Introduction to GLP

Troy Gobbett, MS

Director, Research Operations

PreClinOmics, Inc

PreClinOmics

• Preclinical contract research company

• Screening and efficacy models of Metabolic Syndrome, Diabetes, Obesity, PKD

• ZDSD rat and Fatzo mouse

• Intern/Extern

• AAALAC

• Non-GLP

Overview

• Regulatory History

• What is GLP?

• Applications of GLP

• Why GLP?

• GLP Elements

Biologics Control Act 1902 • Deaths related to contamination of a diphtheria antitoxin

Pure Food and Drugs Act 1906 • Official standards of strength and purity

• Prohibition of misbranding

Formation of the Food and Drug Administration 1930

Federal Food, Drug, and Cosmetic Act (Sulphanilamide) 1938 • Required proof of safety

• Authorization of FDA to issue Regulations

• Gave FDA enforcement power

• Prohibited false claims

Kefauver-Harris Amendment to FFDC (Thalidomide) 1962 •FDA approval of NDA

•FDA evaluation of data

•Reporting of adverse effects

•Manufacturer compliance with GMPs

•Informed consent

Final GLP rulings published by FDA 1978 •Effective 1979

Protection of Human Subjects 1981 •Informed consent (21 CFR 50) requirements clarified

•IRB (21 CFR 56) standards

GLP rulings published by EPA 1983

Financial Disclosure (21 CFR 54) 1998 •Investigators must disclose interests

Why GLP?

• Inspections in the 1970’s of US toxicology labs by the FDA found

– Little to no attempts at Quality Control

– No standardized methods

– Poor experimental planning

– Falsified data

– Data “cherry picking”

– Minimal documentation

What is GLP?

• Defined in the Code of Federal Regulations

21 CFR Part 58

Sec. 58.1 Scope.

(a) This part prescribes good laboratory practices for conducting nonclinical laboratory studies that support or are intended to support applications for research or marketing permits for products regulated by the Food and Drug Administration, including food and color additives, animal food additives, human and animal drugs, medical devices for human use, biological products, and electronic products. Compliance with this part is intended to assure the quality and integrity of the safety data filed pursuant to sections 406, 408, 409, 502, 503, 505, 506, 510, 512-516, 518-520, 721, and 801 of the Federal Food, Drug, and Cosmetic Act and sections 351 and 354-360F of the Public Health Service Act.

What is GLP?

• Quality system of management controls to ensure:

– Reliability

– Quality

– Consistency

– Reproducibility

– Integrity

Of non-clinical safety tests

Purpose of GLP

• Inform industry of agency expectations

• Provide guidance for an industry standard

• Improve quality of research

• Mandate documentation for reconstruction of study events

• Increase confidence in validity of results

• Allow flexibility to various applications

Requirements of GLP

• Ability to reconstruct study events from documentation and data

• Document, record, verify

• If it isn’t written down, IT DIDN’T HAPPEN

Elements of GLP

• Organization and Personnel

• Facilities

• Equipment

• Testing Facilities Operation

• Test and Control Articles

• Protocol for and Conduct of a Nonclinical Laboratory Study

• Records and Reports

• Disqualification of Testing Facilities

Organization and Personnel

• Personnel – Each person engaged shall have

education, training and experience to enable the performance of assigned tasks

• Testing facility management – Assign Study Director – Assure Quality Assurance Unit – Assure what is needed is

available – Assure personnel understand job

functions – Assure deviations from

regulations are reported by QAU to Study Director and appropriate actions are taken

Study Director

• “That guy” • Single point of study control • Responsible for:

– Technical conduct – Interpretation, analysis,

documentation & reporting

• Shall assure: – Protocol is followed – Data is accurately recorded and

verified – Any unforeseen circumstances that

affect quality or integrity of study are noted, actions taken and documented

– Applicable GLPs are followed – All data, documents, protocols,

specimens and final reports are archived

Quality Assurance Unit

• Independent • Assure management that:

– All aspects of study are in conformance of the regulations

• Maintain Master Schedule • Inspect study as it is being

conducted to assure integrity • Submit periodic reports to

management and Study Director

• Review final report • Maintain written and indexed

records of all activities

Facilities

• Shall be of suitable size and construction to facilitate proper conduct of study

• Shall be designed so that there is a degree of separation that will prevent any function or activity from adverse effects on the study

Animal Care Facilities

• Separation of species or test systems

• Isolation of individual projects

• Quarantine of animals

• Routine or specialized housing of animals

• Animal rooms for separation of studies using hazardous agents

• Separate areas for diagnosis, treatment, and control of lab animal diseases

• Separate areas for collection and disposal of waste and refuse

Additional Facilities

• Animal supply areas

• Handling test and control articles

• Laboratory operations

• Specimen and data storage

Equipment

• Appropriate design

• Must be maintained and calibrated

• SOPs for operation, cleaning, maintenance, calibration, what to do if malfunction

• Written records maintained

Testing Facility Operations

• SOPs for – Animal room prep – Animal care – Handling of test and control articles – Test system observations – Laboratory tests – Handling of dead or moribund animals – Necropsy – Collection of specimens – Hisopathology – Data handling, storage, and retrival – Maintenance and calibration of

equipment – Transfer and identification of animals

• SOPs must be available in the area where activities are performed

• Historical file of revisions must be maintained

Animal Care

• SOPs for housing, feeding, handling and care of animals

• Animals should be isolated and health status evaluated

• Animals should be free of any disease which may interfere with the purpose of the study

• Animals need to be identified and identification info shall appear on the outside of housing unit

• Different species should be housed in different rooms

• Same species should not be housed together where inadvertent exposure to test or control articles could affect study outcome

• Animal cages, racks, and accessories should be cleaned and sanitized at appropriate intervals

Animal Care

• Feed and water shall be analyzed periodically to ensure they are free of contaminants that may interfere with study outcome

• Bedding shall not interfere with purpose or conduct of study and changed to keep animals dry and clean

• Pest control and cleaning agents shall not be used if they will interfere with study

Test and Control Articles

• Characterization

• Handling

• Mixture with carriers

Protocol for and Conduct of Nonclinical Study

• Title and statement of purpose • Test and control article

identification, preparation and use

• Contact information of Sponsor • Identification of test system • Description of experimental

design • Description of laboratory tests,

and frequency • Records to be maintained • Date of approval by sponsor and

study director • Statistical methods to be used

Conduct of study

• Must be in accordance with the protocol

• Test system monitoring in conformity of protocol

• Identification of specimens

• Records of gross findings from postmortem evaluation available to pathologist

• All data recorded directly, promptly and legibly – Any change in entry should be

dated and signed at the time of entry

Reporting of Results

• Final report is to be prepared for each study

• Includes: – Identification of testing facility – Dates of study – Description of test and control articles

used – Description of methods used – Description of test system – Description of dosing regimen – Names of Director, scientists,

supervisors involved – Description of data analysis – Location of specimen, raw data, and

final report storage – Quality Assurance statement

• Must be signed and dated by the Study Director

Record Retention and Retrival

• All raw data, documentation, protocols, final reports, and specimens generated shall be maintained

• SOPs • Training records • Equipment records • Master schedule • Individual responsible for

archives • Know where its at and how

to get to it • 2-5 year retention

To be compliant

• What was done?

• Who did it?

• When was it done?

• How was it done?

• Where it was done?

• Was it documented?

• Who made the decisions?

• Who knew about it?

Summary

• GLPs resulted from a need to regulate quality of nonclinical safety studies

• Define expectations

• Provide standardization

• Level the playing field

If it’s not written down – IT DIDN’T HAPPEN