1. Principles of quality control of registered medicines, non- registered medicines and counterfeits of medical products Jean-Marc Spieser, Head of Department of Biological Standardisation, OMCL Network & HealthCare (DBO), EDQM/ Council of Europe, Strasbourg

2. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 2 Content EDQM – General Background Legal environment of registered medicines Tools available for the quality control of registered medicines The case of non-registered medicines and their vast environment How to control non-registered products Counterfeits of medical products How, why, and where it happens How to control it

3. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 3 The Council of Europe –Founded in 1949 –Development of European common and democratic principles –47 member countries –Strasbourg

4. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 4 The Council of Europe –Founded in 1949 –Development of European common and democratic principles –47 member countries –Strasbourg European Convention on Human Rights (protection of individuals) & European Court of Human Rights

5. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 5

6. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 6 The European Union

7. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 7 EDQM - Short History 1964: –Convention on the Elaboration of a European Pharmacopoeia signed by 8 Member States 1992: –1 st co-operation contract with the EU Commission on the Biological Standardisation Programme 1994: –European Community signs the Convention –CEP – Implementation of the “Certification of Suitability scheme” –Official Medicines Control Laboratory (OMCL) – Creation of the Network

8. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 8 Short History Change of name: the Secretariat of the European Pharmacopoeia becomes the European Department (and later “Directorate”) for the Quality of Medicines (and later “& HealthCare”)…

9. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 9 Progressive Transfer of Activities 2007 – Blood Transfusion and Organ Transplantation 2008 – Pharmaceuticals and Pharmaceutical Care (general pharmaceutical activities) 2009 – Cosmetics and Food Packaging

10. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 10 Ph.Eur.+ Eur. Observers

11. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 11 In the World

12. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 12 European Directorate for the Quality of Medicines & HealthCare (EDQM) Mission: to contribute to the basic human right of access to good quality medicines and healthcare Health is a social human right indispensable for the exercise of all other human rights, for prosperity and democratic stability of people in Europe

13. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 13 European Directorate for the Quality of Medicines & HealthCare

14. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 14 European Regulatory Network European Authorities European Union Council of Europe European Union Council Parliament Commission DG Entreprise Brussels European Medicines Agency Medicines AgencyEMEALondon EuropeanDirectorate for the Quality of Medicines & HealthCare EDQMStrasbourg Ph. Eur.** Certification*** OMCL*Network *OMCL :Official Medicines Control Laboratories **Ph.Eur : European Pharmacopoeia ***Certification : Certification of Suitability of Monographs of the European Pharmacopoeia Organ Transplantation Blood Transfusion Pharmaceuticals Pharmaceutical care

15. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 15 Quality Assurance Quality is obtained through the combination of: Definition and concept of the product based on development work Good manufacturing processes steadily under control -starting, in-process and final controls -continuous optimisation -VALIDATED controls of the final product based on suitable and appropriate limited testing (necessary and fully sufficient), All the above should be totally traceable

16. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 16 Quality Assurance As a general conceptQUALITY manufactured is manufactured and not only controlled

17. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 17 Quality Control QC Principles Laboratory of high quality Good equipment: validated, regularly maintained Good reagents Good operators

18. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 18 Quality Control QC PrinciplesQC Principles Working environment QA/QMS in place Good reporting Procedures PTS Follow up and corrective actions Procedures in place Training

19. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 19 Regulations Medicines are submitted to very strict regulations Each individual preparation requires a Marketing Authorisation (MA)

20. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 20 Regulations A fully detailed registration dossier is filed based on:  Quality – Production using appropriate process, suitable ingredients controlled and released by validated tests  Safety - toxicology and pharmacology  Efficacy – clinical

21. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 21 Regulations All information and documentation compiled by producers and/or authorised importer are filed to Health Authorities in accordance with legal procedures and assessed by experts using defined rules  Official Authorisation

22. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 22 Regulations The product is continually assessed throughout its lifetime:  Inspections  Controls through laboratory testing  Pharmacovigilance If non-conformities are found  administrative, legal and/or financial penalities

23. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 23 Tools The MAA: QA part CTD part Pharmacopoeias such as National Pharmacopoeias, International Pharmacopoeias, Ph. Eur., USP -General Chapters -Individual Monographs Guidelines/ aide mémoire for inspections, sampling Literature/ data

24. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 24 Sampling Ensure representativity -withdrawn by authority or mandated persons -not by manufacturer -define place where samples are taken, how and how much Ensure good storage -temperature -humidity -transportation

25. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 25 Non registered “medicines” Traditional origin -Mostly oral and very restricted data available -Origin not always traceable but should be -How to control the claims and attributes given to these products -What to control, which criteria and indicative parameters Legal environment??

26. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 26 Non registered “medicines” Controls -Based on visual recognition of the substance or the plant -If plant is chopped or ground use of of organoleptic properties, microscopic aspect and basic wet chemistry(test tube ) assays -Important to verify that the right species is there -Need of specialists

27. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 27 Non registered “medicines” Controls -Based on traditional knowledge -Sometimes described in literature bust mostly oral -No official standards but need to develop it in known recognised compendia -Be carefull on adulterated, counterfeits -ILLEGAL

28. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 28 COUNTERFEITED MEDICINES By definition not known When and where it will happen -ILLEGAL of course by defition -2 basic areas attacked -Blockbusters, expensive, well known, attractive…….organised crime -Local, smallsmugglers for small quantities of every possible things

29. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 29 COUNTERFEITED MEDICINES How to combat these products -Through multisectorial surveillance -Forensic analysis -Custom vigilance -Police controls

30. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 30 COUNTERFEITED MEDICINES To start with –Visual check of packaging very important Followed by analysis –Simple and more and more sophisticated Need to have comparator –Reference substance(s) –Authentic samples

31. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 31 COUNTERFEITED MEDICINES Simple comparative tests Then sophisticated –HPLC using different detectors, coupled with mass spectrum Usefulness of network

32. Jean-Marc Spieser, 23/09/09 ©2009 EDQM, Council of Europe, All rights reserved 32 Thank you!