In the experimental (non-clinical) research arena, good laboratory practice or GLP is a quality system of management controls for research laboratories and organizations to ensure the uniformity, consistency, reliability, reproducibility, quality, and integrity of products in development for human or animal health (including pharmaceuticals) through non-clinical safety tests; from physio-chemical properties through acute to chronic toxicity tests. [1] [2]
GLP was first introduced in New Zealand and Denmark in 1972, and later in the US in 1978 in response to the Industrial BioTest Labs scandal. It was followed a few years later by the Organization for Economic Co-operation and Development (OECD) Principles of GLP in 1992; the OECD has since helped promulgate GLP to many countries.
GLP applies to non-clinical studies conducted for the assessment of the safety or efficacy of products in development (including pharmaceuticals) for people, animals, and the environment. [1] GLP, a data and operational quality system, is not the same as standards for laboratory safety – appropriate gloves, glasses and clothing to handle lab materials safely. The principles of GLP aim to ensure and promote safety, consistency, high quality, and reliability of chemicals in the process of non-clinical and laboratory testing. GLP is not limited to chemicals and also applies to medical devices, food additives, food packaging, colour additives, animal food additives, other non-pharmaceutical products or ingredients, biological products, and electronic products.
[3] The historical events leading to the proposal of the Good Laboratory Practice (GLP) regulations are crucial for understanding why these regulations are important for assuring the quality and integrity of nonclinical safety data. These regulations were developed in response to concerns about the reliability and consistency of safety data used in assessing the potential risks of chemicals and products to humans and the environment. The GLP regulations aim to standardize procedures and practices in nonclinical studies to ensure accurate, reliable, and traceable data. This background helps highlight the significance of adhering to GLP standards in research and regulatory contexts. [4]
GLP was first introduced in New Zealand and Denmark in 1972. [5]
During the 1960s and 1970s in the United States, a growing concern for environmental issues and health impacts of chemicals prompted increased federal regulation, particularly in the chemical and pharmaceutical sectors, leading to more stringent product testing requirements and the development of inspection programs targeting laboratories conducting animal research. These initiatives, initiated by the Office of New Drugs and the Office of Marketed Drugs in 1969 and later expanded with the Office of Compliance, included inspections of facilities with questionable study validity or misconduct tips, revealing significant quality control issues and deficiencies in animal toxicological testing standards and data reporting [4] .
Industrial BioTest Labs (IBT) was the most notable case where thousands of safety tests for chemical manufacturers were either falsely claimed to have been performed or were of such poor quality that police investigators could not determine the extent of the work completed, despite superficially delivering test results as specified in their contracts with the manufacturers. [6] IBT, a contract laboratory based in Northbrook, Illinois, conducted research for the United States government and various chemical and pharmaceutical companies, both from the U.S. and abroad, and submitted toxicology data to several federal agencies, covering a wide range of products including drugs, insecticides, herbicides, food additives, pesticides, cosmetics, and cleaning products. [4]
These issues were made public in the hearings at the US Congress, which led to the FDA's publication of Proposed Regulations on GLP on November 19, 1976 [7] , and establishment of the Final Rule in June 1979 [8] which became effective on June 20, 1979 [9] . Proposed amendments were introduced on October 29, 1984 [10] . The GLP amendment Final Rule was published on September 4, 1987 [11] and became effective on October 5, 1987 [4] .
The Environmental Protection Agency (EPA) had also encountered similar problems in data submitted to it, and issued its own draft GLP regulations in 1979 and 1980, publishing the Final Rules in two separate parts (40 CFR 160 and 40 CFR 792) in 1983. [12] [13] [14]
The FDA requires nonclinical laboratory studies on new drugs, food additives, and chemicals to assess their safety and potential effectiveness in humans in compliance with 21 CFR Part 58, Good Laboratory Practice for Nonclinical Studies under the Federal Food Drug and Cosmetic Act and Public Health Service Act [15] . These regulations set the standards for conducting nonclinical laboratory studies that support or are intended to support applications for research or marketing permits for products such as food additives, drugs, medical devices, or biological products [16] . Conducting these studies with rigorous adherence to scientific principles and quality control is crucial, as the decisions based on their outcomes directly affect human health and safety [4] . By adhering to the requirements outlined in 21 CFR Part 58, laboratories conducting nonclinical studies can ensure that the data generated are of high quality, reliable, and suitable for submission to the Agency as part of product approval processes.
Compliance with GLP regulations helps to protect the safety and welfare of humans and animals involved in studies and contributes to the overall integrity of scientific research in the development of FDA-regulated products [4] . GLP compliance inspections are assessed and performed under the Agency's Bioresearch Monitoring (BIMO) program and carried out by trained BIMO inspectors [4] [16] [17] [18] . Serious noncompliance is dealt with by procedures ranging from study rejection to laboratory disqualification [16] .
Since June 20, 1979, the FDA has received many questions about Good Laboratory Practice (GLP) regulations (21 CFR 58). The responses to these inquiries are stored in the Dockets Management Branch (HFA-305) and shared with the Agency's Bioresearch Monitoring (BIMO) program managers and district offices to ensure consistency. Consequently, the US FDA published the 1981 Questions & Answers - Good Laboratory Practice Regulations document to consolidate and clarify these responses. This Q&A document categorizes responses by specific GLP provisions to make them more useful for both the FDA headquarters and field offices. [19]
The FDA has signed a memorandum of understanding (MOU) with Canada, [20] France, [21] Germany, [22] Italy, [23] Japan, [24] The Netherlands, [25] Sweden, [26] and Switzerland [27] to enhance cooperation on good laboratory practice (GLP) for nonclinical laboratory studies supporting product approvals, aiming to facilitate information exchange and inspections for regulatory oversight. [28]
Proposed amendments were published in the Federal Register on August 24, 2016, which aimed to require a comprehensive quality system approach known as a GLP Quality System to enhance the current quality system approach for nonclinical laboratory studies. [29] [30] This system would be mandatory for safety and toxicity studies that support or are intended to support applications or submissions for products regulated by the FDA. [31] Proposed modifications to the GLP Quality System include additional responsibilities for testing facility management and SOP maintenance, along with expanded definitions applicable to all nonclinical laboratory studies, aiming to enhance roles and functions aligned with the revised testing facility definition and to establish a framework for improving data reliability in regulatory decision-making. [29] [30]
The EPA's Good Laboratory Practice Standards (GLPS) compliance monitoring program guarantees the accuracy and reliability of test data submitted to the Agency to support pesticide product registration under the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), section 5 of the Toxic Substances Control Act (TSCA), and in accordance with testing consent agreements and rules issued under section 4 of TSCA. The Agency utilizes data obtained from laboratory inspections and audits to oversee the use of pesticides and industrial chemicals. [32]
40 CFR Part 160, Good Laboratory Practice Standards pertains specifically to the Good Laboratory Practice (GLP) standards for pesticide chemicals. It establishes the requirements for conducting studies and generating data used for the registration of pesticides under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). This regulation applies primarily to studies conducted to support the registration or re-registration of pesticide products under FIFRA. It includes studies related to human health and environmental effects of pesticides. It focuses specifically on studies related to pesticide products, including toxicity studies, residue chemistry studies, environmental fate studies, and other types of studies required for pesticide registration. It operates within the context of pesticide regulation under FIFRA, which is specific to the registration and use of pesticides in the United States. [13]
40 CFR Part 792, Good Laboratory Practice Standards, covers the broader application of GLP standards for nonclinical laboratory studies conducted for assessing the safety or efficacy of chemical substances, including pesticides, under various regulatory programs overseen by the EPA. This regulation applies to nonclinical laboratory studies conducted for various purposes beyond pesticides, encompassing studies related to chemicals, drugs, food additives, and other substances regulated by the EPA. This part has a broader scope and is applicable to a wider range of substances and regulatory programs. It covers a more diverse range of nonclinical studies, including those related to chemical substances other than pesticides. This could include studies conducted for assessing the safety of industrial chemicals, pharmaceuticals, food additives, and other substances subject to EPA regulation. It operates across various regulatory programs within the EPA, reflecting a broader framework for ensuring the quality and reliability of nonclinical study data used in regulatory decision-making. [14]
While both 40 CFR Part 160 and 40 CFR Part 792 address GLP standards for laboratory studies, they differ significantly in terms of scope, applicability, and the specific regulatory context in which they operate. Part 160 is tailored to pesticide registration under FIFRA, whereas Part 792 is a more comprehensive framework applicable to a wider range of nonclinical studies conducted for regulatory purposes across different EPA programs. [32]
Following Decision C(97),186/Final of the OECD Council, data generated in the testing of chemicals in one OECD Member Country, in accordance with OECD Test Guidelines and the Principles of GLP are accepted in all other OECD Member Countries. OECD: ENV/MC/CHEM(98)17 part two
GLP is a quality system concerned with the organizational process and conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported. [33]
GLP principles include
In June 2004, the US FDA published a comparison chart of FDA and EPA Good Laboratory Practice (GLP) regulations alongside OECD Principles for GLP, aiding in understanding the key differences and similarities in GLP standards across these regulatory bodies.
Since 1987 the European Council had adopted two basic Directives and a Decision relating to the application of the GLP principles. Directive 2004/10/EC has replaced Directive 87/017/EEC as of 11 March 2004; Directive 2004/9/EC has replaced Directive 88/320/EEC as of 11 March 2004.
This directive lays down the obligation of the Member States to designate the authorities responsible for GLP inspections in their territory. It also comprises requirements for reporting and for the internal market (i.e., mutual acceptance of data).
The Directive requires that the OECD Revised Guides for Compliance Monitoring Procedures for GLP and the OECD Guidance for the Conduct of Test Facility Inspections and Study Audits must be followed during laboratory inspections and study audits.
There are also 'Product Oriented Directives' referring to GLP obligations:
In the meantime the EU has concluded Mutual Acceptance Agreements in the area of GLP with Israel, Japan and Switzerland. By means of the Treaty of the European Economic Area of 13 September 1993, the European Regulations and Directives also apply to Iceland, Liechtenstein and Norway.
The Clinical Trials Facilitation Group (CTFG) of the Heads of Medicines Agency issued a Q&A document in 2017 addressing Good Laboratory Practice (GLP) requirements within the context of clinical trials for human medicines. This document aims to provide clarification and guidance on GLP principles applicable to non-clinical safety studies conducted as part of clinical trial applications. [35]
In March 2024, the Clinical Trials Coordination Group (CTCG) of the Heads of Medicines Agencies released a new recommendation paper on the principles of Good Laboratory Practices (GLP) for clinical trial applications governed by the EU Clinical Trials Regulation (Regulation (EU) No 536/2014). [36] This paper was developed in collaboration with relevant groups from the European Medicines Agency (EMA) and the European Commission (EC) to clarify the applicable regulatory requirements and ensure transparency regarding the level of information required about GLP status in Clinical Trial Applications. [36] [37] This will assist researchers and sponsors in understanding what is expected and how to include the necessary information to support their applications. [37]
An inspection in non-member economies by OECD inspectors will not guarantee that data generated in compliance with GLP will be accepted in other member countries than the one to which they are submitting data and which has thus sent inspectors to verify the accuracy of their compliance statement.
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Industrial Bio-Test Laboratories was an American industrial product safety testing laboratory. IBT conducted significant quantities of research for pharmaceutical companies, chemical manufacturers and other industrial clients; at its height during the 1950s, 1960s, and 1970s, IBT operated the largest facility of its kind and performed more than one-third of all toxicology testing in the United States. IBT was later confirmed of engaging in extensive scientific misconduct and fraud, which resulted in the indictment of its president and several top executives in 1981 and convictions in 1983. The revelations of misconduct by IBT Labs led to reforms in the regulation of pesticides in the United States and Canada.
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