1. Current Issues & Challenges in the Development of Pharmacopoeial Monographs: European Pharmacopoeia Dr. Susanne Keitel European Directorate for the Quality of Medicines & HealthCare (EDQM) Beijing, 30 March 2010

2. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 2 The Council of Europe –Founded in 1949 –Development of European common and democratic principles –47 member countries –Headquarters in Strasbourg Core values : Protection of human rights (European Convention on Human Rights &Fundamental Freedoms), pluralist democracy & the rule of law

4. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 4 The European Union

5. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 5 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

6. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 6 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”)…

7. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 7 Progressive Transfer of Activities 2007 – Blood Transfusion and Organ Transplantation 2008 – Pharmaceuticals and Pharmaceutical Care (general pharmaceutical activities) 2009 – Cosmetics and Food Packaging

8. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 8 Ph.Eur.+ Eur. Observers

9. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 9 In the World

10. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 10 Content 1.Is There a Need for A Pharmacopoeia? – Scope 2.Challenges of Globalisation – What Can Pharmacopoeias Contribute? 3.Prospective Harmonisation – a Way to Speed-up the Process?

11. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 11 The role of Pharmacopoeias is to Guarantee the Quality of Medicines Harmonised specifications for substances of different origins (worldwide trade) Transparent monographs (impurity profile) Specifications and valid analytical working methods Common Reference Substances

12. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 12 Why a Monograph ? A public standard, an independent evaluation One single quality for everybody Protection of public health via a standard which represents one known quality Simplify the compilation of dossiers for industry and as a result of this the evaluation of marketing authorisation

13. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 13 What Type of Monograph ? All active ingredientes and excipients of general interest Priority: therapeutic interest, number of patients treated, number of countries where the product is approved, mandatory quality

14. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 14 Fields Covered Active substances (organic, inorganic) Excipients Substances of biological and biotechnological origin (insulin, somatropin…) Vegetable drugs and preparations, essential and fatty oils Radiopharmaceuticals Vaccines, sera (human, veterinary), blood derivatives Homoeopathic preparations ….

15. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 15 The Users Pharmaceutical industry Pharmaceutical industry suppliers Regulatory authorities (medicines agencies) OMCLs Others…

16. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 16 The European Pharmacopoeia is… A public health instrument A source of standardisation A reference and a model for quality in the field of medicines Harmonisation of work for 36 European countries  free movement Competition of industry at « eye level » as they are bound by the same health standards Activities based on an international Convention under the aegis of the Council of Europe

17. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 17 Content 1.Is There a Need for A Pharmacopoeia? – Scope 2.Challenges of Globalisation – What Can Pharmacopoeias Contribute? 3.Prospective Harmonisation – a Way to Speed-up the Process?

18. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 18 Impact of Globalisation New routes of API synthesis may result in different impurity profiles Cost pressure in public health systems may cause frequent changes in suppliers A globally acting industry needs harmonised regulatory requirements ….

19. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 19 General Principles in Elaborating Monographs SAFETY FIRST! Products of proven safety Products evaluated and approved by competent authorities of Member States Impurity profiles for existing, approved synthetic routes Robust, validated analytical methods based on collaborative laboratory testing

20. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 20 Directive 2003/63/EC “The monographs of the European Pharmacopoeia shall be applicable to all substances, preparations and pharmaceutical forms appearing in it. In respect of other substances, each Member State may require observance of its own national pharmacopoeia.

21. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 21 Directive 2003/63/EC However, where a material in the European Pharmacopoeia … has been prepared by a method liable to leave impurities not controlled in the pharmacopoeia monograph, these impurities and their maximum tolerance limits must be declared and a suitable test procedure must be described.” Directive 2003/63/EC, 3.2 Content: basic principles and requirements

22. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 22 Need to Stay Up-Dated To serve its purpose, the pharmacopoeia has to stay up-dated with changes in medical practice and technological developments, for example: –The significant growth of biotechnologically manufactured API –The growing importance of ethnic medicines, e.g. Traditional Chinese Medicines

23. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 23 Need to Stay Up-Dated To follow developments in the pharmaceutical industry (change in paradigm introduced by the ICH guidelines Q8, Q9, Q10), while taking into consideration the specific needs of the globally acting industry and small and medium-sized enterprises, BUT The protection of public health stays FIRST PRIORITY!

24. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 24 Content 1.Is There a Need for A Pharmacopoeia? – Scope 2.Challenges of Globalisation – What Can Pharmacopoeias Contribute? 3.Prospective Harmonisation – a Way to Speed-up the Process?

25. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 25 Background International Harmonisation of general monographs and excipients within PDG ongoing, but not on APIs Harmonisation of long-existing texts has proven to be –difficult due to different approaches / traditions –slow to take account of stakeholders’ needs in the different regions who need to adapt

26. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 26 Pilot Project Ph.Eur. and USP Common initiative of 2 manufacturers, Ph.Eur. and USP in 2008 JP has been informed and will observe process and outcome Main idea: harmonise prospectively based on EDQM “P4” procedure for substances still under patent

27. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 27 Pilot Procedure 1.Submission of identical data packages to EDQM and USP 2.After paper review, a common list of questions is sent to the manufacturer 3.EDQM reviews the replies and prepares a draft to a joint EDQM- P4/USP expert group 4.The draft is verified in parallel in laboratories of EDQM, USP, national authorities (OMCLs) or FDA.

28. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 28 Pilot Procedure (2) 5.The manufacturer may test in parallel 6.All labs reports are exchanged 7.The P4 Rapporteur co-ordinates the discussion on the reports and proposes potential changes of the first draft to the manufacturer 8.A consensus draft is published in Pharmeuropa and Pharmacopoeial Forum

29. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 29 Pilot Procedure (3) Review of public comments coordinated by the P4 Rapporteur in consultation with the joint expert group Common version of the final draft must be agreed by all parties Sent for adoption by Ph.Eur. Commission and USP committee

30. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 30 Pilot Procedure (4) Any changes during the approval process must be notified to all parties Target: identical implementation date Evaluation of the pilot process is part of the project

31. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 31 Where Do We Stand Today ? 4 dossiers from 2 manufacturers received 08-10/2008 Reviewed by EP and USP Joint list of questions sent (10-11/2008) Answers from manufacturers received 02/2009-03/2009 First drafts to be published

32. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 32 Potential Problems Non-harmonised general chapters such as chromatography, heavy metals, water determination etc. Establishment of reference substances e.g. availibility of sufficient amounts of impurity samples

33. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 33 Outlook Communication worked well so far All parties committed to progress The experience might give stimulus to International Harmonisation process

34. Dr. Susanne Keitel, 30/03/10 ©2010 EDQM, Council of Europe, All rights reserved 34 Quality is never an accident. It is always the result of high intention, sincere effort, intelligent direction and skilful execution; it represents the wisest choice of many options. John Ruskin