THE APPLICATION OF GLP PRINCIPLES IN THE EU

VADEMECUM ON THE APPLICATION OF GLP PRINCIPLES IN THE EUROPEAN UNION

Table of Contents

1. The GLP Directives
2. The Product Oriented Directives
2.1. Chemical substances & Preparations
2.2. Medicinal products
2.3. Veterinary Medicinal Products
2.4. Cosmetics
2.5. Feedingstuffs
2.6. Foodstuffs
2.7. Novel Foods and novel food ingredients
2.8. Pesticides
2.9. Biocides
2.10. Detergents
3. Community eco-label
3.1. All-purpose cleaners and cleaners for sanitary facilities



1. The GLP Directives

Since 1987 the Council had adopted two basic Directives and a Decision relating to the application of the GLP principles.

  1. 87/018/EEC Council Directive of 18 December 1987 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.

    Lays down the obligation of the Member States to designate the authorithies responsible for GLP inspections in their territory.
    It also comprises reporting and internal market (=mutual acceptance of data) requirements

    Directive 2004/10/EC has replaced Directive 87/018/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."


  2. 88/320/EEC Council Directive of 9 June 1988 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.

    Directive 2004/9/EC has replaced Directive 88/320/EEC as of 11 March 2004

    " 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)".

  3. 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.


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2. The Product Oriented Directives

2.1. Chemical substances (REACH) & Preparations

-Directive 2006/121/EC of 18 December 2006 amending Council Directive 67/548/EEC on the approximation of laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances in order to adapt it to Regulation (EC) No 1907/2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) and establishing a European Chemicals Agency.

Article 3 (Testing and assessment of the properties of substances) requires that tests on substances carried out within the framework of this Directive shall be conducted according to the requirements of Article 13 of Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) and establishing a European Chemicals Agency.

Regulation (EC) N° 1907/2006 of 18 december 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC,93/67/EEC, 93/105/EC and 2000/21/EC.

Article 13.4 of the Regulation requires that “ecotoxicological and toxicological tests and analyses shall to be carried out in compliance with the principles of good laboratory practice provided for in Directive 2004/10/EC or international standards recognised as being equivalent by the commission or the Agency and with the provisions of Directive 86/609/EEC, if applicable”.
(N.B.: No other international standards have yet been recognized as being equivalent to GLP.)
Annex XI of REACH (GENERAL RULES FOR ADAPTATION OF THE STANDARD TESTING REGIME SET OUT IN ANNEXES VII TO X) provides for some exemptions for existing data in case that testing does not appear scientifically necessary.
For more information see also section R.4.2 (Reliability of information) in the Guidance on information requirements and chemical safety assessment.

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-Council Directive 67/548/EEC of 27 June 1967 on the approximation of laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances

Article 3(1) of the Directive requires: “that laboratory tests on chemical substances to assess the effects on health and the environment have to be carried out in compliance with the principles of good laboratory practice provided for in Directive 87/18/EEC”

-Council Regulation (EEC) No 793/93 (corrigendum) organises the collection, diffusion and accessibility of information on existing substances which appear in the European Inventory of Existing Commercial Substances (EINECS) with a view to assess the risks of these substances for man and the environment.

Article 10(5) requires that: “necessary laboratory tests must be performed in accordance with the GLP principles as laid down in Directive 87/18/EEC “

Amended :

-Directive 1999/45/EC (corrigenda 1, 2, 3 & 4) of the European Parliament and of the Council adapts and extends the procedures and standards for the classification and labelling of dangerous substances of Council Directive 67/548/EEC to dangerous preparations placed on the market in the EU. The objective of this Directive is to reduce animal testing and to promote international recognition of tests.

In article 6(2) the Directive requires that: “tests regarding human health and environmental safety have to carried out in compliance with the principles of GLP as specified in Directive 87/18/EEC”

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2.2. Medicinal products for humans

Directive 2001/83/EC on the Community code relating to medicinal products for human use of 6 november 2001as amended by Commission Directive 2003/63/EC.

The Good Laboratory Practice (GLP) requirement is contained in the Introduction and General Principles chapter of Directive 2003/63/EC: “Non-clinical (pharmaco-toxicological) studies shall be carried out in conformity with the provisions related to GLP laid down in Council Directives 87/18/EEC on the harmonisation of regulations and administrative provisions relating to the application of the principles of GLP and the verification of their application for tests in chemical substances; and 88/320/EEC on the inspection and verification of GLP.”

Note for Guidance (NfG) on Safety pharmacology studies for human pharmaceuticals (ICH S7A)

Primary pharmacodynamic studies do not need to be conducted in compliance with GLP.
Generally, secondary pharmacodynamic studies do not need to be conducted in compliance with GLP.
results from secondary pharmacodynamic studies ... may contribute to the safety pharmacology evaluation; when there is no cause for concern (e.g., there are no findings for the safety pharmacological endpoint or the chemical or therapeutic class), these studies need not be repeated in compliance with GLP. In some circumstances, results of secondary pharmacodynamic studies may make a pivotal contribution to the safety evaluation for potential adverse effects in humans, and these are normally conducted in compliance with GLP.
The safety pharmacology core battery should ordinarily be conducted in compliance with GLP. Follow-up and supplemental studies should be conducted in compliance with GLP to the greatest extent feasible.
Safety pharmacology investigations can be part of toxicology ,studies; in such cases, these studies would be conducted in compliance with GLP.

Note for Guidance on Safety pharmacology studies for human pharmaceuticals (ICH S7A)

… data quality and integrity in safety pharmacology studies should be ensured even in the absence of formal adherence to the principles of GLP.
When studies are not conducted in compliance with GLP, study reconstruction should be ensured through adequate documentation of study conduct and archiving of data.
Any study or study component not conducted in compliance with GLP should be adequately justified, and the potential impact on evaluation of the safety pharmacology endpoints should be explained.

Note for Guidance on non-clinical evaluation of the potential for delayed ventricular repolarization by human pharmaceuticals (ICHS7B)

Principles and recommendations described in ICH S7A also apply to the studies conducted in accordance with the present guideline.
In vitro IKr and in vivo QT assays … when performed for regulatory submission should be conducted in compliance with good laboratory practice (GLP).
Follow-up studies … should be conducted in compliance with GLP to the greatest extent feasible.

Toxicokinetics: the assessment of systemic exposure in toxicity studies (ICH S3A)

It should be noted that for those toxicity studies whose performance is subject to Good Laboratory Practice (GLP) the concomitant toxicokinetics must also conform to GLP.
Toxicokinetic studies retrospectively designed to generate specific sets of data under conditions which closely mimic those of the toxicity studies should also conform to GLP when they are necessary for the evaluation of safety.

Repeat Dose Toxicity

Repeated dose toxicity studies should be carried out in conformity with the provisions relating to GLP laid down by Council Directives 87/18/EEC and 88/320/EEC

Reproductive toxicology (ICH S5A)&(ICH S5B (M)

For necessary compliance to GLP, reference is made to such regulations.
If adequate preliminary studies are performed, they are part of the justification of the choice of dose for the main study. Such studies should be submitted regardless of their GLP-status in principle. This may avoid unnecessary use of animals.

Guideline on the Non-Clinical Investigation of the Dependence Potential of Medicinal Products (CHMP/SWP/94227/04)

Studies referred to under the first tier – except those belonging to the safety pharmacology regarding the CNS as outlined under ICH S7A - generally do not need to meet the requirements of GLP, although scientifically high standards should also be maintained in these studies.
The behavioural pharmacology studies for investigating dependence potential referred to in the chapter on the second tier should be conducted in compliance to GLP to the greatest extend possible.
When studies are not conducted in compliance with GLP, study reconstruction should be ensured through adequate documentation of study conduct and archiving of data. Any study or study component not conducted in compliance with GLP should be adequately justified, and the potential impact on evaluation of the behavioural pharmacology endpoints should be explained

Note for Guidance on immunotoxicity studies for human pharmaceuticals (ICHS8)

Immunotoxicity studies are expected to be performed in compliance with GLP. It is recognized that some specialized assays, …, might not comply fully with GLP.

Guideline on environmental risk assessment of medicinal products for human use (CPMP/SWP/4447/00)

Experimental studies should preferably follow the test protocols issued by the EC, OECD or ISO.… Studies should be conducted in compliance with GLP.

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2.3. 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

This Directive assembles the various existing Directives relating to veterinary medicinal products in a single text. The GLP requirement is now contained in Part 3, "Safety and residues testing": “Member States shall ensure that the tests are carried out in accordance with the provisions relating to good laboratory practice laid down by Directives 87/18/EEC and 88/320/EEC”.

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2.4. Cosmetics

Council Directive 93/35/EEC amending for the 6th time directive 76/768/EEC on the approximation of the laws of the Member Sates relating to cosmetic products.

This directive introduces a new article 7a, which states in paragraph 2, “that the assessment of the safety for human health shall be carried out in accordance with the principles of good laboratory practice laid down in Council Directive 87/18/EEC”.

A consolidated version is avaliable here.

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2.5. Feeding Stuff

Commission Regulation (EC) 429/2008 on detailed rules for the implementation of Regulation (EC) 1831/2003 as regards the preparation and the presentation of applications, the assessment and the authorisation of feed additives: Annex II of the Commission Regulation (General requirements to be satisfied by the dossier provided for in article 3) foresees that studies, including those that have been conducted and published previously or coming from peer review, shall be performed and documented according to appropriate quality standards (e.g. GLP or ISO).
Metabolic and residue studies (see 3.2.1) and toxicological studies (see 3.2.2) must be carried out using internationally validated test methods and shall be performed in accordance with European legislation in force or OECD Guidelines for methodological details and according to the principles of GLP.
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2.6. Food stuffs

Food additives are regulated by Directive 89/107/EEC.

Only food additives authorised in accordance with that Directive may be used in the manufacture or preparation of foodstuffs.

The guidance on submission for food additive evaluations

93/99/EEC On the subject of additional measures concerning the official control of foodstuffs.

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2.7. Novel Foods and novel food ingredients (+GGO)

Regulation (EC) No 258/97 of the European Parliament and of the Council of 27 January 1997 concerning novel foods and novel food ingredients.

The commission Recommendation 97/618/EC concerning to scientific aspects and the presentation of information necessary to support applications for the placing on the market of novel foods and novel food ingredients and the preparation of initial assessment reports demands: under par. 3.1. The potential occurrence of allergic reactions to novel proteins or other constituents of NF should be explored. ….. All studies should comply with relevant elements and ethical principles of guidelines on good clinical practice and good laboratory practice.
under XI: XI. Nutritional information on the NF: …..All studies should comply with relevant elements and ethical principles of guidelines on good clinical practice and good laboratory practice.

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2.8. Pesticides (Plant protection)

Council Directive 91/414/EEC of 15 July 1991 concerning the placing of plant protection products on the market

The introductions to annexes II and III to the Directive require that: “tests regarding the safety for human health and the environment for active ingredients and plant protection products must be conducted in accordance with the principles laid down in Directive 87/18/EEC. Guidance Documents

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2.9. Biocidal products

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 Article 8(8) of the Directive requires that: “as a general principle, tests on biocides must be conducted according to the methods described in annex V to Directive 67/548/EEC and Directive 87/18/EEC relating to the application of the principles of good laboratory practice”.

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2.10. Detergents

Regulation (EC) No 648/2004 of the European Parliament and of the Council of 31 March 2004 on detergents

Article 7 of the Regulation requires that: “as a general principle, tests on detergents must be conducted according to either the EN ISO/IEC standard or the principles of good laboratory practice, except for those tests for which the principles of good laboratory practice have been made mandatory:"

According to Annex IV, 4.2.2; following test should be conducted according to the principles of GLP
Fish: the test recommended is that in Annex V.C.1 of Directive 67/548/EEC
Daphnia: the test recommended is that in Annex V.C.2 of Directive 67/548/EEC
Algae: the test recommended is that in Annex V.C.3 of Directive 67/548/EEC
Bacteria: the test recommended is that in Annex V.C.11 of Directive 67/548/EEC

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3. Community Eco-Label

3.1. Award of the Community eco-label to all-purpose cleaners and cleaners for sanitary facilities

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

requires that "Where possible, the testing should be performed by laboratories that meet the general requirements of EN ISO 17025 or equivalent".

According to Artikel 1a and 1c of the Commission Decision; " all-purpose cleaners and cleaners for sanitary facilities are detergents."

According to the Final Detergent Ingredient Database report of June 2007, Quality Guidelines for acceptance of test results as source data for the revised DID-list; appendix 2.
" Test done in recent years after 1995 must be done in a laboratory that conforms to GLP Guidelines. If not the case a full test report is required. "



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Updated October 2008


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