good manufacturing practices (gmp), good laboratory practices

1

Good Manufacturing Practices (GMP),

Good Laboratory Practices (GLP)

and Good Tissue Practices (GTP)

Richard E. Giles, Ph.D.Associate ProfessorRegulatory Affairs

Institutional Compliance Office

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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

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

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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.

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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.

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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.

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A Process View of GLPs, GMPs & GTPs

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Test Report Summary: Master Cell Bank for PA317:pVMDR1 Organization: The University of Texas M. D. Anderson Cancer Center Department of Hematology 1515 Holcombe Blvd. Box 179 Houston, TX 77030 Telephone: 713-792-2900 Fax: 713-792-5948

Test Sample: PA317:pVMDR1 Master Cell Bank (MCB) Freeze #11536, ATCC Biosafety Level: BL2 Harvest Date: 10/7/93

Test Reference Org. Started Concluded Results Code

ZI012.510 MA 10/21/93 11/30/93 NEGATIVE for Bacteria & Fungi. Final Rpt. N ZI012.102003 MA 10/21/93 1/4/94 NEGATIVE for Mycoplasma. Final Rpt. N ZI012.018 MA 10/21/93 12/10/93 IDENTITY. Mouse by Isozymes & Cytogenet.

Final Rpt. S

ZI012.003 MA 10/21/93 1/17/94 NEGATIVE for CPE, HAD, HA on VERO, MRC5 & TEST CELLS. Final Rpt.

N

ZI012..004 MA 10/15/93 1/11/94 NEGATIVE for MAP test for 16 viruses. Final Rpt.

N

ZI012.032001 MA 10/21/93 1/5/94 NEGATIVE for BVD, IBR, BAV3, BPV & PI3. Final Rpt.

N

ZI012.033004 MA 10/21/93 01/14/94 NEGATIVE for PPV. Final Rpt. N ZI012.005002 MA 10/22/93 02/18/94 NEGATIVE for the Presence of Inapparent

Viruses (in vivo test). Final Report. N

ZI012.149001 MA 10/21/93 1/19/94 NEGATIVE in Extended XC Plaque Assay. Final Rpt.

N

ZI012.011204 MA 10/21/93 03/15/94 NEGATIVE in Mus dunni Co-Cult. Final Rpt. N ZI012.011502 MA 10/21/93 03/15/94 NEGATIVE in RD Co-Cult. Final Rpt. N MDA COPY NUMBER = 10-201 MDA INTEGRATION PATTERN. S1 MDA INTEGRITY. mRNA Sequence Analysis by

RT PCR. S1

Test Sample Characteristics: Viable cells. PA317 (ATCC CRL 9078) mouse cells transduced with the pVMDR1 replication defective plasmid (MDR = multidrug resistance). PA317 is a packaging cell line used for the production of retrovirus particles from defective vector sequences. PA317 is a derivative of NIH 3T3 (ATCC CRL 1658). Test Sample Aliquots: 1 ml/glass ampoule; 1.4 x 106 cells/ampoule; pre-freeze viability 96%; post freeze viability 77%. Stored in liquid nitrogen vapor/liquid phases (production & reference samples) or below -70oC. Org.: MA = Microbiological Associates, 9900 Blackwell Rd., Rockville, MD 20850, Telephone: 301-738-1000, Fax: 301-738-1036. MDA = M. D. Anderson Cancer Center Code Abbreviations: N = Negative; P = Positive; S = Satisfactory; U = Unsatisfactory; I = Inconclusive; NT = No Test.; and * = Preliminary Report. Remarks: 97 ampoules shipped to MA were received in satisfactory condition on 10/15/93. 40 ampoules for ZI809.510 (20 for FTM & rPYG; 20 for SCDM & SD); 20 ampoules for ZI809.102003; 2 ampoules for ZI012.018. 35 ampoules for the remaining tests were pooled and grown to obtain test samples. An additional 35 ampoules were shipped to MA and were received in satisfactory conditions on 11/12/93 to replace cells lost over a weekend due to inadequate feeding. 1 See Section 8 of the IND. Signatures: Dr. Richard E. Giles, Ph.D.

Chief, Gene Therapy Vector Develop. & Production

Chair, Department of Hematology 03/14/06 01:30 PM

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Certificate of Analysis & Lot Release Report Patient Cells

Report Number: 001 Product: CD34 selected bone marrow cells from patient 123456ABC treated with pVMDR1 Vector Supernatant Produced by PA317:pVMDR1 Cells Lot Identification: 123456ABC ENGBC 11/16/94 DM93-012

Test Specification Result Sterility SATISFACTORY SATISFACTORY Mycoplasma NEGATIVE NEGATIVE Mus dunni Amplification RCR NEGATIVE RCR NEGATIVE Mus dunni Co-Culture RCR NEGATIVE RCR NEGATIVE Transduction Efficiency > or = 1% 2% Intended Use: Autologous transplant into patient 123456ABC. Exceptions: Remarks: Approval/Rejection for Release (Circle & Initial):

Approved

Rejected

Signatures & Initials: Date: Dr. Richard E. Giles, Ph.D.

Chief, Gene Therapy Vector Develop. & Production

Chair, Department of Hematology

08/18/00 06:45 PM PatCOA.doc LC

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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

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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

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Origin of GLPs, GMPs & GTPs

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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.

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FDA Critical Path for Medical Product Development

Basic Research

Protype Design or Discovery

Preclinical Development

Clinical Development

FDA Filing/Approval & Launch Preparation

Market Application

ApprovalGLPs

GMPs &

GTPs

FDA: Challenge and Opportunity on the Critical Path to New Medical Products, March 2004Modified

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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.

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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

Modified from Zoon FDA jhu 99

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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.

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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.

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Historical Background

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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

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Polio Epidemics


Outbreak Paralyzed Killed Year Cases1916 New York 9,000 2,400 1943 27,000

1952 59,000

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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?


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Polio Vaccinations


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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.


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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.


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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)


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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.


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Inactivation Kinetics

Four Point Linearity In the

Observable Region

+ Linear Extrapolation.

Four Point Linearity In the

Observable Region

Requirement Not Followed by

Cutter


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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!

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GLPs & GMPs

Basic Components

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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.

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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

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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

Modified from Zoon FDA jhu 99

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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

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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.

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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

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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

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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

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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

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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.

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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

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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.

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Production SuiteGMP

Central Materials

Section (CMS)

GMP Materials Storage

BL 2 Cell Culture

GMP StorageIn Process

Product

GMP StorageMCBs & MWCBs

GMP CMS AreaClass 10,000 Microbiology

GMP Entry/ExitPersonnel

Change RoomsBathrooms

GMP StorageReleased Product Microscopy

BL 3QC & Process

R & D

DecontaminationDisposal

GMP ShippingDocuments &

RecordsBiochemistry

Reception AreaAdministrative & Laboratory Staff

General Receiving, Storage, Shipping & Disposal Bathrooms

Movement of Materials & Personnel Gene Therapy Vector Production

MaterialsOnly

Materials

Materials

Shipped ProductExpired ProductMaterials

Personnel

MaterialsOnly

A

MaterialsOnly

Personnel

PersonnelPersonnel

Materials

Personnel

Personnel

Personnel

Personnel

Entry/Exit

Entry/Exit

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Criteria for Biologics & Drugs

• Safety

• Identity

• Potency/Strength

• Purity/Quality Efficacy

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Production Process

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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

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Project Management for GMP Gene Therapy Vector Production

Replication Defective

Adenovirus Vector AdRB94

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Project Flow Chart

Start Task 1 Task 2

Task 5

Task 6 Task 7

Task 3

MilestonePhase I

Task 4

End

Tasks 1, 2, & 3 are Sequential Tasks

Tasks 2, 5, & 6 are Parallel

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AdRB94 Task List & Gantt Chart: Critical Tasks

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

• 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

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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

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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.

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GMPs for Phase I and Exploratory INDs

• Challenge & Opportunity on the Critical Path to New Medical Products. http://www.fda.gov/oc/initiatives/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

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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

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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/index.html• FDA, http://www.fda.gov/• CBER, http://www.fda.gov/cber/index.html

;ntations, http://www.fda.gov/cber/summaries.htm

• CBER Guidelines, http://www.fda.gov/cber/guidelines.htm

• FDA Guidance for HGT http://www.fda.gov/cber/gdlns/somgene.pdf

• Warning Letters, http://www.fda.gov/cber/efoi/warning.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/initiatives/criticalpath/whitepaper.html

• US Office of Public Health and Science, http://phs.os.dhhs.gov/ophs/ Gene Therapy Links, http://www3.mdanderson.org:80/depts/genetherapy/links.html

• National Gene Vector Laboratories, http://www.ngvl.org/facilities.php?facility=iu

• Biosafety in Microbiological & Biomedical Laboratories, http://www.cdc.gov/od/ohs/biosfty/biosfty.htm

• CDC, http://www.cdc.gov/• Foundation for the Accreditation of

Hematopoietic Cell Therapy (FAHCT), http://www.unmc.edu/Community/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/guidelines/guidelines.html US Dept of Health & Human Services http://www.os.dhhs.gov/

• Office for Human Research Protections (OHRP), http://ohrp.osophs.dhhs.gov/

http://www.gpoaccess.gov/cfr/index.html

http://www.gpoaccess.gov/fr/index.html

http://www.fda.gov/

http://www.fda.gov/cber/index.html

http://www.fda.gov/cber/summaries.htm

http://www.fda.gov/cber/guidelines.htm

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