Good Manufacturing Practices (GMP), Good Laboratory Practices (GLP) and Good Tissue Practices (GTP) - PowerPoint PPT Presentation

1 / 58
About This Presentation

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


Good Manufacturing Practices are defined in 21 CFR for ... National Foundation Field Trial Salk Vaccine 420,000 children ... General. Animal care ... – PowerPoint PPT presentation

Number of Views:7925
Avg rating:5.0/5.0
Slides: 59
Provided by: Richa162


Transcript and Presenter's Notes

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

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
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

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

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.

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

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.

A Process View of GLPs, GMPs GTPs
(No Transcript)
(No Transcript)
Applicability of GLPs, GMPs, and GTPs in Health
Care Clinical Research Institutions
  • Blood, Bone Marrow Tissue Collection and
    Processing for Use in Human Recipients.
  • Clinical Trials
  • In-House Manufacturing.
  • Contract Manufacturing.
  • Pharmaceutical Operations
  • Laboratory Medicine Medical Diagnostics (CAP
  • Standard Diagnostic Tests
  • Standard Infectious Agents Tests
  • Custom Testing Services
  • Production of Imaging Agents

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

Origin of GLPs, GMPs GTPs
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.

FDA Critical Path for Medical Product Development
FDA Challenge and Opportunity on the Critical
Path to New Medical Products, March 2004 Modified
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
  • 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
  • Facilities Equipment Validated for GMP work.
  • Personnel trained in GLP GMP.

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

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
  • 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.

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
  • Monoclonal Antibody An antibody preparation of
    uniform composition and specificity produced from
    a single cell origin clone of an antibody
    producing cell.

Historical Background
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
Polio Epidemics
"The Cutter Incident", Paul A. Offit, M.D., Yale
Univ. Press, 2005
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
Polio Vaccinations
"The Cutter Incident", Paul A. Offit, M.D., Yale
Univ. Press, 2005
National Foundation Field TrialResult Salk
  • 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
  • No polio cases were specifically associated with
    Salk vaccine.

"The Cutter Incident", Paul A. Offit, M.D., Yale
Univ. Press, 2005
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
  • Vaccines shipped shortly thereafter from 13 lots
    approved by the Laboratory of Biologics Control.
    Overall, forty lots of approximately 5 M doses

"The Cutter Incident", Paul A. Offit, M.D., Yale
Univ. Press, 2005
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
Problem Areas
  • Mahoney Strain of Type 1 Polio (Highly
  • 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
  • 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
  • Inactivation Difficulties
  • Cutter never acknowledge difficulties in
    obtaining consistent inactivation (9 of 27 lots

"The Cutter Incident", Paul A. Offit, M.D., Yale
Univ. Press, 2005
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
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
  • 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!

  • Basic Components

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
  • 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
  • Viewed as recommendation unless regulatory or
    statutory requirement cited.
  • Points to Consider.
  • Replaced by Guidance Documents.
  • Still relevant for understanding FDA/CBER

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
  • Good Tissue Practices (GTP)
  • 21 Code of Federal Regulations (CFR) Parts 50, 56
  • 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

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

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

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.

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,
  • 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 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
  • 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

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
  • QA units typically report directly to senior
    management and not through Production Units or QC
  • QA units for Clinical Trials report directly to
    senior management

  • 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

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.

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

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.

(No Transcript)
Criteria for Biologics Drugs
  • Safety
  • Identity
  • Potency/Strength
  • Purity/Quality Efficacy

Production Process
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
  • 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

Project Management for GMP Gene Therapy Vector
Replication Defective Adenovirus Vector AdRB94
Project Flow Chart
AdRB94 Task List Gantt Chart Critical Tasks
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

Interaction With Commercial SponsorsTypes of
  • 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

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.

GMPs for Phase I and Exploratory INDs
  • Challenge Opportunity on the Critical Path to
    New Medical Products. http//
  • 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

  • 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

Where Do I Go From Here?
  • Define Your Needs
  • Consult the References Section Relevant Web
  • Review Your Institutional Supporting Offices
  • Consult with Professional Colleagues

Internet References
  • Code of Federal Regulations, http//www.gpoaccess.
  •  Federal Register, http//
  •  FDA, http//
  •  CBER, http//
    , http//
  • CBER Guidelines, http//
  • FDA Guidance for HGT http//
  • Warning Letters, http//
  •  International Conference on Harmonization (ICH),
  • FDA Challenge Opportunity on the Critical Path
    to New Medical Products. http//
  • US Office of Public Health and Science,
    http// Gene Therapy  Links,
  • National Gene Vector Laboratories,
  • Biosafety in Microbiological Biomedical
    Laboratories, http//
  • CDC, http//
  • Foundation for the Accreditation of Hematopoietic
    Cell Therapy (FAHCT), http//
  • American Association of Blood Banks,
  • NIH, http//
  • Office of Biotechnology Activities (OBA formerly
  • http//
  • NIH Guidelines, http//
    delines/guidelines.html  US Dept of Health
    Human Services http//
  • Office for Human Research Protections (OHRP),

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?

Interaction with Commercial Contractors or
  • 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
Write a Comment
User Comments (0)