What is Good Laboratory Practice (GLP)
Good Laboratory Practice (GLP): The Principles of Good Laboratory Practice (GLP) set forth guidelines and standards for a quality system that manages the processes and conditions involved in planning, conducting, monitoring, recording, reporting, and archiving non-clinical health and environmental safety studies. These principles are applied to the non-clinical safety testing of substances in various products to ensure the reliability and accuracy of the safety data submitted to regulatory agencies worldwide.
Understanding the historical context of the Good Laboratory Practice (GLP) regulations is essential for grasping their role in ensuring the quality and integrity of nonclinical safety data. These regulations emerged from concerns over the reliability and consistency of safety data used to evaluate the risks of chemicals and products to human health and the environment. GLP regulations are designed to standardize procedures and practices in nonclinical studies, ensuring that data is accurate, reliable, and traceable. This background underscores the importance of adhering to GLP standards in both research and regulatory environments.
Good Laboratory Practice: The concept of GLP was first introduced in New Zealand and Denmark in 1972.
In the 1960s and 1970s in the United States, growing environmental and health concerns regarding chemicals led to increased federal regulation, particularly within the chemical and pharmaceutical industries. This resulted in stricter product testing requirements and the development of inspection programs targeting laboratories involved in animal research. Initiatives by the Office of New Drugs and the Office of Marketed Drugs in 1969, later expanded by the Office of Compliance, included inspections of facilities suspected of poor study validity or misconduct. These inspections revealed significant quality control issues and deficiencies in toxicological testing standards and data reporting.
The case of Industrial BioTest Labs (IBT) was particularly notable. The lab, based in Northbrook, Illinois, conducted safety tests for chemical manufacturers but was found to have either falsified test results or provided data of such poor quality that investigators could not ascertain the extent of the actual work done. Despite these issues, IBT delivered results as stipulated in their contracts with manufacturers. IBT’s operations included research for the U.S. government and various chemical and pharmaceutical companies, and it submitted toxicology data covering a wide range of products, including drugs, pesticides, and cosmetics.
These problems were brought to light during Congressional hearings, leading to the FDA’s proposal of GLP regulations on November 19, 1976. The Final Rule was established in June 1979 and became effective on June 20, 1979. Amendments were proposed on October 29, 1984, with the Final Rule for these amendments published on September 4, 1987, and effective on October 5, 1987.
Similarly, the Environmental Protection Agency (EPA) faced issues with submitted data and issued its own draft GLP regulations in 1979 and 1980. The Final Rules were published in two parts (40 CFR 160 and 40 CFR 792) in 1983.
U.S. Food and Drug Administration (21 CFR Part 58) Good Laboratory Practice
The U.S. Food and Drug Administration (FDA) mandates nonclinical laboratory studies on new drugs, food additives, and chemicals to evaluate their safety and effectiveness in humans, following 21 CFR Part 58, which outlines Good Laboratory Practice (GLP) for Nonclinical Studies under the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act. These regulations establish the criteria for conducting nonclinical studies that support applications for research or marketing permits for various products, including food additives, drugs, medical devices, and biological products. Adhering to scientific principles and quality control in these studies is essential, as their results significantly impact human health and safety. Compliance with 21 CFR Part 58 ensures that the data produced are high-quality, reliable, and acceptable for submission to the FDA for product approval.
Following GLP regulations safeguards the well-being of humans and animals involved in studies and upholds the integrity of scientific research in the development of FDA-regulated products. The FDA’s Bioresearch Monitoring (BIMO) program, which involves trained inspectors, conducts compliance inspections. Severe instances of noncompliance can result in actions ranging from rejection of study results to disqualification of the laboratory.
Since June 20, 1979, the FDA has addressed numerous queries about GLP regulations (21 CFR 58). These responses are archived by the Dockets Management Branch (HFA-305) and distributed to BIMO program managers and district offices to maintain consistency. To consolidate and clarify these responses, the FDA published the 1981 Questions & Answers – Good Laboratory Practice Regulations document. This document organizes responses by specific GLP provisions for easier reference by both FDA headquarters and field offices.
The FDA has also established memoranda of understanding (MOUs) with Canada, France, Germany, Italy, Japan, the Netherlands, Sweden, and Switzerland to improve collaboration on GLP for nonclinical studies supporting product approvals. These MOUs aim to enhance information exchange and regulatory oversight through inspections.
On August 24, 2016, proposed amendments published in the Federal Register sought to implement a comprehensive GLP Quality System. This system would be mandatory for safety and toxicity studies that support or are intended to support FDA-regulated product submissions. The proposed changes include additional responsibilities for testing facility management and standard operating procedures (SOPs), expanded definitions for all nonclinical laboratory studies, and a framework designed to improve data reliability and regulatory decision-making.
U.S. Environmental Protection Agency Good Laboratory Practice
The Environmental Protection Agency (EPA) oversees the Good Laboratory Practice Standards (GLPS) compliance monitoring program to ensure that the test data provided for pesticide product registration is accurate and dependable. This program supports pesticide registration under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), Section 5 of the Toxic Substances Control Act (TSCA), and testing consent agreements and regulations under Section 4 of TSCA. The EPA monitors pesticide and industrial chemical use through data collected from laboratory inspections and audits.
40 CFR Part 160 pertains to the GLP standards specifically for pesticide chemicals. It sets out the requirements for conducting studies and producing data necessary for the registration of pesticides under FIFRA. This regulation is focused on studies that support the registration or re-registration of pesticide products and includes research on the human health and environmental impacts of pesticides. It addresses various types of studies such as toxicity, residue chemistry, and environmental fate studies required for pesticide registration, all within the context of FIFRA’s regulatory framework for pesticides in the U.S.
40 CFR Part 792 deals with the broader application of GLP standards for nonclinical laboratory studies that evaluate the safety or efficacy of chemical substances, including pesticides, under various EPA regulatory programs. This regulation extends to nonclinical studies related to a wide range of substances beyond pesticides, including chemicals, drugs, and food additives. It encompasses a more extensive range of studies compared to Part 160, reflecting its application to a variety of regulatory programs within the EPA. This part ensures the quality and reliability of data from nonclinical studies used in regulatory decisions across different substance categories.
In summary, while both 40 CFR Part 160 and 40 CFR Part 792 establish GLP standards for laboratory studies, Part 160 is specifically aimed at pesticide registration under FIFRA, whereas Part 792 provides a broader regulatory framework for a variety of nonclinical studies across multiple EPA programs.
The Organisation for Economic Co-operation and Development Good Laboratory Practice
The Organisation for Economic Co-operation and Development (OECD) sets out Principles of Good Laboratory Practice (GLP) to guide the testing of chemicals and chemical products in both laboratory and environmental settings, such as greenhouses and field experiments. These principles do not apply to studies involving human subjects. In OECD member countries, these GLP principles might also cover non-clinical safety testing for other regulated products like medical devices, depending on local regulations.
Typical studies conducted under GLP in OECD countries include:
- Physical-chemical testing
- Toxicity assessments
- Mutagenicity tests
- Environmental toxicity evaluations for aquatic and terrestrial life
- Behavior studies in water, soil, and air, including bioaccumulation
- Pesticide residue analysis in food and animal feed
- Effects studies on mesocosms and natural ecosystems
- Analytical and clinical chemistry testing
For a product to be authorized for marketing, its safety testing data must be submitted to regulatory authorities. This data is verified for GLP compliance, and the testing facility’s GLP status is confirmed through national GLP compliance monitoring programs.
In OECD countries, national GLP Compliance Monitoring Programs (CMPs) oversee the adherence to GLP standards by inspecting test facilities and auditing studies. Facilities that pass these inspections are recognized as GLP compliant.
Testing facilities in OECD countries can apply to their national CMP for GLP recognition. The CMP conducts inspections to ensure compliance with the OECD GLP Principles. In other countries, CMPs are authorized to inspect facilities claiming to follow GLP standards.
Mutual Acceptance of Data (MAD)
The chemicals industry, encompassing industrial chemicals, pharmaceuticals, pesticides, biocides, food and feed additives, and cosmetics, is one of the largest global industrial sectors. Aligning national chemical regulations provides several advantages, including streamlined industry requirements, a unified framework for government collaboration, and reduced trade barriers. The OECD Mutual Acceptance of Data (MAD) system, which includes OECD Council Decisions, OECD Guidelines for Testing Chemicals, and OECD Principles of Good Laboratory Practice (GLP), plays a crucial role in this harmonization process.
The MAD system is designed to prevent conflicting or redundant national regulations, promote cooperation among national authorities, and eliminate trade barriers. It operates on the principle that safety tests conducted in accordance with OECD Test Guidelines and GLP principles in one country should be accepted by other OECD member countries for assessment purposes—often summarized as “tested once, accepted for assessment everywhere.” This approach helps the chemicals industry avoid the costs of duplicate testing for products sold in multiple countries. While the receiving country must accept the study, it has the right to evaluate the results based on its own criteria.
Under OECD Council Decision C(97)186/Final, chemical testing data generated in any OECD member country following OECD Test Guidelines and GLP principles is recognized by other OECD members, such as Australia, Canada, Korea, and the USA. This recognition also extends to certain non-OECD countries that fully adhere to MAD principles under OECD Council Decision C(97)114/Final, including Brazil, India, Malaysia, Singapore, and South Africa, with Argentina included for industrial chemicals, pesticides, and biocides only.
In June 2004, the US FDA released a comparison chart detailing FDA and EPA GLP regulations alongside OECD GLP principles, which helps clarify the key differences and similarities in GLP standards across these regulatory bodies.
European Union
The Principles of Good Laboratory Practice (GLP) are designed to ensure the quality and reliability of data in chemical testing, and to prevent fraud. These principles, developed by the Organisation for Economic Cooperation and Development (OECD), have been adopted by the European Union (EU). They also extend to European Economic Area (EEA) countries, including Iceland, Liechtenstein, and Norway. GLP guidelines are crucial for the non-clinical safety testing of substances in various products, as required by specific EU/EEA legislation.
Directive 2004/9/EC requires EU/EEA countries to appoint authorities responsible for GLP inspections and outlines the reporting and acceptance of data within the internal market. It incorporates the OECD’s Revised Guides for Compliance Monitoring Procedures for GLP and Guidance for Test Facility Inspections and Study Audits. This directive, which took effect on March 11, 2004, replaced Directive 88/320/EEC.
Directive 2004/10/EC, another key GLP regulation, standardizes laws and administrative procedures for applying and verifying GLP principles in chemical substance testing. It includes GLP principles in Annex I and mandates that laboratories conducting safety studies on chemical products adhere to OECD GLP principles. This directive replaced Directive 87/18/EEC.
In 2017, the Clinical Trials Facilitation Group (CTFG) from the Heads of Medicines Agencies issued a Q&A document providing guidance on GLP requirements in the context of clinical trials for human medicines. This document aims to clarify GLP principles relevant to non-clinical safety studies in clinical trial applications.
In March 2024, the Clinical Trials Coordination Group (CTCG) released a new recommendation paper on GLP principles for clinical trial applications under the EU Clinical Trials Regulation (Regulation (EU) No 536/2014). Developed with input from the European Medicines Agency (EMA) and the European Commission (EC), this paper provides clarity on regulatory requirements and transparency about the GLP information needed in Clinical Trial Applications. It is intended to help researchers and sponsors understand expectations and include necessary details in their applications.
GLP facilitates the exchange of test data between countries, reducing the need for duplicate testing, benefiting animal welfare, and saving costs for businesses and governments. By establishing common GLP standards, it also aids in information sharing, prevents trade barriers, and contributes to protecting human health and the environment. The EU has established Mutual Recognition Agreements for GLP with Israel, Japan, and Switzerland.