The Principles of Good Laboratory Practice (GLP) establish rules and criteria for a quality system that oversees the organizational processes and conditions in which non-clinical health and environmental safety studies are planned, conducted, monitored, recorded, reported, and archived.[1][2] These principles apply to the non-clinical safety testing of substances found in various products to ensure the quality and integrity of the safety data submitted to regulatory authorities globally.[3][4]
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.[5] 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.
GLP was first introduced in New Zealand and Denmark in 1972.[6]
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.[5]
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.[7] 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.[5]
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,[8] and establishment of the Final Rule in June 1979[9] which became effective on June 20, 1979.[10]Proposed amendments were introduced on October 29, 1984.[11] The GLP amendment Final Rule was published on September 4, 1987[12] and became effective on October 5, 1987.[5]
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.[13][14][15]
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.[16] 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.[17] 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.[5] 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.[5] GLP compliance inspections are assessed and performed under the Agency's Bioresearch Monitoring (BIMO) program and carried out by trained BIMO inspectors.[5][17][18][19] Serious noncompliance is dealt with by procedures ranging from study rejection to laboratory disqualification.[17]
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.[20]
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.[30][31] 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.[32] 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.[30][31]
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.[33]
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.[14]
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.[15]
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.[33]
The OECD Principles of Good Laboratory Practice (GLP) cover the testing of chemicals or chemical products in non-clinical settings, either in laboratory conditions or environmental settings, such as greenhouses and field experiments. These principles exclude studies involving human subjects. Depending on the location or governing rules in an OECD-member country, the OECD Principles of GLP might also extend to non-clinical safety testing of other regulated items, like medical devices.[3]
Examples studies conducted under GLP in OECD-member countries include:
Physical-chemical testing;
Toxicity studies;
Mutagenicity studies;
Environmental toxicity studies on aquatic and terrestrial organisms;
Studies on behavior in water, soil, and air; bioaccumulation;
Studies to determine pesticide residues in food or animal feedstuffs;
Studies on effects on mesocosms and natural ecosystems;
Analytical and clinical chemistry testing.
Safety testing data must be submitted to regulatory authorities for product marketing authorization. During the review process, the submitted data undergoes verification to ensure compliance with Good Laboratory Practice (GLP) standards. Additionally, the GLP compliance status of the testing facility where the study was conducted is assessed by referring to inspection information from national GLP compliance monitoring programs.
OECD member countries where non-clinical health and environmental safety testing follows the OECD Principles of Good Laboratory Practice (GLP) have established national GLP Compliance Monitoring Programs (CMP) responsible for overseeing GLP compliance of test facilities within their jurisdictions. These CMPs verify GLP compliance through inspections of test facilities and audits of GLP studies. Test facilities that undergo periodic inspections by a CMP and are found to operate in accordance with GLP principles are recognized as GLP compliant.
In OECD-member countries, testing facilities seeking recognition as GLP compliant can apply to the national CMP. The CMP then conducts inspections to assess if the test facility adheres to the OECD Principles of GLP. In other countries, CMPs have the authority to inspect any test facility that claims to conduct studies according to GLP standards.
The chemicals industry, which includes industrial chemicals, pharmaceuticals, pesticides, biocides, food and feed additives, and cosmetics, ranks as one of the largest industrial sectors in the world.[34] Harmonizing national approaches to chemical regulation offers several benefits: it streamlines requirements for industry, provides governments with a common framework for collaboration, and reduces trade barriers.[3] The OECD Mutual Acceptance of Data (MAD) system, comprising a series of OECD Council Decisions along with OECD Guidelines for Testing Chemicals and OECD Principles of Good Laboratory Practice (GLP), is instrumental in achieving this harmonization.
The MAD system aims to avoid conflicting or redundant national regulations, foster cooperation among national authorities, and eliminate trade barriers. Under this system, OECD countries and full adherents agree that safety tests conducted according to OECD Test Guidelines and Good Laboratory Practice in one country should be accepted by others for assessment purposes—a principle known as "tested once, accepted for assessment everywhere." This approach saves the chemicals industry from the expense of duplicative testing for products marketed in multiple countries. Although the receiving government must accept the study, it retains the discretion to interpret the study results according to its own criteria.[3][34]
According to 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 member countries, such as Australia, Canada, Korea, and the USA. This recognition also extends to some non-OECD countries that fully adhere to the mutual acceptance of data (MAD) under OECD Council Decision C(97)114/Final, including Brazil, India, Malaysia, Singapore, and South Africa, as well as Argentina for industrial chemicals, pesticides, and biocides only.[35]
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.[36]
The Principles of Good Laboratory Practice (GLP) ensure the quality and accuracy of data in chemical testing and help prevent fraud. These principles are developed by the Organisation for Economic Cooperation and Development (OECD) and adopted by the European Union (EU).[4][37][38] European GLP Regulations and Directives also apply to European Economic Area (EEA) member states which include Iceland, Liechtenstein, and Norway. GLP principles govern the non-clinical safety testing of substances in various products, mandated by product-specific legislation in the EU/EEA.[4][35][39]
Directive 2004/9/EC mandates EU/EEA countries to designate GLP inspection authorities and includes requirements for reporting and mutual acceptance of data within the internal market. Annex I of the Directive incorporates OECD Revised Guides for Compliance Monitoring Procedures for GLP, along with OECD Guidance for the Conduct of Test Facility Inspections and Study Audits. It ensures compliance with these guidelines during laboratory inspections and study audits. This directive replaced Directive 88/320/EEC as of 11 March 2004.[4][35][37]
Directive 2004/10/EC, the second core EU GLP Directive, harmonizes laws and administrative provisions for applying GLP principles and verifying their implementation in chemical substance tests. It includes GLP principles in Annex I and requires EU/EEA countries to ensure that laboratories conducting safety studies on chemical products comply with OECD GLP principles. It replaces Directive 87/18/EEC.[4][35][38]
GLP supports the sharing of test data between countries, which helps avoid repeated testing, benefits animal welfare, and saves money for businesses and governments. Having common GLP standards also makes it easier to share information and prevents trade barriers, while helping to protect human health and the environment. The EU has established Mutual Recognition Agreements for GLP with Israel, Japan, and Switzerland.[35]
Current good manufacturing practices (cGMP) are those conforming to the guidelines recommended by relevant agencies. Those agencies control the authorization and licensing of the manufacture and sale of food and beverages, cosmetics, pharmaceutical products, dietary supplements, and medical devices. These guidelines provide minimum requirements that a manufacturer must meet to assure that their products are consistently high in quality, from batch to batch, for their intended use.
In drug development, preclinical development is a stage of research that begins before clinical trials and during which important feasibility, iterative testing and drug safety data are collected, typically in laboratory animals.
GxP is a general abbreviation for the "good practice" quality guidelines and regulations. The "x" stands for the various fields, including the pharmaceutical and food industries, for example good agricultural practice, or GAP.
The regulation of therapeutic goods, defined as drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency. In other jurisdictions they are regulated at the state level, or at both state and national levels by various bodies, as in Australia.
The Food and Drug Administration's (FDA) New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Some 30% or less of initial drug candidates proceed through the entire multi-year process of drug development, concluding with an approved NDA, if successful.
Good clinical practice (GCP) is an international quality standard, which governments can then transpose into regulations for clinical trials involving human subjects. GCP follows the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), and enforces tight guidelines on ethical aspects of clinical research.
Pesticide residue refers to the pesticides that may remain on or in food, after they are applied to food crops. The maximum allowable levels of these residues in foods are stipulated by regulatory bodies in many countries. Regulations such as pre-harvest intervals also prevent harvest of crop or livestock products if recently treated in order to allow residue concentrations to decrease over time to safe levels before harvest.
The process of establishing documentary evidence demonstrating that a procedure, process, or activity carried out in testing and then production maintains the desired level of compliance at all stages. In the pharmaceutical industry, it is very important that in addition to final testing and compliance of products, it is also assured that the process will consistently produce the expected results. The desired results are established in terms of specifications for outcome of the process. Qualification of systems and equipment is therefore a part of the process of validation. Validation is a requirement of food, drug and pharmaceutical regulating agencies such as the US FDA and their good manufacturing practices guidelines. Since a wide variety of procedures, processes, and activities need to be validated, the field of validation is divided into a number of subsections including the following:
In drug development and medical device development the Investigator's Brochure (IB) is a comprehensive document summarizing the body of information about an investigational product obtained during a drug trial. The IB is a document of critical importance throughout the drug development process and is updated with new information as it becomes available. The purpose of the IB is to compile data relevant to studies of the IP in human subjects gathered during preclinical and other clinical trials.
The South African National Accreditation System (SANAS) is the official accreditation body for South Africa. Founded in 1996, SANAS is headquartered in Pretoria, South Africa. SANAS accreditation certificates are a formal recognition by the Government of South Africa that an organisation is competent to perform specific tasks.
The Food Quality Protection Act (FQPA), or H.R.1627, was passed unanimously by Congress in 1996 and was signed into law by President Bill Clinton on August 3, 1996. The FQPA standardized the way the Environmental Protection Agency (EPA) would manage the use of pesticides and amended the Federal Insecticide, Fungicide, and Rodenticide Act and the Federal Food Drug and Cosmetic Act. It mandated a health-based standard for pesticides used in foods, provided special protections for babies and infants, streamlined the approval of safe pesticides, established incentives for the creation of safer pesticides, and required that pesticide registrations remain current.
Verification and validation are independent procedures that are used together for checking that a product, service, or system meets requirements and specifications and that it fulfills its intended purpose. These are critical components of a quality management system such as ISO 9000. The words "verification" and "validation" are sometimes preceded with "independent", indicating that the verification and validation is to be performed by a disinterested third party. "Independent verification and validation" can be abbreviated as "IV&V".
Safety pharmacology is a branch of pharmacology specialising in detecting and investigating potential undesirable pharmacodynamic effects of new chemical entities (NCEs) on physiological functions in relation to exposure in the therapeutic range and above.
Clothianidin is an insecticide developed by Takeda Chemical Industries and Bayer AG. Similar to thiamethoxam and imidacloprid, it is a neonicotinoid. Neonicotinoids are a class of insecticides that are chemically similar to nicotine, which has been used as a pesticide since the late 1700s. Clothianidin and other neonicotinoids act on the central nervous system of insects as an agonist of nAChR, the same receptor as acetylcholine, the neurotransmitter that stimulates and activating post-synaptic acetylcholine receptors but not inhibiting AChE. Clothianidin and other neonicotinoids were developed to last longer than nicotine, which is more toxic and which breaks down too quickly in the environment.
A glossary of terms used in clinical research.
The regulation of genetic engineering varies widely by country. Countries such as the United States, Canada, Lebanon and Egypt use substantial equivalence as the starting point when assessing safety, while many countries such as those in the European Union, Brazil and China authorize GMO cultivation on a case-by-case basis. Many countries allow the import of GM food with authorization, but either do not allow its cultivation or have provisions for cultivation, but no GM products are yet produced. Most countries that do not allow for GMO cultivation do permit research. Most (85%) of the world's GMO crops are grown in the Americas. One of the key issues concerning regulators is whether GM products should be labeled. Labeling of GMO products in the marketplace is required in 64 countries. Labeling can be mandatory up to a threshold GM content level or voluntary. A study investigating voluntary labeling in South Africa found that 31% of products labeled as GMO-free had a GM content above 1.0%. In Canada and the US labeling of GM food is voluntary, while in Europe all food or feed which contains greater than 0.9% of approved GMOs must be labelled.
Pesticide regulation in the United States is primarily a responsibility of the Environmental Protection Agency (EPA). In America, it was not till the 1950s that pesticides were regulated in terms of their safety. The Pesticides Control Amendment (PCA) of 1954 was the first time Congress passed guidance regarding the establishment of safe limits for pesticide residues on food. It authorized the Food and Drug Administration (FDA) to ban pesticides they determined to be unsafe if they were sprayed directly on food. The Food Additives Amendment, which included the Delaney Clause, prohibited the pesticide residues from any carcinogenic pesticides in processed food. In 1959, pesticides were required to be registered.
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.
Craven Laboratories was an American research company based in Austin, Texas.
Guidances for statistics in regulatory affairs refers to specific documents or guidelines that provide instructions, recommendations, and standards pertaining to the application of statistical methodologies and practices within the regulatory framework of industries such as pharmaceuticals and medical devices. These guidances serve as a reference for statisticians, researchers, and professionals involved in designing, conducting, analyzing, and reporting studies and trials in compliance with regulatory requirements. These documents embody the prevailing perspectives of regulatory agencies on specific subjects. It is worth noting that in the United States, the term "Guidances" is used, while in Europe, the term "Guidelines" is employed.
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