Good Laboratory Practices and Drug Discovery Frank Zaldivar, PhD - - PowerPoint PPT Presentation

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Good Laboratory Practices and Drug Discovery Frank Zaldivar, PhD - - PowerPoint PPT Presentation

Mar 15, 2023 375 likes •1k views

Good Laboratory Practices and Drug Discovery Frank Zaldivar, PhD Director, Biobanking & Bioprocessing Core Institute for Clinical & Translational Sciences Department of Pediatrics UCI Health | University of California Irvine Which of

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Good Laboratory Practices

and Drug Discovery

Frank Zaldivar, PhD Director, Biobanking & Bioprocessing Core Institute for Clinical & Translational Sciences Department of Pediatrics UCI Health | University of California Irvine

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Which of the following actions would you be willing to take to ensure that your research is perceived as reproducible?

  • Reagents
  • Use standardize/validated reagents
  • Methods
  • Perform rigorous QC, including repeats
  • Outside the laboratory
  • Have another lab reproduce findings
  • Obtain outside expert statistical analysis
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In your lab how many times do you conduct an experiment before including a result into a publication? Do you believe it is necessary for individuals working in translational research to be held to a higher standard of laboratory practice, experimental design that those working in basic research?

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1) STUDIES ARE BLINDED 2) All results are shown 3) Experiments are repeated 4) Positive and negative controls are shown 5) Reagents are validated 6) Appropriate statistical tests are applied

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 Introductions  FDA and regulatory

bodies

 Introduction to sample

tracking

 Why Good Laboratory

Practices

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Regulations and Acronyms

 Code of Federal Regulation  CFR  21 CFR 58 – Good Laboratory Practices

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FDA

CDER

Five Centers of the FDA Center for Drug Evaluation and Research

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FDA

CDER CBER

Five Centers of the FDA Center for Biologic Evaluation and Research

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FDA

CDER CDRH CBER

Five Centers of the FDA Center for Device and Radiological Health

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FDA & 21 CFR 58

FDA

CDER CDRH CFSAN CBER

Center for Food Safety and Nutrition

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21 CFR 58 and FDA

 Drug and finished pharmaceuticals

 21 CFR 210 & 211

 Biologicals

 21 CFR 600

 Drug and finished pharmaceuticals

 21 CFR 820

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Pre-Clinical Research & Development

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Discovery

Drug Discovery / Development / Marketing

3-5 yrs

Targets Hits Leads Candidate

  • Absorption
  • Distribution
  • Metabolism
  • Excretion

Take place in our laboratories

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Majority of funding is from NIH and Disease Center Foundations Consult the FDA and File Investigational New Drug

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Pharmaceutical Development

Drug discovery Pre-Clinical Research Clinical validation or trial

GLP GMP GCP

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GLP organization

  • GLP subpart K – Disqualification of

testing facilities

  • Section 58.200 – Retention of Records
  • To exclude from consideration those studies

conducted by a testing facility which has FAILED TO COMPLY with GLP regulations

  • Until demonstration that data integrity
  • To exclude from consideration all studies

completed after disqualification until the facility can satisfy the FDA COMMISSIONER that it will conduct studies in compliance with GLP regulations

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Pharmaceutical Development

  • What is the role of the FDA:
  • The Food, Drug and Cosmetic Act

mandates the FDA to assure safety and efficacy of new drugs

  • Review laboratory data and rule its

safety in humans

  • Review human data and rule if drug

can be put on market

  • Determine the drug label and labeling

contents

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GLP:

History, Background and recent trends

  • Good Laboratory Practices
  • 21 Code of Federal Regulations 58
  • Scope:
  • This part
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Good Laboratory Practices 21 CFR 58

  • Applications
  • Food and color additives
  • Animal and food additives
  • Human and animal drugs
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Good Laboratory Practices 21 CFR 58

  • Definition of a DRUG
  • Food and color additives
  • Animal and food additives
  • Human and animal drugs
  • Medical devices and human use
  • Biologics
  • Electronic products
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Definitions: So What Is A:

Drug? Biologic? Device? Combination Product?

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Drug

Center for Drug Evaluation and Research

Any article:

 Intended for use in diagnosis, cure,

mitigation, treatment or prevention

  • f disease in man or animals

 Intended to affect the structure or

any function of the body of man or animals (except for food)

 Recognized in the official

compendium

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Biologics:

Center for Biologic Evaluation and Research

 Virus,  Therapeutic serum,  Toxin,  Antitoxin or  Analogous product  Blood and blood products  Recombinant DNA-derived

products

 Intended for use in diagnosis,

cure, mitigation, treatment or prevention of disease of man

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Medical Device

Center for Device and Radiological Health

 Any instrument, apparatus,

implement, machine, contrivance, implant, in vitro reagent or other similar/related article, including any part, which is

 Intended for use in diagnosis,

cure, mitigation, treatment or prevention of disease

 AND...

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Medical Device

 Does not achieve its intended

purpose through:

 Chemical action within or on the

body and

 Is not dependent upon being

metabolized

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Combination Products

 Drug/Device Combinations

 Transdermal patch  Pre-loaded autoinjector  Drug coated stent

 Biologic/Device Combinations

 Biologic in a syringe

 Other Strange Things

 In vitro diagnostic test kits used to test

the blood supply

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Good Laboratory Practices 21 CFR 58

 Good Laboratory Practices (GLP):

how to test products in the lab and in animals

 EPA has responsibility for non-

pharmaceutical chemical-pesticides and toxic chemical substances

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Preparation for GLP inspections

QCU QC QA

As per regulations, QCU has two functions

Does testing in the laboratory under GMP’s

  • A test is defined
  • A method is established
  • And upper, lower and acceptable limits

have been established

  • QA is now defined
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Preparation for GLP inspections

  • QA provides assurance that all

manufacturing and testing has been done in compliance to regulation, internal policies, procedures and guidelines and submissions

  • QA director can release or reject a lot at

this point!!

QC QA

As per regulations, QCU has two functions

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Preparation for GLP inspections

  • QAU
  • QA unit role includes
  • Ensure study follow protocol
  • Maintain master schedule
  • Conduct audits
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Preparation for GLP inspections

  • Establishment inspections
  • The facility inspection is guided by the

GLP regulations with the following areas being inspected:

  • Organization and personnel
  • QA
  • Facilities
  • Equipment
  • Testing facility and operations
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Preparation for GLP inspections

  • Establishment inspections
  • The facility inspection is guided by the

GLP regulations with the following areas being inspected:

  • Organization and personnel
  • QA
  • Facilities
  • Equipment
  • Testing facility and operations
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Preparation for GLP inspections

  • Establishment inspections
  • The facility inspection is guided by the

GLP regulations with the following areas being inspected:

  • Reagents and solutions
  • Animal care
  • Test and control articles
  • Protocol and conduct of non-clinical

study

  • Records and reports
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Preparation for GLP inspections

  • Establishment inspections
  • Organization and Personnel
  • Management responsibilities
  • Assignment of a Study Director
  • Review and approval of protocols

and SOP’s

  • Providing QAU oversight
  • Providing study personnel,

facilities, equipment and materials

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Preparation for GLP inspections

  • Establishment inspections
  • Organization and Personnel
  • Management responsibilities
  • Providing GLP or technical

training as needed

  • Training and job descriptions
  • Study Director involvement and

participation

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Preparation for GLP inspections

  • Quality Assurance Unit
  • Independent QAU
  • Maintenance of a master schedule
  • Maintenance of protocol copies and

amendments

  • Summary of in-process inspections

and audits

  • Maintenance of records of each unit
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Preparation for GLP inspections

  • Quality Assurance Unit
  • Notification to the study director of

problems likely to affect the integrity

  • f the study
  • Review and approval of the study final

report

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Preparation for GLP inspections

  • Facilities
  • Facility floor plans
  • Environmental control and monitoring

procedures for critical areas

  • Animal rooms
  • Test article storage areas
  • Laboratories
  • Data storage
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Preparation for GLP inspections

  • Facilities
  • Overall look of facility
  • Cracked floors
  • Holes in walls
  • Stained ceiling tiles
  • Facility floor plans
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Preparation for GLP inspections

  • Equipment
  • General maintenance and operation
  • HVAC
  • Equipment storage
  • Cleaning and documentation
  • Procedures to prevent cross –

contamination

  • Maintenance and schedule logs
  • Procedures for emergency back-up
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Preparation for GLP inspections

  • Testing facility operation
  • Distribution of current SOP’s
  • SOP authorization
  • SOP content
  • Training of SOP’s
  • Periodic review of SOP’s
  • Calibration documentation
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Preparation for GLP inspections

  • Reagents and solutions:
  • Quality of reagents
  • Reagent labels with identity,

concentration, storage requirements and expiration date

  • Mobile phases – preparation and

expiration dating

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Preparation for GLP inspections

  • Animal care:
  • Animal care housing
  • SOP’s and study records
  • Environment, housing, feeding,

handling and care

  • Pest control procedures, chemicals
  • IACUC = Institutional Animal Care and

Use Committee for the welfare of the animals

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Preparation for GLP inspections

  • Test and Control Articles:
  • Receipt, identification and storage
  • Handling of test and control articles
  • Prevention of deterioration and

contamination

  • Documented identity, strength,

purity…

  • Stability
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Preparation for GLP inspections

  • Test and Control Articles:
  • Stability
  • Samples transfer to analytical
  • Storage containers
  • Reserve samples
  • labeling
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Preparation for GLP inspections

  • Protocol and conduct of non-clinical

study:

  • SOP for protocol preparation and

approval

  • Protocol amendments and copies
  • Storage and identification of

specimens

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Preparation for GLP inspections

  • Protocol and conduct of non-clinical

study:

  • Data recording
  • Procedures for collection and ID of

specimens

  • Restricted access
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Preparation for GLP inspections

  • Records and reports:
  • Storage and retrieval of study data,

reports, slides and specimens

  • Study director’s SIGNATURE
  • Amendments to the final reports
  • Identity of sub-contractors and

licenses

  • Retention policy
  • Computer data and back-up copies
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Preparation for GLP inspections

  • Summary:
  • UNDERSTAND the regulations!!!
  • Review prior observations and

inspections

  • Understand exposure to non-

compliance issues

  • Audit GLP test sites
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Internal and External Audits

  • Internal and vendor (external) audits
  • Introduction

Internal Audit vs Vendor External Audit

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Internal and External Audits

  • At a firm whether GMP or GLP Tox:
  • All conduct internal audits & self

assessments

  • NO FDA guideline nor mandates
  • Are the needed?
  • Yes, because if you don’t you will GET

CITED!!!!!

  • SO DO THEM!!!!!
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Internal and External Audits

  • If you contract with a GLP Tox firm:
  • You MUST do an audit, you are the

external audit

  • You will generate a report with
  • bservations and recommendations