REGULATORY COMPLIANCE GUIDE SERIES (GxP Guides)

Excerpt of Good Laboratory Practice Guide

This Guide examines the GLP regulations of the United States and other countries in detail and provides guidelines for compliance, using as a basis the GLP requirements published in the US Code of Federal Regulations, Title 21, Part 58, 2008 Edition. These regulations are intended to assure the quality and integrity of any safety or efficacy data, especially animal testing data, submitted in support of an application to move into clinical trials or for approval to market the new drug. The United States was the first country to implement formal legislation for this purpose and thus other regulatory bodies have tended to use the US text as a basis for their domestic documentation. The move toward harmonization of international drug regulations, strongly propagated by FDA, the Organization for Economic Cooperation and Development (OECD) and subsequently the European Union (EU), has meant that current regulations are virtually interchangeable.

Good Laboratory Practice (GLP) is “a quality system concerned with the organizational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported.” Since compliance with GLP ensures that the study is properly performed and reported, the economic advantages of understanding the regulations and managing the laboratories so that the regulations may be observed are enormous. Following this Guide’s recommendations, scientists and managers responsible for academic research, commercial start-up research and development operations, or established industrial laboratories can understand the impact of GLP requirements on their work and assist them in achieving full compliance simply and inexpensively.

There are, however, several critical compliance issues about which companies need to be concerned. One important aspect to achieving GLP compliance is the attitude of management. Senior management as well as the Study Director must make the operating staff aware of their precise position and responsibilities and how their work is allocated and managed. The most obvious, yet critical, criterion for the personnel of the laboratory is that they must be qualified to do their job. The QA unit (QAU), including the Quality Assurance Manager, is the conscience of the facility and one should “always let your conscience be your guide”. Remember, inspectors will look very closely at the way management supports the QAU and how well QA does the job.

The quality of the test article is another critical compliance issue. Management must ensure that the samples to be tested in the study have been properly characterized and are fully representative of a particular stage in the development or manufacture of the drug or biological under study. Tests are required for identity, strength, purity, stability, and uniformity, as appropriate. The samples for regulatory safety or toxicity testing should be submitted to the testing facility accompanied by a written Certificate of Analysis. These requirements extend the GLP requirements beyond those studies specifically involved in safety/toxicity into the other areas of product characterization and testing. There is general acceptance that qualified test methods may be used in the early, non-clinical and Phase 1 clinical stages of drug development. However, there are certain types of tests which should be validated early in the drug development program. Regardless of whether the methods are qualified or validated, the laboratory must assure that correct test procedures are written up and followed. The FDA’s unwritten motto is “If it is not written down, it did not occur, or it does not exist”. The records are the only proof that the job has been performed properly.

Ultimately the records generated from GLP studies are submitted to a regulatory authority to either gain approval to conduct a clinical study or to obtain market approval. In 2003 the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) issued the specification for the Common Technical Document (CTD) as part of the harmonization of technical requirements for registration of pharmaceuticals for human use. The content of the CTD does not differ much from that defined by the CFR, but the document’s organization and format are very different. All new drug applications in Europe and Japan now have to contain the technical information in CTD format. In the US, the FDA is accepting electronic submissions for the clinical study of Investigational New Drugs (INDs) and New Drug Applications (NDAs) in the CTD format, and it would make sense for a paper submission to use the same guidance. To initiate a clinical study, the regulatory submission must contain a description of the pharmacological effects of the drug (pharmacodynamics, PD) and its adsorption, distribution, metabolism, and excretion (ADME) (pharmacokinetics, PK) in animals.

Since compliance is ultimately determined by inspections of the laboratory organization, special attention is paid to documentation and the preparations for internal and external inspections and audits. GLP compliance of the facility operations, and any study performed therein, must be confirmed by an independent inspection of the facility and by audits of the study data. These actions are carried out by specialist staff of the regulatory agency or, occasionally, by consultants hired by the agency to perform a specific inspection or audit. The FDA and OECD have published guidelines for such inspections and audits and for the preparation of reports on these activities. In the United States, inspections are now performed under the FDA’s Office of Regulatory Affairs (ORA) Bioresearch Monitoring (BIMO) Program.

The recommendations presented in this Guide have been distilled from a large body of information and opinion. The most recent guidelines issued by the FDA and other regulatory authorities to industry and to inspection staff have been referenced. Opinion and advice collected from other regulatory consultants, including ex-FDA personnel, has been reviewed and taken into consideration.

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