Hana Danan

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 	

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:				

QAU. Establishing the QAU is perhaps the first step towards GLP implementation in a facility. The function of this group, as described by Part 58, is to ensure that the regulations have been followed, and to update the study director and facility management regarding the status of compliance. Because of its function, the QAU must be independent from the groups conducting GLP studies, but to ensure implementation, it is important that it is assigned a primary position within the organizational chart. During an FDA inspection, the QAU is a main reference point for the agency to obtain information. Some of the key QAU functions8 are as follows:	

Maintenance of the master schedule sheet, which is a descriptive list of all GLP projects in the facility. 

Review of critical documents such as procedures, protocols and reports, to ensure GLP compliance.

Establishment of procedures pertaining to the QAU function such as procedures for internal audits.

Regular inspections to assess the compliance status in the test facility, and submission of the findings reports to the study director and management. 

Assure and provide evidence to FDA that internal inspections have been implemented, reported and documented.

Organization and personnel. Regarding personnel, it is essential that: 	

management and personnel are properly trained to perform their tasks.

FDA does not set requirements for the organizational structure in a facility; however, responsibilities must be clearly defined and communicated to employees. In fact, during an FDA inspection, the organization chart is a very important document that must be available to inspectors. 	

To fulfil the second criterion, regulations require that both management and personnel understand their jobs and are qualified to perform them safely, according to GLP principles. Thus, job descriptions that clearly define each task are important and it is management's responsibility to provide evidence that employees understand and know how to accomplish their tasks. Consequently, training records become critical documents and must be maintained and updated periodically as evidence of personnel qualifications. The more qualified personnel are, the better their work and the less chance of errors.	

Table I:  Important elements of a non-clinical GLP study.			

Although the regulations do not set requirements for the organizational structure, they identify management tasks, which include:	

ensuring that resources are available for the proper execution of GLP projects

ensuring that personnel understand their jobs and are appropriately trained

ensuring that studies are in compliance with GLP principles and regulations 

storing and archiving records and data, including organizational charts; personnel training records and job descriptions; historical records of all facility procedures; and all documentation regarding GLP studies such as protocols, final reports and raw data.

Study directors. One key management function is the formal appointment of the study director and investigators. The study director is responsible for the scientific conduct of the study, including planning, documentation, and approval of its protocols and reports. He/she must co-ordinate with the QAU and management to ensure GLP compliance.9 The study director is considered to be a reference for the scientific and regulatory assessment of a project, and must have the appropriate experience and knowledge of GLP principles and regulations to allow him/her to successfully perform their task. Any decisions regarding replacing a study director must be documented.	

Training. Training, according to GLP, should improve personnel skills. Procedures should be established to describe training methods, frequency and how to document it.10 In practice, this requirement may include the following areas:	

Technical. Technical qualifications can be achieved through education, experience or a combination of both, and can be confirmed by appropriate records (for example, attendance certificates). However, it is management's responsibility to ensure that personal technical skills are continually updated. 

GLP. In most cases, this type of training is received in situ and is important. Management must ensure that personnel understand the scope of GLP regulations and know how to apply their principles routinely to research. GLP training must include topics such as how to use and develop SOPs and proper documentation practices.

Safety. Safety training must be continuous, performed on site and be provided by authorized trainers. It should include, for example, training on how to use protective clothing; how to access the facility; emergency operations; disposal of chemical and biological materials; and how to use equipment safely.

Facilities and equipment. It is the responsibility of management to ensure the proper and safe operation of the facility. 	

Facility. Facilities must be of adequate size and the design should allow critical functions to be separated. In a facility where animal testing is the main activity, the major issues are mix-ups and cross-contamination among test systems - each of which can have adverse effects on the integrity of GLP studies. Part 58 requires that:	

Facility design must allow sufficient separation among animal species, projects, and among healthy and sick animals. 

Articles

Good laboratory practice (GLP) regulations became effective in 1979 under 21 CFR Part 58 and apply to all non-clinical safety studies intended to support research permits or marketing authorizations. This article introduces some key elements regarding the application of GLP regulations as a quality system and how GLPs are perceived internationally.