What Is GLP? Good Laboratory Practice for Nonclinical Studies in the United States

GLP stands for Good Laboratory Practice: a quality system for the planning, conduct, monitoring, recording, and reporting of nonclinical safety studies. For FDA-regulated nonclinical safety studies, GLP requirements are codified at 21 CFR Part 58, which applies to nonclinical laboratory studies that support applications for FDA-regulated products, including human drugs, biologics, and medical devices.^[S1] EPA has separate GLP regulations at 40 CFR Parts 160 and 792.^[S3][S4] Under the OECD system of Mutual Acceptance of Data (MAD), acceptance applies when the study follows the applicable OECD Test Guidelines and OECD GLP, the facility is covered by an evaluated national compliance-monitoring program, and the tested product is within that program's scope.^[S5]

Which nonclinical studies need GLP

GLP governs how a study is organized and documented: the roles of the study director and the quality assurance unit (QAU), facilities and equipment, standard operating procedures (SOPs), test and control article handling, the protocol, and the retention of raw data and reports.^[S1] It is primarily expected for the nonclinical safety studies that support first-in-human dosing and later clinical trials: repeat-dose toxicology, safety pharmacology, genotoxicity, and reproductive toxicology, as outlined in ICH M3(R2) and S7A.^[S8][S9]

Primary pharmacology (efficacy) studies and most discovery-stage pharmacokinetic work are not usually run under GLP. They still have to be scientifically sound and traceable. An IND may include non-GLP studies; for each nonclinical laboratory study covered by 21 CFR 312.23(a)(8)(iii), the submission must state that it complied with Part 58 or briefly explain the noncompliance.^[S2]

The GLP legal framework in the United States

FDA GLP: 21 CFR Part 58

Part 58 prescribes good laboratory practices for conducting nonclinical laboratory studies that support or are intended to support applications for research or marketing permits for products regulated by FDA, including food and color additives, human and animal drugs, medical devices, biological products, and electronic products.^[S1] A "nonclinical laboratory study" is an in vivo or in vitro experiment in which a test article is studied prospectively in a test system under laboratory conditions to determine its safety; the definition excludes human studies, clinical studies, and field trials in animals, as well as basic exploratory studies carried out to determine whether a test article has any potential utility.^[S1]

The regulation is organized into subparts covering organization and personnel (including the study director and an independent quality assurance unit), facilities, equipment, testing facility operation (SOPs, animal care), test and control articles, the protocol and conduct of a study, records and reports (including retention periods), and disqualification of testing facilities.^[S1]

EPA GLP: 40 CFR Part 160 and Part 792

EPA maintains two GLP regulations that mirror FDA's: 40 CFR Part 160 for studies submitted under the pesticide law (FIFRA)^[S3] and 40 CFR Part 792 for studies submitted under the Toxic Substances Control Act (TSCA).^[S4] They matter to drug developers mainly when choosing a CRO. Ask whether the CRO can conduct your specific study under FDA GLP, EPA GLP, or both. Do not treat a statement of EPA GLP compliance as evidence that an IND-enabling study will be conducted under FDA 21 CFR Part 58.^[S3][S4]

OECD Principles of GLP and Mutual Acceptance of Data

The OECD Principles of Good Laboratory Practice are the international reference on which national GLP rules are aligned. Under MAD, participating authorities accept covered nonclinical safety data when the study follows applicable OECD Test Guidelines and OECD GLP, the test facility has been inspected by a national monitoring program successfully evaluated by OECD, and the product type falls within that program's scope.^[S5] Each member operates a GLP compliance monitoring program; in the United States, FDA and EPA are the monitoring authorities.^[S5] For a US sponsor, whether a study run outside the United States can be used in a US submission therefore depends on those conditions being met.

GLP statements and data formats in FDA submissions

An IND must include, for each nonclinical laboratory study, a statement that the study was conducted in compliance with 21 CFR Part 58 or, if it was not, a brief statement of the reason for the noncompliance.^[S2] The same GLP framework applies to drugs, biologics, and devices; there are no separate GLP regulations by product type as there are in Japan. In addition, nonclinical study data submitted to FDA for certain applications must follow FDA-supported electronic data standards, including the Standard for Exchange of Nonclinical Data (SEND), so a CRO's ability to deliver SEND-conformant datasets is a practical selection criterion.^[S12]

For medical devices, biological safety (biocompatibility) testing that supports a premarket submission is likewise expected to be conducted under Part 58. FDA's guidance on the use of ISO 10993-1 describes the biological evaluation framework that such studies follow.^[S13]

Planning studies under FDA GLP (21 CFR Part 58): what sponsors should look for

For an emerging biotech, the GLP status of each pivotal safety study is a design decision that must be made before the study starts, not a label added afterward. Decide before study initiation whether each study will be conducted under FDA GLP (21 CFR Part 58); the protocol, QAU oversight, records, and final report must meet the applicable Part 58 requirements.^[S1] Because the IND requires a compliance statement for every nonclinical laboratory study,^[S2] sponsors should decide, for each study in the IND-enabling package, whether it will be GLP and document the rationale for any non-GLP study. GLP is also internationally recognized through the OECD system,^[S5] which matters if the program will be filed outside the United States.

The United States does not issue GLP certificates or accreditations; FDA assesses compliance through inspection.^[S6][S7] What exists is the inspection record: FDA inspects nonclinical laboratories under its BIMO program and may issue a Form FDA 483 listing observations.^[S6] Sponsors typically ask a CRO for its recent inspection history and conduct their own qualification audit.

Study governance: roles, protocol, and quality assurance

Part 58 assigns clear responsibilities. Testing facility management appoints a study director, who is the single point of study control, and maintains a quality assurance unit (QAU) that is independent of the personnel engaged in the study.^[S1] The QAU inspects each study at intervals adequate to assure its integrity, keeps a master schedule, and reports findings to management and the study director.^[S1] The protocol must clearly indicate the objectives and all methods for the conduct of the study and be approved by the sponsor before the study begins; changes are made by documented amendment.^[S1] Written SOPs must cover the routine operations of the facility, from animal room preparation to data handling, and deviations must be authorized by the study director and documented.^[S1] When evaluating a CRO, ask to see the QAU organization chart, a sample master schedule, and how protocol amendments and deviations are handled.

Facilities, equipment, and animal care

The facility must be of suitable size and construction, with separation of areas to prevent contamination or mix-ups between studies, test systems, and test and control articles.^[S1] Animal care facilities need sufficient rooms or areas for species separation, isolation of animals with disease, and quarantine, together with controls for environmental conditions and documented pest and sanitation programs.^[S1] Equipment used to generate, measure, or assess data must be adequately tested, calibrated, and maintained, with written records of inspections, maintenance, and any malfunctions.^[S1] Test and control articles must be characterized, properly stored, and tracked through receipt, distribution, and reserve sampling.^[S1] Sponsors should consider a facility walk-through, including archive and sample-storage areas, as part of CRO qualification.

Questions to ask a CRO about GLP

• Which GLP regulation will this study follow: FDA 21 CFR Part 58, EPA 40 CFR Part 160/792, or OECD GLP? Will the final report include the study director's GLP compliance statement and the QAU statement required by 21 CFR Part 58?^[S1]
• Which site will run the study, and what is that site's regulatory inspection history (dates, agencies, any Form FDA 483 observations, and how they were closed)?^[S6]
• Is the QAU independent of study conduct, and how often are in-process inspections performed?
• Can the CRO deliver SEND-conformant datasets for FDA submission?^[S12]
• Does the site hold AAALAC International accreditation, USDA registration, or an NIH OLAW Assurance? Ask for the current documents. These cover the site's animal care and use program; they do not establish that a particular study was conducted under 21 CFR Part 58.^[S1]

Why GLP matters for your nonclinical program

GLP is what allows a regulator to trust that a nonclinical safety study happened as reported: defined responsibilities, an approved protocol, SOPs, an independent QAU, and complete, retained raw data.^[S1] FDA's Part 58 applies to nonclinical laboratory studies intended to support FDA research or marketing applications.^[S1] International acceptance under OECD MAD is subject to the system's stated conditions.^[S5] FDA assesses Part 58 compliance through inspections rather than facility certification.^[S6][S7] Understanding what GLP does and does not cover will help you decide which studies to run under GLP, how to qualify a CRO, and how to describe the resulting data accurately in your submissions.