1. GLP in the European Union Maik Schmahl Zagreb, 17/12/2010 Chemicals Unit

2. Outline What is GLP? How has it developed? GLP and accreditation: differences and similarities The role of the Member States, the European Commission and the OECD Cooperation with European Agencies and regulatory authorities

3. Good Laboratory Practice - Definition: Quality system concerned with the organisational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported.

4. GLP – Objectives: Promote the quality and validity of data generated in the testing of chemicals Protect human health and the environment Facilitate data recognition  Avoidance of duplicative testing  Animal welfare  Time and resource efficiency  Avoidance of non-tariff barriers to trade

5. GLP vs ISO 17025 Laboratory accreditation addresses and underwrites the technical competence of a laboratory to carry out specified determinations on a continuing basis to defined standards. A laboratory accredited according to ISO 17025 can be considered to have satisfied many of the GLP requirements. However, certain fundamental requirements of the GLP Principles are not covered by or are less stringent in laboratory accreditation

6. GLP vs ISO 17025 Not covered:  use of study plans  Study Director as a concept More stringent requirements under GLP:  recording and reporting of data  management of data retained in archives to allow complete reconstruction of a study  programme of independent quality assurance including internal audits of every study.

7. GLP – the history 1975 FDA inspections were made at a contract research laboratory (Industrial Biotest Corporation), 20.000 studies for hundreds of drugs and pesticides Experiments were poorly conceived, carelessly executed or inaccurately analyzed or reported Data fraud:  Reporting of observations for animals previously designated as dead or euthanized  Pathology summary altered to present more favorable findings Original records were unavailable for review

8. GLP – FDA Survey Incomplete or absent drug administration records Questionable experience of personnel involved in the studies Original records neither signed or dated Management did not assure critical review of data or proper supervision of personnel

9. GLP - History: 1976 : GLP regulation of FDA on non-clinical laboratory studies 1978 : OECD establishes expert group 1981 : OECD Council Decision on Mutual Acceptance of Data (MAD): GLP-Principles contained in Annex II 1983 : Recommendation concerning compliance monitoring 1987/88 : EU adopts GLP Directives 1989 : OECD Council Decision-Recommendation on Compliance Guides for Compliance Monitoring Procedures for GLP Guidance for the Conduct of Laboratory Inspections and Study Audits 1995 : REVISED GUIDANCE FOR GLP MONITORING AUTHORITIES FOR COMPLIANCE MONITORING PROCEDURES FOR GOOD LABORATORY PRACTICE (GUIDES) + New expert group on GLP - Principles 1997 : Adoption of Revised GLP- Principles 1999 : Amendment of EU GLP Directives following OECD 2004: Codification of GLP Directives

10. GLP in the EC - Legal Framework Directive 2004/10/EC on the harmonisation of laws, regulations and administrative provisions relating to the application of the principles of GLP Directive 2004/9/EC on the inspection and verification of GLP = Codified versions of Directive 87/18 EEC and Directive 88/320/EEC + amendments.

11. GLP in the EC - Legal Framework Internal Market For Chemicals: REGULATION (EC) No 1272/2008 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL on classification, labelling and packaging of substances and mixtures (replacing Directive 67/548/EEC (classification, packaging and labelling of chemical substances) and Directive 88/379/EEC (for preparations, as replaced by Dir. 1999/45/EC))  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)

12. GLP in the EC - Legal Framework Internal Market Directives for special chemicals: Medicinal Products (Directive 2001/83/EC amended by 2003/63/EC) Veterinary Medicinal Products (Directive 2001/82/EC ) Plant Protection Products (91/414/EEC) Biocides (98/8/EC) Feed Additives (Regulation 429/2008: detailed rules for 1831/2003) Food Additives (89/397/EEC – GLP required in guidance) Cosmetics (76/768/EEC, 93/35/EEC as amended)

13. GLP: Role of the Member States Article 3.1 of Directive 2004/10/EC: Member States shall adopt the measures necessary for verification of compliance with the principles of good laboratory practice. These measures shall include, in particular, inspections and study checks in accordance with the recommendations of the OECD in this area.

14. Some statistics (2006) Laboratories in EU Member State programmes Austria16 Belgium16 Czech Rep.15 Denmark27 Finland13 France118 Germany163 Greece6 Hungary39 Ireland5 Italy97(including 42 efficacy-residue study sites) Netherlands29 Poland6 Portugal7 Romania6(no MJV yet !) Slovakia25 Slovenia2 Spain57 Sweden14 United Kingdom130 791

15. GLP in the EU - Practicalities Role of the Commission inside the EU:  ensure uniform application of the GLP principles and compliance monitoring in all Member States  facilitate acceptance of data among MS

16. GLP - Role of the Commission inside the EU What we do to achieve this: Regular meetings of Member State experts in the Working Group on Good Laboratory Practice Management of lists of inspected laboratories (CIRCA website) Build up contacts between receiving authorities and monitoring authorities (e.g. EMEA, ECHA) Specific exercises for confidence building: evaluation visits

17. The GLP web site http://ec.europa.eu/enterprise/sectors/chemicals/documents/classification/laboratory-practice/

18. The password-protected CIRCA web site

19. GLP in the EU - Foreign Relations Role of the Commission outside the EU:  supplement and co-ordinate views of MS in international fora (OECD)  correct application of MAD Decision between EU and other OECD countries  acceptance of data through formal agreements on Mutual Recognition (MRA) (Japan, Switzerland, Israel)

20. GLP in the EU - Foreign Relations OECD:  The OECD Principles of GLP are an integral part of the 1981 Council Decision on the Mutual Acceptance of Data in the Assessment of Chemicals (revised 1997)  Countries can have confidence in the quality and rigour of safety tests

21. OECD Non member-countries:  South Africa, Slovenia, Israel and Singapore are full adherents to Council Acts on Mutual Acceptance of Data.  Non-clinical safety data must be accepted by OECD and adhering countries

22. OECD More non-member economies to join : Period of provisional adherence began in 2007 (India, Argentina and Brazil) and 2008 (Malaysia) Provisional adherents will accept data from OECD member countries and other adhering economies while they establish GLP compliance monitoring programme Brasil and India will join MAD in 2011 Next: China?

23. Relevant agencies European Medicines Agency (EMA) http://www.ema.europa.eu ECHA (European Chemicals Agency) http://echa.europa.eu/ EFSA (European Food Safety Authority) http://www.efsa.europa.eu/

24. Example: EMA GLP Inspections 1995 - 2003 : only 2 GLP Inspection Requests by CPMP 2004 - 2007: 6 GLP Inspection Requests by CHMP – study audits 2008 – 4 GLP Inspection Requests by CHMP – study audits 9 Marketing Authorisation Applications for medicines for human use  9 Test facilities, 2 in EU, 4 in Canada, 3 in Non-OECD  41 studies audited, inspection duration of 3 – 6 days  29 studies so far found to be GLP compliant  12 studies found to be not compliant with GLP (in full or partially)

25. Co-operation with receiving authorities 24,675 chemical registration dossiers on 30 November 2010 (first deadline under the REACH regulation). Automated completeness check for these dossiers Compliance check will be performed for at least 5% of the submitted dossiers for each tonnage band. For studies claimed to be done according to GLP, a GLP claim verification procedure has been developed. Procedure includes checking status of the laboratory, requesting full study report and requesting, if deemed necessary, a study audit from a GLP monitoring authority. However, ECHA does not anticipate a need to initiate study audits frequently.

26. GLP – Costs and benefits True: GLP is more demanding and costly than ISO 17025 Has to be seen as part of OECD mutual aceptance of data system OECD estimate: Environment, Health and Safety Programme safes € 153 mn p.a. Source: Cutting Costs in Chemicals Management - How OECD Helps Governments and Industry, Paris 2010 Cutting Costs in Chemicals Management - How OECD Helps Governments and Industry, Paris 2010

27. Conclusions EC has strong interest in effective and correct implementation of GLP in the Member States and in the world:  Necessity for Internal Market  High level of protection of Health and Environment GLP is there for you: Good co-operation with receiving authorities necessary for the effective and correct implementation of GLP Unnecessary to require laboratories already working under GLP to get ISO 17025 accreditation

28. Any questions ? Disclaimer : This presentation does not constitute any formal commitment on behalf of the European Commission and represents the views and opinions of its author only.