1. FEDERAL INSTITUTE FOR RISK ASSESSMENT Good Laboratory Practice GLP in practice Dr. Wolf Burchard Bulling Federal Institute for Risk Assessment Thielallee 88-92 D-14195 Berlin Tel. +49 30-8412-3936 Fax +49 30-8412-3970 w.bulling@bfr.bund.de www.bfr.bund.de

2. Wolf Burchard Bulling, Workshop on GLP, 17 December 2010, ZagrebPage 2 OECD Council Decision 1981 OECD 1981 Decision of the OECD Council concerning the Mutual Acceptance of Data in the Assessment of Chemicals C(81)30(Final) GLP Data accepted OECD 1981 Decision of the OECD Council concerning the Mutual Acceptance of Data in the Assessment of Chemicals C(81)30(Final) Validated Methods Annex 1: OECD Test Guidelines Annex 2: OECD GLP Principles

3. Wolf Burchard Bulling, Workshop on GLP, 17 December 2010, ZagrebPage 3 Safety Studies Scientific Test Guidelines (scientific method) Use of the current state of the art Interpretation of data Technical GLP-Principles (organisational framework) Reliability of test facility and data Reconstruction of study conduct Quality assurance Report/Archiving Regulatory Authority Monitoring Authority Recognition of Data

4. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, Zagreb Page 4 GLP International EU EC Directives Harmonised EU GLP-System Implementation in MS Mutual Acceptance OECD OECD-Decisions Consensusdocuments Interpretation None OECD-MC MJV Verification Global Mutual Acceptance of Data Support of new EU-MS Candidate Countries Support of OECD-MC and None OECD-MC Cooperation

5. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, Zagreb Page 5 Legal aspects Principles OECD Council Decision 1981 Mutual Acceptance of Data Annex 2: GLP Principles (rev. 1997) EU Council Directive 2004/10/EC (87/18/EEC 99/11/EC) D: Chemicals Act (ChemG) 2008 (1990,1994, 2002) Monitoring OECD Decision-Recommendation 1989, - Monitoring Procedures rev. 1995 - Conduct of Inspections - Exchange of Information EU Council Directive 2004/9/EC (88/320/EEC 90/18/EEC, 99/12/EC) D: GLP General Administrative Provision (ChemVwV-GLP) 1997 (1990)

6. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, Zagreb Page 6 Documents –OECD GLP Principles (1) –Compliance Monitoring (2,3,9) –Consensus Documents (4,5,6,7,8,10,13) –Advisory Documents (11,12,14,15) Documents are available on the OECD GLP Website www.oecd.org/env/glp OECD Series on GLP Additional National Consensus Documents (e.g. Germany): - Archiving, Computerised systems, Multi-Site Studies, GLP Inspectors Manual (www.bfr.bund.de)www.bfr.bund.de Checklists for Inspection (not in Germany)

7. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, ZagrebPage 7 Overview GLP Headquarter Pre-Inspection On-site Inspection Post-Inspection GLP Headquarter Application (or selection by MA) Formation of Inspection Team Document Check Subsequent demand Preliminary inspection Conduct of inspection Verification of corrective actions Inspection report Decision Payment GLP Certificate Entering GLP Monitoring Programme Information exchange among authorities Inspection Team

8. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, ZagrebPage 8 GLP Inspectors University degree Regular training activities Relevant experience Exchanging experience External experts At least two inspectors Communication skills GLP training courses

9. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, ZagrebPage 9 GLP Area of Expertise Studies required by regulations for the purpose of licensing of pharmaceuticals, pesticides, food and feed additives, cosmetic products, veterinary drugs and industrial chemicals GLP Study (Definition OECD Principles, 97) Non-clinical health and environmental safety study, means an experiment or set of experiments in which a test item is examined under laboratory conditions or in the environment to obtain data on its properties and/or its safety, intended for submission to appropriate regulatory authorities. GLP Studies are summarized in 9 OECD Test Categories

10. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, ZagrebPage 10 GLP Area of Expertise Activities not covered by GLP (Scope of GLP)  Studies not required by Regulatory Authorities for risk assessment  Test Guidelines  Suitability of the design of studies or the studies objectives  Suitability of the test system used  Scientific issues  Interpretation of the findings of the studies  Compliance with animal welfare legislation  Compliance with health and safety legislation If study results are not influenced

11. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, ZagrebPage 11 Key Elements of GLP ORGANISATION adequate environment for the experimental work PLAN - PERFORM - REPORT a study in a proper way and while doing so RECORD (for traceability) MONITOR (for quality) ARCHIVE (for reconstruction)

12. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, ZagrebPage 12 Key Elements of GLP  Organisation and Personnel  Quality Assurance Programme  Facilities  Apparatus, Materials, Reagents and Specimens  Test Systems  Test and Reference Substances  Standard Operating Procedures  Performance of the Study  Reporting of Study Results  Storage and Retention of Records (Headlines of the GLP Principles)

13. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, ZagrebPage 13 Outline of an on-site GLP Inspection Structure  Pre-Inspection  Starting Conference  Laboratory Walk  Study Audits (on-going, completed)  Closing Conference

14. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, ZagrebPage 14 Practical auditing Audit strategy All items from the Principles should be covered  Discussion of submitted documents  Selection and detailed check of specific examples (Personnel, Equipment, SOPs, Studies …)  Systematic approach to problematic areas  Procedures verified by documentation

15. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, ZagrebPage 15 Practical auditing The W rule for documentation Who did What, When, Where, What with, and Why The fundamental principle of GLP: not recorded = not done G iant L ot of P aper

16. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, ZagrebPage 16 Practical auditing  Good working atmosphere  Be friendly, helpful and diplomatic  Be open and really Listen  Try to understand  Sharing information  Lead when you must GLP Inspector

17. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, ZagrebPage 17 Practical auditing Each test facility may find their own way to implement all the requirements of the GLP Principles, because room is left in GLP for flexibility

18. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, ZagrebPage 18 Inspection Report Compulsary part of each GLP inspection Finalised in a timely manner after the inspection Confidential OECD Guidance (No. 9) for the Preparation Summary Introduction Narrative Exit Discussion Annexes Other Information

19. Wolf Burchard Bulling, September 2008, DGGF International MeetingPage 19 Follow-up to inspections/study audits Violations Corrective measurements by TF no credibly documented yes Afflict validity of study (TF) Re-inspection In compliance Inspection Report Not in compliance Report EU/OECD Decision None GLP Certificate directlyAnnually

20. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, ZagrebPage 20 Annual Report to EU / OECD

21. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, ZagrebPage 21 Mutual Acceptance of Data EU Directive 1987/18/EEC Legal binding OECD MAD Decision 1981 EU Member States EU MRA OECD Member Countries Non-OECD Member Countries OECD and EU Prerequisite National program, outsourcing of inspection functions possible full implementation of GLP regulations, successful on-site evaluations

22. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, ZagrebPage 22 GLP can not always prevent poor quality or falsification of data, but a robust GLP quality system makes it difficult and acts as a good deterrent.

23. Wolf Burchard Bulling, 17 December 2010, Workshop on GLP, ZagrebPage 23 Thank you for your attention! A N Y Q U E S T I O N S ? Wolf Burchard Bulling