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
Five Centers of the FDA Center for Drug Evaluation and Research FDA CDER
Five Centers of the FDA CDER FDA Center for Biologic CBER Evaluation and Research
Five Centers of the FDA CDER FDA CBER CDRH Center for Device and Radiological Health
FDA & 21 CFR 58 CDER FDA CBER CDRH Center for Food Safety and Nutrition CFSAN
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
Drug Discovery / Development / Marketing • Absorption Discovery Targets • Distribution Hits Leads • Metabolism Candidate 3-5 yrs • 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 GLP GCP Clinical validation or trial GMP
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 As per regulations, QCU has two functions Does testing in the laboratory under GMP’s • A test is defined QCU • A method is established • And upper, lower and acceptable limits have been established • QA is now defined QA QC
Preparation for GLP inspections As per regulations, QCU has two functions • 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
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
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