and Drug Discovery
Transcript of 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
Five Centers of the FDA
Center for Biologic
Evaluation and
Research
FDA
CDER
CDRHCBER
Five Centers of the FDA
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
Good Laboratory Practices
21 CFR 58
• Applications
• Food and color additives
• Animal and food additives
• Human and animal drugs
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
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
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
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
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
Preparation for GLP inspections
• QAU
• QA unit role includes
• Ensure study follow protocol
• Maintain master schedule
• Conduct audits
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
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
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
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
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
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
Preparation for GLP inspections
• 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
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
Preparation for GLP inspections
• Facilities
• Overall look of facility
• Cracked floors
• Holes in walls
• Stained ceiling tiles
• Facility floor plans
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
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
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
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
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
Preparation for GLP inspections
• Test and Control Articles:
• Stability
• Samples transfer to analytical
• Storage containers
• Reserve samples
• labeling
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
Preparation for GLP inspections
• Protocol and conduct of non-clinical
study:
• Data recording
• Procedures for collection and ID of
specimens
• Restricted access
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
Preparation for GLP inspections
• 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
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!!!!!
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
observations and recommendations