Good Manufacturing Practices (GMP), Good Laboratory Practices (GLP) and Good Tissue Practices (GTP)

1. Good Manufacturing Practices (GMP), Good Laboratory Practices (GLP) and Good Tissue Practices (GTP) Richard E. Giles, Ph.D. Associate Professor Regulatory Affairs Institutional Compliance Office

2. What? GLPs, GMPs & GTPs General Definitions Scope & Details Who? Users Oversight Why? Need Based Origin Ethical Requirements Statutory Requirements Institutional Impacts Where? Applicability in Processes Institution/Sponsors/ & Outside Providers When? Project/Program Stage Key Milestones How? Tasks Personnel Resources The Questions

3. What Are They? Regulatory Requirements for the Manufacture and Testing of Drugs, Biological Products, Human Cells & Human Tissues and Devices.

4. What are GLPs? • GLPs describe good laboratory practices for conducting non-clinical laboratory studies that support or are intended to support applications for research or marketing permits for products regulated by the FDA. 21 CFR Part 58. • Compliance with GLPs is intended to assure the quality and integrity of the safety data filed pursuant to the Food, Drug and Cosmetic Act and sections of the Public Health Service Act. • Applicable to drugs, biologicals, devices, INDs (Investigational New Drug application) & IDEs (Investigational Device Exemption). • Compliance with GLPs not required for research outside the regulatory scope of the FDA. • Requirements for CLIA (Clinical Laboratory Improvement Act) Compliance, CAP (College of America Pathologist) Compliance and FACT (Foundation for the Accreditation of Cellular Therapies) Accreditation are similar in many aspects to GLPs.

5. What Are GMPs? • Good Manufacturing Practices are defined in 21 CFR for Drugs and Pharmaceuticals in parts 210 & 211 and for Biologicals in parts 600-680. • Overlapping requirements occur. • GMPs pertain to the minimum current good manufacturing practice for preparation of drug products for administration to humans or animals or for preparation of biological products for administration to humans. • There are overlaps between GMPs, GTPs and FACT requirements.

6. What are GTPs? • The FDA has defined Good Tissue Practices for Human Cells, Tissues, and Cellular and Tissue-Based Products for the Prevention of the Introduction, Transmission, or Spread of Communicable Diseases. • Definition: HCT/P = ‘‘human cells, tissues, or cellular or tissue-based products.’’ • 1270—Human Tissue Intended for Transplantation. • 1271—Human Cells, Tissues, & Cellular and Tissue-Based Products.

7. A Process View of GLPs, GMPs & GTPs

10. Applicability of GLPs, GMPs, and GTPs in Health Care & Clinical Research Institutions • Blood, Bone Marrow & Tissue Collection and Processing for Use in Human Recipients. • + FACT, CAP & CLIA • Clinical Trials • In-House Manufacturing. • Contract Manufacturing. • Pharmaceutical Operations • Laboratory Medicine & Medical Diagnostics (CAP & CLIA) • Standard Diagnostic Tests • Standard Infectious Agents Tests • Custom Testing Services • Production of Imaging Agents

11. Who is Responsible for GLPs, GMPs & GTPs? • Institutional components performing tasks covered by GLPs, GMPs & GTPs • Institutional components performing oversight tasks • Compliance Office • Office or Regulatory Affairs • IRBs • Office of Research Administration

12. Origin of GLPs, GMPs & GTPs

13. FDA's Mission Statement • #1 The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation. • #2 The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health.

14. FDA Critical Path for Medical Product Development FDA: Challenge and Opportunity on the Critical Path to New Medical Products, March 2004 Modified

15. Objectives address basic questions about function test hypotheses & therapeutic approaches Sources & Quality of Materials may use uncharacterized outside materials partial or minimal characterization Minimal Use of Characterized Lab Reference Banks Scale & Systems: small to medium Limited repertoire of QC tests Facilities & Equipment capable of GLP work. Performance & Validation inconsistent Personnel training & experience in GLP variable; GMP very limited Objectives. produce FDA qualified materials for phase I-III trials. Sources & Quality of Materials. outside materials completely characterized & qualified prior to use in production. Establishment & Maintenance of Well Characterized Reference Banks. Scale & Systems: small through large. Extensive in house repertoire of QC tests QA oversight. Facilities & Equipment Validated for GMP work. Personnel trained in GLP & GMP. Preclinical Versus Clinical Production

16. Modified from Zoon FDA jhu 99 Centers in the FDA • Center for Biologics Evaluation and Research • Center for Drug Evaluation and Research • Office of Regulatory Affairs • Center for Devices and Radiological Health • Center for Food Safety and Applied Nutrition • Center for Veterinary Medicine • National Center for Toxicological Research

17. Combination Products • Combination products are assigned to a Center for review and regulation in accordance with the products' primary mode of action. • When a product's primary mode of action is attributable to a type of biological product assigned to CDER, the product will be assigned to CDER. • Similarly, when a product's primary mode of action is attributable to a type of biological product assigned to CBER, the product will be assigned to CBER.

18. Useful Terms • Adventitious Microbial Agents: Agents such as bacteria, fungi, mycoplasma, or viruses not an integral part of a material that may be present as chance contaminants; extrinsic. • Gene Transfer Vector (used herein as “vector”): A vehicle composed of DNA (or RNA) for transferring a gene or other nucleic acid sequence of interest; frequently based on viruses, bacteriophage or bacterial plasmids. May be replication defective or competent. • Gene Therapy: Transfer of a gene or other nucleic acid sequence by means of a “vector” into a patient to obtain a therapeutic effect. • Transduce/Transduction: Transfer of a gene or nucleic acid sequence into a target cell or organism. • Monoclonal Antibody: An antibody preparation of uniform composition and specificity produced from a single cell origin “clone” of an antibody producing cell.

19. Historical Background

20. PolioDisease Incidence ~ 0.03%, 1953 National Foundation Field Trial: Largest and Most Comprehensive Test of a Medical Product "The Cutter Incident", Paul A. Offit, M.D., Yale Univ. Press, 2005

21. Polio Epidemics "The Cutter Incident", Paul A. Offit, M.D., Yale Univ. Press, 2005

22. National Foundation Field Trial Salk Vaccine • 420,000 children; Salk vaccine (Parke-Davis & Eli Lilly). 200,000 placebo. 1.2 million, nothing. Total 1.8 million. • 20,000 physicians & health officers; 40,000 registered nurses; plus 264,000 volunteer principals, teachers & citizens. Cost $7.5 M; today $ 5 B? "The Cutter Incident", Paul A. Offit, M.D., Yale Univ. Press, 2005

23. Polio Vaccinations "The Cutter Incident", Paul A. Offit, M.D., Yale Univ. Press, 2005

24. National Foundation Field TrialResult: Salk Vaccine • 16 children died of polio, none of whom received Salk vaccine. • 36 children developed severe polio (iron lung required) only two of whom received Salk vaccine. • Children who did not receive Salk vaccine were 3.3 times as likely to be paralyzed as vaccine recipients. • No polio cases were specifically associated with Salk vaccine. "The Cutter Incident", Paul A. Offit, M.D., Yale Univ. Press, 2005

25. National Foundation Field TrialLicensing & Distribution: Salk Vaccine • Results announced the morning of April 12, 1954 Ann Arbor, Michigan. • HEW Secretary Hobby signed licenses April 12, 1954, 5:15 pm for Parke-Davis; Eli Lilly; and three additional companies that had submitted prior samples of vaccine (Pitman-Moore, Wyeth & Cutter). • Vaccines shipped shortly thereafter from 13 lots approved by the Laboratory of Biologics Control. Overall, forty lots of approximately 5 M doses distributed. "The Cutter Incident", Paul A. Offit, M.D., Yale Univ. Press, 2005

26. Polio Among Recipients of Licensed Vaccine Lots • April 25, 1954, reports of polio among vaccine recipients begin. 6 cases of paralysis reported by 4/26 received vaccine from the same manufacturer, Cutter. • Cutter recalls vaccine 4/27. • Langmuir study follow-up. • 57 Children paralyzed; 5 died. • Vaccine induced disease more likely to be severe. • Infection of family & other contacts. • Estimates based on Shaw study in Idaho (per Offit) of Cutter lots with residual live virus • 200,000 infected. • 70,000 develop muscle weakness. • 164 severe paralysis. • 10 deaths. • Note: Wyeth also made vaccine that caused paralysis (lower frequency of contaminated lots) "The Cutter Incident", Paul A. Offit, M.D., Yale Univ. Press, 2005

27. Problem Areas • Mahoney Strain of Type 1 Polio (Highly pathogenic) • Good representative of a “hot” virus strain for a protective immune response. • Bad if inactivation is incomplete. • Filtration • Seitz vs. Porous Glass. • Change in Quality of Porous Glass Filters. Due to change in staff (one key retirement). • Safety Tests • Cell Culture. Sample volume (0.1% of final vaccine). • Monkey. Subsequent studies revealed that cortisone treated monkeys demonstrated live virus in Cutter samples previously tested in monkeys without steroid. Inoculation into the spinal cord found to be 500 fold more sensitive for detecting live virus. • Bulk Intermediate Storage • Salk’s lab treated with formaldehyde within days of filtration. • Cutter often stored for weeks or sometimes months before inactivation. • Viral particle clumping over time. • Inactivation Kinetics • Salk recommended at least four sampling time points, with the last negative for virus. Total time of formaldehyde exposure = 3 x the time to reach the no detectable virus level. • Eli Lilly & Parke-Davis, six time points. • Cutter never determined when live virus FIRST eliminated. Disregard of Salk’s inactivation theory. • Inactivation Difficulties • Cutter never acknowledge difficulties in obtaining consistent inactivation (9 of 27 lots failed). • National Foundation selected Eli Lilly & Parke-Davis because they were the only companies to make at least 11 consecutive lots passing safety tests. "The Cutter Incident", Paul A. Offit, M.D., Yale Univ. Press, 2005

28. Inactivation Kinetics Four Point Linearity In the Observable Region + Linear Extrapolation. Four Point Linearity In the Observable Region Requirement Not Followed by Cutter "The Cutter Incident", Paul A. Offit, M.D., Yale Univ. Press, 2005

29. Adventitious Agents • SV40 in Polio • An “adventitious viral agent”. Was present in monkey kidney cells used to grow polio virus. • Found in both Salk & Sabin Vaccines, 1955-1963. • SV40 is more resistant to formaldehyde inactivation. • IOM Report 10/22/02. • Studies of groups of people who received polio vaccine during 1955-1963 provide evidence of no increased cancer risk. • However, because these epidemiologic studies are sufficiently flawed, the committee concluded in this report that the evidence was inadequate to conclude whether or not the contaminated polio vaccine caused cancer. In light of the biological evidence supporting the theory that SV40-contamination of polio vaccines could contribute to human cancers, the committee recommends continued public health attention in the form of policy analysis, communication, and targeted biological research. • CDC • Over 98 million Americans received one or more doses of polio vaccine during the period (1955-1963) when some of the vaccine was contaminated with SV40. SV40 has been found in certain types of human cancers, but it has not been determined that SV40 causes these cancers. The majority of evidence suggests there is no causal relationship between receipt of SV40-contaminated vaccine and cancer; however, some research results are conflicting and more studies are needed. • Qualification of MCBs & MSVs are Important!

30. GLPs & GMPs Basic Components

31. FDA Documents • Code of Federal Regulations. • Compliance Required. • Revisions & New Regulations Published in the Federal Register in draft version for comments before a Final Rule is Issued. • Guidance Documents. • Published initially on CBER & CDER web page for comments. • “… draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the appropriate FDA staff.” • Do not establish legally enforceable responsibilities. • Viewed as recommendation unless regulatory or statutory requirement cited. • Points to Consider. • Replaced by Guidance Documents. • Still relevant for understanding FDA/CBER positions.

32. FDA Regulations: INDs & Clinical Trials • 21 Code of Federal Regulations (CFR) Part 58 • Good Laboratory Practices (GLP) • 21 Code of Federal Regulations (CFR) Part 210-211 • Good Manufacturing Practice (GMP) • 21 Code of Federal Regulations (CFR) Part 1270-1271 • Good Tissue Practices (GTP) • 21 Code of Federal Regulations (CFR) Parts 50, 56 & 312 • Good Clinical Practices (GCP) • Protection of Human Subjects, Part 50 • Informed Consent Requirements, Part 50 • IRB functions & responsibilities, Part 56 • Investigational New Drug Application (IND), Part 312. General Provisions; Application Content & Format; Administrative Actions; Responsibilities of Sponsors & Investigators

33. Modified from Zoon FDA jhu 99 Other Relevant Regulations for Title 21, Code of Federal Regulations (CFR) • Parts 600 - 680 – Biologics • Part 820 - Quality System Regulation • Part 25 - Environmental Assessments • Part 201, 202 - Labeling & Advertising • Part 800 - In Vitro Diagnostics

34. GLPs Organization & Personnel Facilities Equipment Testing Facilities Operation Test and Control Articles Protocol for and Conduct of a Nonclinical Laboratory Study Records and Reports GMPs Organization & Personnel Buildings & Facilities Equipment Control of Components, Containers & Closures Production & Process Control Holding & Distribution Laboratory Controls Records & Reports Returned & Salvaged Products What Is Covered in GLPs & GMPs?

35. Organization and Personnel Personnel. Testing facility management. Study director. Quality assurance unit. Facilities General. Animal care facilities. Animal supply facilities. Facilities for handling test and control articles. Laboratory operation areas. Specimen and data storage facilities. Equipment Equipment design. Maintenance and calibration of equipment. Testing Facilities Operation Standard operating procedures. Reagents and solutions. Animal care. Test and Control Articles Test and control article characterization. Test and control article handling. Mixture of articles with carriers. Protocol for and Conduct of a Nonclinical Laboratory Study Protocol. Conduct of a Nonclinical laboratory study. Records and Reports Reporting of nonclinical laboratory study results. Storage and retrieval of records and data. What Is Covered in GLPs?

36. Organization & Personnel QC Unit Responsibilities Personnel Qualifications Personnel Responsibilities Buildings & Facilities Design & Construction Lighting Ventilation, Air Filtration, Heating & Cooling Plumbing Equipment Design, Size, Location, Construction, Cleaning, Maintenance Validation Control of Components, Containers & Closures Receipt & Storage Untested Materials Testing & Approval/Rejection Use of Approved Materials Production & Process Control Written Procedures, Deviations Yield Calculation Equipment Identification Sampling & Testing of In-process Materials Sterility Reprocessing What Is Covered in GMPs?

37. Packaging & Labeling Materials & Usage Issuance Operations Expiration Dating Holding & Distribution Laboratory Controls Protocols & SOPs Drafted by the Appropriate Unit & Approved by QC Unit Documentation at the Time of Performance Any Deviations Documented and Justified Conformance to Written Specifications for Acceptability Laboratory Controls Description of Sampling Procedure In-Process Testing Instrument & Apparatus Calibration & Validation Testing & Release Stability Testing Special Testing Reserve Samples Animals Penicillin Contamination Records & Reports Returned & Salvaged Products What Else Is Covered by GMPs?

38. Quality Assurance (QA) • Quality Assurance • Process of monitoring a study to assure management that the facilities, equipment, personnel, methods, practices, records and controls are in accordance with applicable regulations • QA units typically report directly to senior management and not through Production Units or QC Units • QA units for Clinical Trials report directly to senior management

39. GLP QA • Master Schedule Sheet (test article; test system; nature of study; date initiated; current status; sponsor; study director) • Maintenance of Protocols • Lab Inspections • Study Status Reports • Deviations from Protocols or SOPs • Review & Sign Final Study Report

40. Quality Control (QC) I • Quality Control is the process, procedures and authority used to accept or reject all components, drug product containers, closures, in-process materials, packaging material, labeling and drug products and the authority to review production records to assure that no errors have occurred, or if errors have occurred, that they have been fully investigated.

41. Quality Control II • QC unit has responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality and purity of the drug product • QC testing of ingredients, MCBs, MSV, Production Cells, Production Virus, In-Process Materials and Final Container Samples

42. Quality Control III • QC unit tests are used for Lot Release documentation and preparation of Certificates of Analysis (CoAs). • QC units typically report directly to senior management and not through the Production Unit.

44. Criteria for Biologics & Drugs • Safety • Identity • Potency/Strength • Purity/Quality Efficacy

45. Production Process

46. Lab Stocks of Vectors and Producer Cells Reference stocks of vectors and cells Screen reference stocks for identity and adventitious agents Produce Master Cell Bank (MCB) Characterize & Qualify MCB Produce Master Virus Bank (MVB) Characterize & Qualify MVB Produce Working Cell Bank (WCB) Characterize & Qualify WCB Produce Working Virus Bank (WVB) Characterize & Qualify WVB Produce Production Cells Produce Seed Virus Produce a Production Serial Produce Bulk Harvest Qualify Bulk Harvest Processing/Purification of Bulk Harvest Fill Product in Final Containers QC Testing of Bulk & Final Container Samples Completion of QA Completion of Lot Release Documents & Review Lot Release Production Stages

47. Project Management for GMP Gene Therapy Vector Production Replication Defective Adenovirus Vector AdRB94

48. Project Flow Chart

49. AdRB94 Task List & Gantt Chart: Critical Tasks

50. 1 Form 1571 2 Table of Contents 3 Introductory Statement & General Investigational Plan 4 Reserved 5 Investigator’s Brochure 6 Protocol 7 Chemistry, Manufacturing & Control Information 8 Pharmacology & Toxicology 9 Previous Human Experience with the Investigational Drug 10 Additional Information Appendices Investigational New Drug (IND) Applications (21 CFR 312)