Good Laboratory Practices

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By Jerry Hirsch

Good Laboratory Practices (GLPs) were originally developed for research-oriented non-clinical studies to assure the quality of data submitted to support applications to register tested products for use as regulated products. GLPs were also established in part because of concerns about the integrity and calibre of data being produced in some studies. GLPs are used in activities such as toxicology studies of chemicals that are at the pre-market testing phase to ensure the generation and reporting of quality and reliable test data related to the safety and hazard assessment of pharmaceuticals, cosmetics, food and feed additives, pesticides, and industrial chemicals. GLPs define the managerial and organizational procedures and concepts covering test facilities and the conditions under which preclinical safety studies should be designed, conducted, recorded, monitored and reported. Compliance with GLP regulations is assessed or based on the results of inspections and study audits.

International Aspects

Development of GLP Guidelines was driven by the increasing demand for legally enforceable and decision-oriented data and the need for international acceptance of this information. The GLP quality system provides the framework to enable testing facilities to provide acceptable, internationally recognized data.

The Organization for Economic Co-operation and Development (OECD) developed the OECD Principles of Good Laboratory Practice1 in 1982. OECD, in which some 20 countries and a half-dozen international organizations participate, was established in 1960 in part to contribute to the expansion of world trade on a multilateral, nondiscriminatory basis in accordance with international obligations. The 1982 OECD report was revised in 1997 to promote international harmonization and co-operation for preclinical safety studies. The updated OECD document outlines the principles of GLPs and provides guidance to test facilities in the testing of regulated chemicals. OECD also addresses study audits and describes an inspection program that is intended to provide guidance in assuring proper study conduct to permit hazard assessment.

The 1997 OECD document has been widely accepted. The Commission of the European Communities, for example, requires that laboratories performing tests on chemical products comply with this GLP document. OECD indicated to member countries that the testing of chemicals for GLP purposes involving protection of health and the environment must be monitored by test facility inspections and study audits. Another feature was the mutual acceptance of data requirements for all member countries that establish GLP Monitoring Authorities (GLPMA).

Canadian Practice

Through the Standards Council of Canada (SCC), Canada has established a GLP Compliance Program that meets the criteria of the OECD document, Revised Guides for Compliance Monitoring Procedures for Good Laboratory Practice.2 The Pest Management Regulatory Agency (PMRA) of Health Canada, which regulates pesticides in Canada, requires that trials for the use of applied pesticides must be undertaken according to GLPs. PMRA recognizes the role of the SCC as the Canadian authority (the “GLPMA”) for test facilities submitting health and environmental safety studies in support of pest control product regulation. Applications for recognition of GLP compliance in Canada and the corresponding fee structure are available from the SCC’s Conformity Assessment Division. SCC also provides the identity of each facility inspected by the SCC GLPMA, the compliance status, and a summary of its GLP testing capabilities.

American Approach In 1978, the U.S. Food and Drug Administration (FDA) issued regulations regarding GLPs in the conduct of non-clinical laboratory studies.3 The objective was to ensure that data from such studies would be of high quality and integrity to assure product safety in accord with the Federal Food, Drug, and Cosmetic Act and other applicable laws. FDA has also promulgated GLP regulations for human and veterinary drugs that contain requirements for laboratory controls.4 These regulations call for laboratory procedures that include establishing scientifically sound specifications, standards, sampling plans, and test procedures.

The U.S. Environmental Protection Agency (EPA) has also issued regulations for good laboratory practice standards for toxic substances, including pesticides.5 EPA’s GLP compliance monitoring program, through laboratory inspections and data audits, helps assure the validity of test data to regulate pesticides and other industrial chemicals. These regulations parallel those of the FDA, but are more specific in certain respects. EPA has an interagency agreement with FDA that formalizes the co-operative efforts of the two agencies to establish a co-ordinated quality assurance program for their various activities. EPA uses both adherence to GLPs and laboratory accreditation in managing the regulatory responsibilities of the agency.

GLPs, Quality Assurance and ISO 17025

GLP studies, which may involve a wide variety of matrices or test systems, are different from most analytical testing that is typically done according to published or validated methods at the post-registration or post-approval regulatory phase. ISO 17025 focuses on the laboratory and describes the requirements that laboratories must meet to demonstrate that they operate a quality system, while GLP regulations address all aspects of non-clinical studies.

GLP is a quality system concerned with the organization process and the conditions under which non-clinical studies are planned, performed, monitored, recorded and reported. Each GLP study must have a protocol that states the objectives and purpose, all methods, statistical methods and experimental design for conduct of the study. Standard Operating Procedures (SOPs) are also recommended because these written procedures help ensure consistent operating practices and have a positive influence on quality and integrity of data. GLP regulations refer more to specific studies rather than to general operations for testing laboratories, as is the case for ISO 17025. Nevertheless, effective implementation of GLPs generally requires an independent Quality Assurance Unit to monitor each study to help ensure that facilities, equipment, personnel, methods, practices and records all meet and perform according to defined requirements.

ISO 17025 requires that laboratories develop a system appropriate to identify or analyse test samples, while GLP regulations simply specify what information must be included for test items. ISO 17025 identifies much more detailed requirements regarding the selection of methods, and maintenance and calibration of equipment. In addition, one of the fundamental principles of laboratory accreditation is the use of proficiency testing samples, which is not applicable for GLP studies.

GLP regulations, in describing what is expected of an organization to support the safety of regulated products, focus on requirements for a study plan, appointment of a study director, inspections of each study by a Quality Assurance Unit, and specific requirements for data storage. The criteria are similar in some respects to the requirements of any good quality assurance program. In the U.S., FDA requirements for GLPs fostered interest in laboratory quality assurance and the interest of some private and governmental agencies in accreditation programs. The GLP regulations provide for inspection of the testing facility by the FDA.

Integration of GLPs and ISO Requirements

An increasing number of analytical laboratories are involved in both pre-registration activities covered by GLPs and in post-registration activities addressed by ISO 17025. These laboratories are thus confronted with the need to meet both GLP and ISO 17025 standards, and possibly also ISO 9002, a quality assurance program governing production, installation and service of products. This represents a significant burden in terms of dealing with two or three different standards and organizations, each with its own audit requirements and cost recovery charges. One approach to consider regarding laboratory compliance with both GLP regulations and ISO 17025 requirements is to develop a Quality System including a Quality Manual and SOPs to satisfy ISO 17025, and also include additional specifications for GLP studies.

While developing a unified approach to assessing adherence to these standards is one possible approach, emphasis is now being placed on integrating these two standards into a single document.6 EURACHEM has indicated its support for greater harmonization of ISO 17025, ISO 9000 and GLPs.7 Discussions between the OECD Panel on GLPs and the European co-operation for Accreditation (EA) suggest that there is a realistic possibility of combining EN 45001 and OECD-GLPs. Closer integration of these quality standards would be consistent with the international emphasis on facilitating international trade, reducing duplication, and promoting the quality and validity of decision-oriented test data.

Acceptance of Data

A key factor in the development of GLP Guidelines was the requirement for legally enforceable data and the need for international acceptance of this information. Acceptance by one country of data from other countries requires that certain criteria be met. These include acceptable ethics, well-designed and well-conducted studies, qualified investigators, and study trials approved by an independent review committee.

Canada and the U.S. have developed a memo of understanding on GLPs for the development of pesticide data. The SCC GLP Recognition Program is recognized by PMRA and is therefore directed primarily towards domestic test facilities. CAN-P-1583, available from the SCC, describes Guidelines for the Recognition of GLP Compliant Test Facilities (April 1998).

Audits

GLP audits focus on comprehensive physical inspections of lab facilities and operations, and data audits of selected studies. Inspections and data audits look at elements including general provisions, organization and personnel, equipment, test facility operation, test facility management, test and control articles, protocol for conduct of a non-clinical laboratory study, records and reports, disqualifications of testing facilities, study director, quality assurance unit, animal-care facilities, equipment, and SOPs. The most common deficiencies observed include failure to adequately and accurately record experimental data; lack of SOPs; failure to maintain and calibrate equipment; inadequate analytical testing; and inadequate animal and testing facilities.

Conclusions

GLPs continue to be useful tools to assure the quality and integrity of data required to support the approval of regulated products. Organizations interested in meeting GLPs should contact SCC or PMRA and obtain an application form, checklists and GLP documents.

References
1) OECD Principles on Good Laboratory Practice (revised in 1997) (ENV/MC/CHEM (98) 17, 1998).

2) Revised Guides for Compliance Monitoring Procedures for Good Laboratory Practice (Environment Monograph No. 110, 1995).

3) “Non-Clinical Laboratory Practices, Good Laboratory Practice Regulations,” p60013 (21 CFR Part 58), Federal Register (December 22, 1978).

4) Code of Federal Regulations, Title 21, Part 210, “Current Good Manufacturing Practices in Manufacturing, Processing, or Holding Drugs,” and Part 211 “Current Good Manufacturing Practices for Finished Pharmaceuticals.”

5) “Toxic Substances Control, Good Laboratory Practice Standards,” p. 53922 (40 CFR Part 792); and “Pesticide Program, Good Laboratory Practice Standards,” p. 53946 (40 CFR Part 160), Federal Register (November 29, 1983).

6) Chaput, Dan. Multiple Quality Assurance Systems in Analytical Chemistry Laboratories — A Viewpoint. 5th Chemical Congress of North America, ACS Symposium, in press.

7) DeBievre, P., R. Kaarls and B. King. Accreditation and Quality Assurance 2, 101 — 102 (1997).

Jerry Hirsch, PhD is director of JH TechRight Consulting, providing advice on quality systems, laboratory accreditation, natural health products, food safety, and technical projects. Hirsch retired in 2001 from the Canadian Food Inspection Agency (CFIA) Burnaby Food Laboratory. Prior to the formation of CFIA he was chief of the Burnaby Health Canada Food/Drug Laboratory. He is a member of the BC Functional Food and Nutraceutical Network, BC Food Technologists, and AOAC International.