Good laboratory practice

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In the experimental (non-clinical) research arena, the phrase good laboratory practice or GLP specifically refers to a quality system of management controls for research laboratories and organizations to try to ensure the uniformity, consistency, reliability, reproducibility, quality, and integrity of chemical (including pharmaceuticals) non-clinical safety tests; from physio-chemical properties through acute to chronic toxicity tests.

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 Organisation 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 chemicals (including pharmaceuticals) to man, animals and the environment. An internationally recognized definition of GLP can be found on the website for the Medicines and Healthcare products Regulatory Agency-UK which defines GLP as:

Good Laboratory Practice (GLP) embodies a set of principles that provides a framework within which laboratory studies are planned, performed, monitored, recorded, reported and archived. These studies are undertaken to generate data by which the hazards and risks to users, consumers and third parties, including the environment, can be assessed for pharmaceuticals (only preclinical studies), agrochemicals, cosmetics, food additives, feed additives and contaminants, novel foods, biocides, detergents etc.... GLP helps assure regulatory authorities that the data submitted are a true reflection of the results obtained during the study and can therefore be relied upon when making risk/safety assessments.

GLP, a data quality system, should not be confused with standards for laboratory safety - appropriate gloves, glasses & clothing to handle lab materials safely.

History[edit]

GLP was first introduced in New Zealand and Denmark in 1972.[1] GLP was instituted in US following cases of fraud generated by toxicology labs in data submitted to the FDA by pharmaceutical companies. Industrial BioTest Labs (IBT) was the most notable case, where thousands of safety tests for chemical manufacturers were falsely claimed to have been performed or were so poor that police investigators could not piece together what work had been done...even though IBT superficially delivered the test results their contracts with the manufacturers specified. [2]

These issues were made public in the hearings at the US Congress, which led to the FDA’s publication of Proposed Regulations on GLP in 1976, with establishment of the Final Rule in June 1979 (21 CFR 58). 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.[3]:5

The OECD[edit]

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: EMV/MC/CHEM(98)17 part two

GLP is a quality system concerned with the organisational processing process and conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported.[4]

GLP principles include

  1. Organization and Personnel
    • Management-Responsibilities
    • Sponsor-Responsibilities
    • Study Director-Responsibilities
    • Principal Investigator-Responsibilities
    • Study Personnel-Responsibilities
  2. Quality assurance program
    • Quality Assurance Personnel
  3. Facilities
    • Test System Facilities
    • Facilities for Test and Reference Items
  4. Equipment, reagents and Materials
  5. Test systems
    • Physical/Chemical
    • Biological
  6. Test & Reference items
  7. Standard operating procedures
  8. Performance of Study
    • Study Plan
    • Conduct of Study
  9. Reporting of results
  10. Storage of Records and Reports

OECD Guidelines for the Testing of Chemicals[edit]

OECD publishes OECD Guidelines for the Testing of Chemicals, which are guidelines that usually have to be followed for GLP compliance. They are widely required by agencies doing risk assessments of chemicals.

The US FDA[edit]

The United States FDA has rules for GLP in 21CFR58. Preclinical trials on animals in the United States of America use these rules prior to clinical research in humans.

Research in the US not conducted under these restrictions or research done outside US not conducted according to the OECD Guidelines (or FDA rules) might be inadmissible in support of a New Drug Application in the US.

European Union[edit]

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.

  • " Directive 2004/10/EC of the European Parliament and of the Council of 11 February 2004 on the harmonisation of laws, regulations and administrative provisions relating to the application of the principles of good laboratory practice and the verification of their applications for tests on chemical substances."

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).

  • " Directive 2004/9/EC of the European Parliament and of the Council of 11 February 2004 on the inspection and verification of good laboratory practice (GLP)".

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.

  • 89/569/EEC Council Decision of 28 July 1989 on the acceptance by the European Economic Community of an OECD decision / recommendation on compliance with principles of good laboratory practice.

There are also 'Product Oriented Directives' referring to GLP obligations:

  • REACH Regulation of 18 December 2006 and Directive 2006/121/EC of 18 December 2006
  • Medicinal products; Directive 2001/83/EC on the Community code relating to medicinal products for human use of 6 November 2001 as amended by Commission Directive 2003/63/EC
  • Veterinary Medicinal Products; Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal products
  • Cosmetics; Council Directive 93/35/EEC amending for the 6th time directive 76/768/EEC
  • Feedingstuffs; Regulation (EC) No 1831/2003 of the European Parliament and of the Council of 22 September 2003 on additives for use in animal nutrition
  • Foodstuffs; Directive 89/107/EEC
  • Novel Foods and novel food ingredients; Regulation (EC) No 258/97 of the European Parliament and of the Council of 27 January 1997 concerning novel foods and novel food ingredients
  • Pesticides; Council Directive 91/414/EEC of 15 July 1991 concerning the placing of plant protection products on the market
  • Biocides; Directive 98/8/EC of the European Parliament and of the Council of 16 February 1998 concerning the placing of biocidal products on the market
  • Detergents; Directive 98/8/EC Regulation (EC) No 648/2004 of the European Parliament and of the Council of 31 March 2004 on detergents
  • EC Ecolabel; Commission Decision 2005/344/EC of 23 March 2005; establishing ecological criteria for the award of the Community eco-label to all-purpose cleaners and cleaners for sanitary facilities

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.

Non-OECD member-countries[edit]

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.

Criticism[edit]

GLP regulations require adequately qualified personnel, adequate facilities, a single qualified study director for each study, a quality assurance unit, adequate test system care facilities, characterized test articles/test items, equipment that has been proven to perform as required and is adequately inspected, cleaned and maintained, standard operating procedures approved by management (not QA), proper documented care of test systems, a study protocol/plan with specified content approved by the study director,and a study report with specified content. The GLP regulations require documentation of any laboratory worksheets, records, memoranda, notes or exact copies thereof, that are the result of original observations and activities of a non-clinical laboratory study and are necessary for the reconstruction and evaluation of the report of that study and an archive for orderly storage and expedient retrieval of all raw data, documentation, protocols/plans, and specimens generated as the result of a non-clinical laboratory study.

Although it is good scientific practice to assure equipment is functioning properly, people are qualified, data are recorded properly, etc... Even though hundreds of facilities around the world, including developing countries, have demonstrated the capability to successfully perform GLP compliant studies, others continue to argue these good scientific practices are too difficult for them to satisfy. Some researchers make the argument that since studies that do not meet these quality standards may be published in peer reviewed scientific journals, good science may be performed without GLP compliance. It is accurate to state that compliance with GLP regulations does not assure good science. Since good and bad science may be performed GLP compliant or non-GLP, this argument misdirects the discussion from the reason why the GLPs are required: to protect public health and safety. Because the data and reports of non-clinical safety studies are used to make public health decisions, it is necessary that these studies can be reconstructed from data that has the integrity, and GLP ensures the integrity of the data.

Klimisch score[edit]

The Klimisch score system tries to rank the reliability of toxicity studies for use by risk assessors (regulatory agencies). It was published in 1997, by BASF (a chemical company) authors.[5] Studies performed according to GLP are assigned the top rank of 1 (reliable without restriction) and are preferred by agencies. When no GLP study is available for a particular endpoint, a study with a rank of 2 is usually accepted by an agency. Lower ranks typically require a new study to be performed. Klimisch scoring is very widely used in chemical risk assessments. Critics say it is a self-interested bias on objectivity, that a quality system from the regulated party gives their own GLP-complying studies the top rank.

Automated systems[edit]

In many instances, the optimal recommended 'no-argument' means of implementing GLP is to develop an automated approach to both Sample Preparation and Sample Measurement. If this can include an overarching 'chain of custody' sample history and data flow, combined with adequate SOP's for calibration & linearization of measuring tools, GLP compliance is virtually assured.

Implementing GLP on an automated system, as an intellectual and labour-intensive task, requires a GxP company to make a great amount of effort. To ease the burden of this management, Webster et al. have provided a tutorial for users to quickly embark on and do the job properly.[6]

Certain Manufacturers & Vendors of Laboratory Instrumentation and/or Laboratory Automation are well-versed in assisting with the application of GLP (and 21CFR11) to their commercial offerings.

Notes and references[edit]

  1. ^ Kevin Robinson for BioPharm International, Aug 1, 2003. GLPs and the Importance of Standard Operating Procedures
  2. ^ Schneider, K (1983(Spring)). "Faking it: The case against Industrial Bio-Test Laboratories". Amicus Journal (Natural Resources Defence Council): 14–26. 
  3. ^ Staff, World Health Organization (2009) Handbook: Good Laboratory Practice (GLP)
  4. ^ "OECD Principles of Good Laboratory Practice (as revised in 1997)". OECD Environmental Health and Safety Publications (OECD) 1. 1998. 
  5. ^ Klimisch HJ, Andreae M, Tillmann U. 1997. A systematic approach for evaluating the quality of experimental toxicological and eco-toxicological data. Regul Toxicol Pharmacol.;25(1):1-5. http://dx.doi.org/10.1006/rtph.1996.1076
  6. ^ Webster, Gregory K. et al.; Kott, L; Maloney, T (2005). "JALA Tutorial: Considerations When Implementing Automated Methods into GxP Laboratories". Journal of the Association for Laboratory Automation (Elsevier) 10 (3): 182–191. doi:10.1016/j.jala.2005.03.003. 

See also[edit]

External links[edit]