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 apply the fundamental concepts of data quality and integrity, FDA requires that the regulations cover all operations in
facilities conducting non-clinical studies and, most importantly, it requires that all facility operations and procedures
are strictly documented. To monitor the adherence of a research laboratory to GLP regulations, FDA has implemented a programme
of regular inspections and data audits (Compliance Monitoring Program), where proper documentation is a key element to assess
GLP compliance.5 This article aims to introduce some key elements of the application of GLP regulations as a quality system
in the pharmaceutical and biotech industries, and how GLPs are perceived internationally.
Figure 1: Examples of studies covered by G3P regulations.
To promote collaboration and co-ordination of policies among global chemical safety organizations, the Organization for Economic
Co-operation and Development (OECD) adopted FDA regulations and, in 1981, formally recommended the use of GLP principles in
member countries. The objective was "assessment of data generated in the testing of chemicals." Later, OECD members reviewed
and updated the GLP principles to focus on the safety testing of chemicals and, in 1997, issued the Series on Principles of
Good Laboratory Practice and Compliance Monitoring.6 This series consists of documents that provide a practical interpretation
of GLPs regarding key activities in non-clinical testing facilities.
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).
Part 58 regulations apply to all facility operations, and impact scientific studies through the planning, conduct and reporting
phases.4 They basically encompass:
- a quality assurance unit (QAU)
- management and personnel
- the study director
- facilities and equipment
- standard operating procedures (SOPs)
- laboratory documentation and raw data
- computerized systems
- study planning (protocols and reports).