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
The Questions

• 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

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.
• 1270Human Tissue Intended for Transplantation.
• 1271Human Cells, Tissues, Cellular and
  Tissue-Based Products.

7
A Process View of GLPs, GMPs GTPs
8
(No Transcript)
9
(No Transcript)
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
  nations 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
Preclinical Versus Clinical Production

• 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.

16
Centers in the FDA
Modified from Zoon FDA jhu 99

• 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
Polio Disease 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, 515 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
• Salks 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 Salks inactivation
  theory.
• Inactivation Difficulties
• Cutter never acknowledge difficulties in
  obtaining consistent inactivation (9 of 27 lots
  failed).

"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 Administrations (FDAs)
  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
Other Relevant Regulations for Title 21, Code of
Federal Regulations (CFR)
Modified from Zoon FDA jhu 99

• Parts 600 - 680 Biologics
• Part 820 - Quality System Regulation
• Part 25 - Environmental Assessments
• Part 201, 202 - Labeling Advertising
• Part 800 - In Vitro Diagnostics

34
What Is Covered in GLPs GMPs?

• 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

35
What Is Covered in GLPs?

• 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.

36
What Is Covered in GMPs?

• 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

37
What Else Is Covered by GMPs?

• 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

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.

43
(No Transcript)
44
Criteria for Biologics Drugs

• Safety
• Identity
• Potency/Strength
• Purity/Quality Efficacy

45
Production Process
46
Production Stages

• 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

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
Investigational New Drug (IND) Applications (21
CFR 312)

• 1 Form 1571
• 2 Table of Contents
• 3 Introductory Statement General
  Investigational Plan
• 4 Reserved
• 5 Investigators Brochure
• 6 Protocol

• 7 Chemistry, Manufacturing Control Information
• 8 Pharmacology Toxicology
• 9 Previous Human Experience with the
  Investigational Drug
• 10 Additional Information
• Appendices

51
Interaction With Commercial SponsorsTypes of
Interactions

• Commercial Sponsor holds the IND
• Commercial Sponsor and Performing Institution(s)
  develop a sponsored research agreement
• Typically the commercial sponsor provides the
  required support commercial sponsor provides
  partial support, e.g. drugs and/or materials
• Institutional IND
• Commercial Sponsor
• Government Grant
• Foundation Support
• Institutional Support
• Mixed Sources

52
Contract Manufacturing Testing

• Evaluate the Contractors Capabilities.
• Compliance with GLPs and GMPs.
• Documentation.
• Testing SOPs Procedures.
• Scheduling Capabilities.
• Updates on tests in progress and tests scheduled.
• FDA track records and records of FDA actions
  concerning the contractor. FDA Form 483s.

53
GMPs for Phase I and Exploratory INDs

• Challenge Opportunity on the Critical Path to
  New Medical Products. http//www.fda.gov/oc/initia
  tives/criticalpath/whitepaper.html
• GMP for Phase I.
• Exploratory INDs.
• Science is rapidly coming to understandings of
  the genetic and molecular mechanisms of not just
  a disease like cancer, but diabetes,
  cardiovascular disease, and on and on. As that
  rapid scientific discovery is occurring, the FDA
  is committed to facilitating the rapid
  translation and the development of that knowledge
  into the development of new drugs or treatments
  that are going to alleviate those diseases. But
  rapid does not mean reckless. There is no
  compromise in the rigor of the clinical trials
  process, no compromise in the rigor of laboratory
  testing and animal testing, or on the standards
  that will be applied. Remarks by Andrew C.
  von Eschenbach, M.D., Acting Commissioner of Food
  and Drugs, Thursday, January 12, 2006

54
Topics

• 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

55
Where Do I Go From Here?

• Define Your Needs
• Consult the References Section Relevant Web
  Pages
• Review Your Institutional Supporting Offices
• Consult with Professional Colleagues

56
Internet References

• Code of Federal Regulations, http//www.gpoaccess.
  gov/cfr/index.html
•  Federal Register, http//www.gpoaccess.gov/fr/ind
  ex.html
•  FDA, http//www.fda.gov/
•  CBER, http//www.fda.gov/cber/index.htmlntations
  , http//www.fda.gov/cber/summaries.htm
• CBER Guidelines, http//www.fda.gov/cber/guideline
  s.htm
• FDA Guidance for HGT http//www.fda.gov/cber/gdlns
  /somgene.pdf
• Warning Letters, http//www.fda.gov/cber/efoi/warn
  ing.htm
•  International Conference on Harmonization (ICH),
  http//www.ich.org/cache/compo/276-254-1.html
• FDA Challenge Opportunity on the Critical Path
  to New Medical Products. http//www.fda.gov/oc/ini
  tiatives/criticalpath/whitepaper.html

• US Office of Public Health and Science,
  http//phs.os.dhhs.gov/ophs/ Gene Therapy  Links,
  http//www3.mdanderson.org80/depts/genetherapy/li
  nks.html
• National Gene Vector Laboratories,
  http//www.ngvl.org/facilities.php?facilityiu
• Biosafety in Microbiological Biomedical
  Laboratories, http//www.cdc.gov/od/ohs/biosfty/bi
  osfty.htm
• CDC, http//www.cdc.gov/
• Foundation for the Accreditation of Hematopoietic
  Cell Therapy (FAHCT), http//www.unmc.edu/Communit
  y/fahct/Home_Page.htm
• American Association of Blood Banks,
  http//www.aabb.org/
• NIH, http//www.nih.gov/
• Office of Biotechnology Activities (OBA formerly
  NIH-RAC),
• http//www4.od.nih.gov/oba
• NIH Guidelines, http//www4.od.nih.gov/oba/rac/gui
  delines/guidelines.html  US Dept of Health
  Human Services http//www.os.dhhs.gov/
• Office for Human Research Protections (OHRP),
  http//ohrp.osophs.dhhs.gov/

57
Discussion Topics

• GMPs for Phase I Clinical Trials
• How much GLP GMP do I need at my institution?
• What can I do in-house what to I contract?

58
Interaction with Commercial Contractors or
Sponsors

• Scientific, Clinical Commercial Objectives
• Project Planning Management
• Protocol Development
• Budget Development
• Sponsored Research Agreement
• Regulatory Documents Approvals
• Development of Written Implementing Protocols,
  SOPs, Testing Procedures and Assay Procedures
• Validation of All Protocols, Tests Assays and
  Reference Standards for Tests Assays