation Practice Documentation should permit the complete reconstruction of a study Record data directly, promptly and legibly in indelible ink (never pencil) Initial and date all observations and any resulting changes, but do not obscure original data Initial and date only work you’ve performed Do not document selectively or in advance of performing the activity

25. Good Documentation Practice Do not use white-out correction fluid or tape Do not use ditto marks as raw data Copy all heat sensitive paper and stamp “exact copy” Explain why any raw data not used was not used Verify critical calculations using a second person and document this Notebook pages requiring a second signature shall be completed with that signature

26. Good Documentation Practice Properly head all pages, tables, columns; identify units Describe Statistical & Calculation Procedures used Sign, Date, and File automated printouts (e.g., QC forms) Retain all Raw Data (original records) in the Study File Do not document by exception. Use positive documentation, even if only a check mark.

27. Good Documentation Practice Documentation must allow another person to be able to accurately reconstruct what you have done Keep all original observationsincluding those observations recorded directly into a computer Sign and date all computer printouts Never back-date anything Follow SOPs and Protocol

28. Good Documentation Practice Document all deviations with accompanying explanations Indicate in the record all applicable units and equipment used

29. Raw Data Correction All changes to raw data must be made without obscuring the original entry All changes must be initialed and dated by the person making the change, accompanied by an explanation for the change

30. Abbreviations for Reasons

31. Reference:Compliance Program Guidance for FDA Staff BIMO – Bioresearch Monitoring 7348.808 Good Laboratory Practice (Nonclinical Laboratories) – FDA version 7348.808A Good Laboratory Practice Program (Nonclinical Laboratories) – EPA Data Audit Inspection

32. Bottom Line… 7348.808 Good Laboratory Practice (Nonclinical Laboratories) is FDA’s instruction manual for its inspectors’: http://www.fda.gov/downloads/ICECI/EnforcementActions/BioresearchMonitoring/ucm133765.pdf

33. INSPECTIONALGeneral Instructions Determine the current state of GLP compliance by evaluating the laboratory facilities, operations, and study performance Organization Chart - If the facility maintains an organization chart, obtain a current version of the chart for use during your inspection

35. Identify any areas that are not used for GLP activities

37. SOP Evaluation (cont.) Verify that changes to SOPs are properly authorized and dated and that a historical file of SOPs is maintained Ensure that there are procedures for familiarizing employees with SOPs Determine that there are SOPs to ensure the quality and integrity of data, including input (data checking and verification), output (data control), and an audit trail covering all data changes

38. SOP Evaluation (cont.) Verify that a historical file of outdated or modified computer programs is maintained. If the firm does not maintain old programs in digital form, ensure that a hard copy of all programs has been made and stored. Verify that SOPs are periodically reviewed for current applicability and that they are representative of the actual procedures in use Review selected SOPs and observe employees performing the operation to evaluate SOP adherence and familiarity

39. Storage and Retrieval of Records Determine how and where computer data and backup copies are stored, that records are indexed in a way to allow access to data stored on electronic media, and that environmental conditions minimize deterioration

40. Assess the procedures by which the study director: Is assigned and replaced Assures the protocol and any amendments have been properly approved and are followed Assures that all data are accurately recorded and verified Assures that data are collected according to the protocol and SOPs

41. Assess the procedures by which the study director also: Documents unforeseen circumstances that may affect the quality and integrity of the study and implements corrective action Assures that study personnel are familiar with and adhere to the study protocol and SOPs Assures that study data are transferred to the archives at the close of the study

42. QAU Operations Ratio QA employees to all employees (5 to 8%) Review and verify QAU SOPs to assure that they cover all methods and procedures for carrying out the required QAU functions, and confirm that they are being followed: Maintenance of a master schedule sheet Maintenance of copies of all protocols and amendments Scheduling of its in-process inspections and audits

43. QAU Operations (cont.) Inspection of each nonclinical laboratory study at intervals adequate to assure the integrity of the study, and maintenance of records of each inspection Immediately notify the SD and management of problems likely to affect the INTEGRITY of the study Submission of periodic status reports on each study to the SD and management

44. QAU Operations (cont.) Review of the final study report Preparation of a statement to be included in the final report that specifies the dates inspections were made and findings reported to management and to the SD Inspection of computer operations Training

45. More scrutiny of QAU Verify that, for any given study, the QAU is entirely separate from and independent of the personnel engaged in the conduct and direction of that study Evaluate the time QAU personnel spend in performing in-process inspection and final report audits Determine if the time spent is sufficient to detect problems in critical study phases and if there are adequate personnel to perform the required functions

46. Facilities Document any conditions that would lead to contamination of test articles or to unusual stress of test systems Determine that computerized operations and archived computer data are housed under appropriate environmental conditions (e.g., protected from heat, water, and electromagnetic forces)

47. Equipment (other than computers) For representative pieces of equipment check the availability of the following: SOPs and/or operating manuals Maintenance schedule and log Standardization/calibration procedure, schedule, and log Standards used for calibration and standardization

48. Testing Facilities Operations Determine if the testing facility has established and follows written SOPs necessary to carry out study operations in a manner designed to ensure the quality and integrity of the data(including method validation) Determine if the testing facility has appropriate controlled storage for study samples Determine if the testing facility maintains and calibrates instrumentation as per SOPs

49. Test and Control Articles Characterization and Stability of Test Articles - The responsibility for carrying out appropriate characterization and stability testing may be assumed by the facility performing the study or by your company If you intend to perform the test article characterization and stability testing, verify that the test facility has the procedure in place to document that this testing will have been conducted according to GLP (or GMP)

50. Archiving Determine the number of archive locations – waterproof? Fireproof? Determine who is the individual assigned as archivist Verify method of indexing and the time period when documents/slides/computer data are archived after completion of the study

51. CONCLUSION! The basic concepts underlying quality systems are quite simple: Say what you do, do what you say, prove it and improve it Janet Woodcook, M.D. Director, Center for Drug Evaluation and Research FDA