Good Laboratory Practice

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) pre-clinical safety tests.

GLP was instituted following cases of animal test fraud by pharmaceutical and industrial chemical (mainly pesticide) manufacturers. 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. [1]

The original GLP regulatory mandate was promulgated in 1978 by US-FDA (though they may have got it from the New Zealand medicines agency) and published in the Federal Register 43 FR 59985-60020. It was followed a few years later by US-EPA, and (as outlined in the Organisation for Economic Co-operation and Development (OECD) Principles of GLP in 1992) the OECD has since help promulgate it to many countries, helping them place it into their national regulations.

GLP applies to nonclinical 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.


Contents

GLP and the OECD

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.[2]

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. Equipments, 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

GLP and the USFDA

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.

GLP and the European Union

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:

  • Chemical substances; Regulation (EC) N° 1907/2006 (also known as the "Evaluation, Authorisation and Restriction of Chemicals" Regulation, or "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.

GLP and non-OECD member-countries

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 of GLP

GLP studies require adequate and permanent documentation of everything involved in an experimental test: staff qualifications, valid study design, standard operating procedures (SOPs), training, performance, formulation and statistical analyses, and the retention of summary/individual data; so that there can be confidence in the study's design, performance and its results, and anyone (as public agencies have access to the GLP records) can subsequently fully reconstruct the study.

In contrast, academic scientists also perform basic/exploratory experimental research to: identify unknown potential hazards of chemicals, elucidate the mode/mechanism of action for known toxicants, and explore novel toxic endpoints. Accordingly, their experimental methods vary in the delivery route of the test chemical, the number of test animals and the range of doses. [3] Overall, their methods are far more varied than the GLP test protocol is; and (at least before peer review) academics do not like to share their results or methods with other laboratories competing for grant money. These factors make it very hard for regulatory agencies to use the results of academic researchers in chemical risk assessment.

Nonetheless, financially-independent academia's methods & data are heavily critiqued by the best experts in their field (at scientific meetings), as well as during peer-review of journal manuscripts. Thus financially-independent academia's data tends to be the most reliable knowledge mankind has.

As a controversy over ubiquitous plastics chemical bisPhenol-A (bPA) continues (including several of the citations on this web page), it perfectly illustrates the differences between GLP studies and independent academia's safety studies.

Regulatory agencies and industry cite the GLP-compliant Tyl 2008 finding[4] of no bPA reproductive or developmental toxicity in etrogen-sensitive mice, which also used a well validated dosing route & amounts. But independent academics criticized its methods (e.g. Myers et al. 2009 [5]), such as using an estrogenic feed for the test animals (bPA binds to various estrogen receptors). Determinative results rebutting specific claims of safety by the regulatory agencies and bPA manufacturers--found that despite the assumption of rapid excretion if the bPA is ingested (vs. directly injected), low doses of bPA by either exposure route caused the same free bPA levels in serum, and the same amount pre-cancerous cell growth in developing rodents' prostate (infants have not the developed systems to excrete toxic chemicals; yet their developing organs, such as the prostate here, are vulnerable to re-programing towards disease by chemicals such as bPA).[6] In fact, not only is free (toxicologically active) bPA transferred in utero to vulnerable developing animals, but fetuses can actually de-conjugate (activate) bound bPA![7]

In contrast, the GLP regulatory safety studies sponsored by a chemical's manufacturer, while uniform & more transparent, critically do not test much at all; as follows:

  • The financial interest of the study sponsor in having their chemical declared safe enough to use has been shown to bias the results of these safety tests (for pharmaceuticals, many literature reviews have found this correlation; for industrial chemicals, at least four literature reviews have found the same thing, as summarized in a recent Commentary [8]);
  • Near poisoning-level doses, with linear extrapolation to the doses humans are estimated to experience (this is due to expense--realistic lower doses require much larger groups of test animals to reliably detect a difference in outcome, versus the un-dosed control group), so our actual exposures go untestsed--while hormone disrupting and perhaps other chemicals are known to be more potent at low dose than at high dose!;
  • No tests of our actual mixed exposures;
  • Failure to test many endpoints, especially during the vulnerable ultra-complexities of development;
  • CRITICALLY, any disease caused by the chemical is not allowed to develop past the human-equivalent age of 60, when the dosing stops and the animals are immediately killed for tissue analysis (in reality, most diseases occur in older animals, including humans).

Critics of industry say that while GLP requirements have improved reliability, regulatory safety and efficacy tests still rely entirely on the data of the party with a massive financial interest that their chemical is declared safe enough (or effective, if a pharmaceutical) to use. Specifically, the GLP requirement entirely excludes the published scientific literature from risk assessment, though they say that the latter is far more reliable than industry's data. GLP acts as a shield to exclude relevant data because: 1) regulatory agencies define GLP studies as being the desired quality and so other data is not accepted, and 2) independent academics do not need or like GLP, so they do not use it--they have their own methods of data quality, as above.

The claimed result is that for many years, not one chemical risk assessment performed to approve an agent for commercial use has used independent toxicity data to determine the potency of its chemical--excluding hundreds of thousands of published papers from the assessment. Instead, all such "regulatory" risk assessments use only the toxicity data supplied by the regulated party. Yet the independent literature invariably invalidates the toxicity claims of industry's GLP studies--when the chemical has been on the market long enough to be studied by academia--for example, Myers et al. 2009. [9]

In short, GLP is alleged to shield industry's safety claims from any independent confirmation.

GLP and automated systems

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.[10]

Notes and references

  1. ^ Schneider, K (1983(Spring)). "Faking it: The case against Industrial Bio-Test Laboratories". Amicus Journal (Natural Resources Defence Council): 14–26. http://planetwaves.net/contents/faking_it.html. 
  2. ^ "OECD Principles of Good Laboratory Practice (as revised in 1997)". OECD Environmental Health and Safety Publications (OECD) 1. 1998. http://www.oecd.org/document/63/0,2340,en_2649_34381_2346175_1_1_1_37465,00.html. 
  3. ^ Tyl, Rochelle W. (2009). "Basic Exploratory Research Versus Guideline-Compliant Studies Used for Hazard Evaluation and Risk Assessment: Bisphenol A as a Case Study". Environmental Health Perspectives (NIEHS) 117 (11): 1644–1651. doi:10.1289/ehp.0900893. PMC 2801172. PMID 20049112. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2801172. Retrieved 29 June 2009. 
  4. ^ Tyl, RW; Myers CB, Marr MC, Sloan CS, Castillo NP, Veselica MM, Seely JC, Dimond SS, Van Miller JP, Shiotsuka RN, Beyer D, Hentges SG, Waechter JM Jr. (Aug 2008). "Two-generation reproductive toxicity study of dietary bisphenol A in CD-1 (Swiss) mice". Toxicol Sci 104 (2): 362–84. 
  5. ^ Myers, JP; vom Saal FS, Akingbemi BT, Arizono K, Belcher S, Colborn T, Chahoud I, Crain DA, Farabollini F, Guillette LJ Jr, Hassold T, Ho SM, Hunt PA, Iguchi T, Jobling S, Kanno J, Laufer H, Marcus M, McLachlan JA, Nadal A, Oehlmann J, Olea N, Palanza P, Parmigiani S, Rubin BS, Schoenfelder G, Sonnenschein C, Soto AM, Talsness CE, Taylor JA, Vandenberg LN, Vandenbergh JG, Vogel S, Watson CS, Welshons WV, Zoeller RT (Mar 2009). "Why public health agencies cannot depend on good laboratory practices as a criterion for selecting data: the case of bisphenol A". Environ Health Perspect. 117 (3): 309–15. doi:10.1289/ehp.0800173. PMC 2661896. PMID 19337501. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2661896. 
  6. ^ Prins, GS; Ye SH, Birch L, Ho SM, Kannan K (Jan 2011). "Serum bisphenol A pharmacokinetics and prostate neoplastic responses following oral and subcutaneous exposures in neonatal Sprague-Dawley rats". Reprod Toxicol 31 (1): 1–9. doi:10.1016/j.reprotox.2010.09.009. PMC 3033961. PMID 20887781. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3033961. 
  7. ^ Nishikawa, Miyu; Hidetomo Iwano, Risa Yanagisawa, Nanako Koike, Hiroki Inoue, Hiroshi Yokot (September 2010). "Placental Transfer of Conjugated Bisphenol A and Subsequent Reactivation in the Rat Fetus". Environ Health Perspect. 118 (9): 1196–1203. doi:10.1289/ehp.0901575. PMC 2944077. PMID 20382578. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2944077. 
  8. ^ Tweedale, AC (2011). "Uses of ‘Good Laboratory Practices’ by regulated industry and agencies, and the safety of bisphenol A". J Epidemiol Community Health (BMJ Group) 65 (6): 475e476. doi:10.1136/jech.2010.127761. 
  9. ^ Myers JP et al. 2009.
  10. ^ 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

External links


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