In 1979, good laboratory practice (GLP) regulations became effective under 21 Code of Federal Regulations (CFR) Part 58,1 which apply to all non-clinical safety studies intended to support research permits or marketing authorizations for products regulated by the US Food and Drug Administration (FDA). Subsequently, during 1979 and 1981, FDA, through its Office of Regulatory Affairs (ORA), published two critical "Guidance for Industry" documents, namely, "Post Conference Report" and "Questions and Answers," to ensure proper and consistent interpretation of the regulations by the industry and FDA field investigators.2,3
GLPs were established after FDA inspected several research laboratories during the mid 1970s, which revealed serious problems with the conduct of safety studies submitted to the agency. The violations included poor record keeping and storage of raw data; lack of proper personnel training and handling of test facilities; and fraud.4 As a result, it was deemed essential to establish rules and requirements regulating the conduct of research activities to assure the quality and integrity of the safety data submitted to FDA.
To protect humans and the environment, and to establish mutual recognition of data among countries, in 1986, the European Union (EU) adopted OECD GLP principles and issued a directive regarding the application of GLP for tests on chemical substances. The directive covered pharmaceuticals, cosmetics and chemicals such as pesticides and industrial chemicals, typically regulated in the US by other agencies. This law became a reference point in each EU country for the development of national policies and directives regarding the subject.
The International Conference on Harmonization (ICH) represents another major co-ordination effort involving the regulators and the pharmaceutical industries in Europe, the US and Japan. The ICH focusses on the technical requirements of medicinal products containing new drugs to ensure their safety, efficacy and quality, and harmonizes the requirements for submissions to facilitate medicine registration in these three regions. Harmonization efforts began in 1993 as part of the agenda for the second ICH conference, and its guidelines and agreements are continually evolving and being updated.7
Where do GLPs apply? A statement in 21 CFR Part 58 concerning the applicability of GLP regulations to "all non-clinical laboratory studies that support or intend to support applications for research or marketing permits for products regulated by FDA" has been the subject of numerous discussions. The FDA definition of non-clinical laboratory studies as "in vivo or in vitro experiments in which a test article is studied under laboratory conditions to determine its safety" needed to be clarified. The guidance documents2,3 provided more specific information regarding the regulations. GLPs not only apply to animal toxicology studies (including, for example, over-dosage studies in target species, tissue accumulation and depletion studies, local and total tolerability, and irritation studies), but also to all chemical procedures used to characterize a test article and its mixtures, or to determine its concentration, and to the chemical procedures used to analyse specimens. Therefore, if a laboratory provides analytical data to support a toxicology study submitted to FDA, then portions of the laboratory, procedures or personnel involved may be subject to GLP regulations. Conversely, examples of studies that are outside the scope of GLP regulations include those utilizing human subjects, which are covered by good manufacturing practice (GMP) and good clinical practice (GCP) guidelines, efficacy studies (covered by GCP guidelines) and basic research (Figure 1).
Application Part 58 regulations apply to all facility operations, and impact scientific studies through the planning, conduct and reporting phases.4 They basically encompass: