and Drug Discovery

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 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

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?

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

Introductions

FDA and regulatory

bodies

Introduction to sample

tracking

Why Good Laboratory

Practices

Regulations and Acronyms

Code of Federal Regulation

CFR

21 CFR 58 – Good Laboratory Practices

FDA CDER

Five Centers of the FDA

Center for Drug Evaluation

and Research

FDA

CDER

CBER


Center for Biologic

Evaluation and

Research

FDA

CDER

CDRHCBER


Center for Device and Radiological

Health

FDA & 21 CFR 58

FDA

CDER

CDRH

CFSAN

CBER

Center for Food Safety and Nutrition

21 CFR 58 and FDA

Drug and finished pharmaceuticals

21 CFR 210 & 211

Biologicals

21 CFR 600

Drug and finished pharmaceuticals

21 CFR 820

Pre-Clinical

Research & Development

Discovery

Drug Discovery /

Development / Marketing

3-5 yrs

Targets

Hits

Leads

Candidate

•Absorption

•Distribution

•Metabolism

•Excretion

Take place in our laboratories

Majority of funding is

from NIH and

Disease Center

Foundations

Consult the FDA

and File

Investigational

New Drug

Pharmaceutical Development

Drug discovery

Pre-Clinical Research

Clinical validation or trial

GLP

GMP

GCP

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

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

GLP: History, Background and recent trends

• Good Laboratory Practices

• 21 Code of Federal Regulations 58

• Scope:

• This part


21 CFR 58

• Applications

• Food and color additives

• Animal and food additives

• Human and animal drugs


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

Definitions: So What Is A:

Drug?

Biologic?Device?

Combination

Product?

Drug Center for Drug Evaluation and Research

Any article:

Intended for use in diagnosis, cure,

mitigation, treatment or prevention

of 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

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

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...

Medical Device

Does not achieve its intended

purpose through:

Chemical action within or on the

body and

Is not dependent upon being

metabolized

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


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

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


• 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


• QAU

• QA unit role includes

• Ensure study follow protocol

• Maintain master schedule

• Conduct audits


• 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





being inspected:

• Organization and personnel

• QA

• Facilities

• Equipment

• Testing facility and operations





being inspected:

• Reagents and solutions

• Animal care

• Test and control articles

• Protocol and conduct of non-clinical

study

• Records and reports



• 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



• Organization and Personnel

• Management responsibilities

• Providing GLP or technical

training as needed

• Training and job descriptions

• Study Director involvement and

participation


• 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


• Quality Assurance Unit

• Notification to the study director of

problems likely to affect the integrity

of the study

• Review and approval of the study final

report


• Facilities

• Facility floor plans

• Environmental control and monitoring

procedures for critical areas

• Animal rooms

• Test article storage areas

• Laboratories

• Data storage


• Facilities

• Overall look of facility

• Cracked floors

• Holes in walls

• Stained ceiling tiles

• Facility floor plans


• 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


• Testing facility operation

• Distribution of current SOP’s

• SOP authorization

• SOP content

• Training of SOP’s

• Periodic review of SOP’s

• Calibration documentation


• Reagents and solutions:

• Quality of reagents

• Reagent labels with identity,

concentration, storage requirements

and expiration date

• Mobile phases – preparation and

expiration dating


• 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


• Test and Control Articles:

• Receipt, identification and storage

• Handling of test and control articles

• Prevention of deterioration and

contamination

• Documented identity, strength,

purity…

• Stability


• Test and Control Articles:

• Stability

• Samples transfer to analytical

• Storage containers

• Reserve samples

• labeling



study:

• SOP for protocol preparation and

approval

• Protocol amendments and copies

• Storage and identification of

specimens



study:

• Data recording

• Procedures for collection and ID of

specimens

• Restricted access


• 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


• Summary:

• UNDERSTAND the regulations!!!

• Review prior observations and

inspections

• Understand exposure to non-

compliance issues

• Audit GLP test sites

Internal and External Audits

• Internal and vendor (external) audits

• Introduction

Internal

Audit vsVendor

External

Audit


• 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!!!!!


• If you contract with a GLP Tox firm:

• You MUST do an audit, you are the

external audit

• You will generate a report with

observations and recommendations

Documents

and Drug Discovery