1. Current Issues & Challenges in the Development of Pharmacopoeial Monographs: Some New Challenges in the Impurities Arena Dr. Susanne Keitel European Directorate for the Quality of Medicines & HealthCare Beijing, 30 March 2010

2. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 2 Structure The European Pharmacopoeia: General Monograph “Substances for Pharmaceutical Use” Specific API Monographs General chapter “Control of Impurities in Substances for Pharmaceutical Use” Residual Solvents Genotoxic Impurities Mesylates Heavy Metals

3. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 3 Contents of the European Pharmacopoeia: more than 2200 monographs

4. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 4 Principles of Impurity Control in the European Pharmacopoeia  Reflect EU regulatory practice in monographs  Application of ICH guideline Q3A to pharmacopoeial substances --> focus on quantitative aspects  Adaptation to globalisation  constant need for updating  Revision of old monographs, in particular progressive replacement of TLC by LC, GC or CZE

5. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 5 Pharmacopoeial Requirements for API Requirement for a substance consists of: –Specific monograph + general monograph(s) Whole set of requirements defines quality

6. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 6 General monograph: Substances for Pharmaceutical Use Related substances Unless otherwise prescribed, organic impurities in active substances are to be reported, identified wherever possible, and qualified as indicated in Table 2034.-1. Unless otherwise prescribed, organic impurities in active substances are to be reported, identified wherever possible, and qualified as indicated in Table 2034.-1. Specific thresholds may be applied for impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects. Specific thresholds may be applied for impurities known to be unusually potent or to produce toxic or unexpected pharmacological effects.

7. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 7 Substances for Pharmaceutical Use (2) > 0.5 per cent0.2 per cent> 0.1 per centNot applicableVeterinary only > 0.05 percent > 0.03 per cent> 2 g/dayHuman or human and veterinary > 0.15 per cent or daily intake > 1.0 mg (whichever is the lower) > 0.10 per cent or daily intake > 1.0 mg (whichever is the lower) > 0.05 per cent≤ 2 g /dayHuman or human and veterinary Qualification threshold Identification threshold Reporting threshold Maximum daily dose Use

8. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 8 Thresholds Do not Apply for*  Biological and biotechnological products  Peptides  Oligonucleotides  Radiopharmaceuticals  Products of fermentation and semi-synthetic products derived therefrom  Crude products of animal or plant origin or herbal products *see chapter 5.10 Control of impurities in substances for pharmaceutical use

9. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 9 Tests in Pharmacopoeial Monographs To detect: organic impurities, inorganic impurities, volatiles Methods: –Physical and physico-chemical –Chemical –Chromatographic

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

11. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 11 Impurities Section Gives impurities that are known to be detected by monograph tests Usually controlled by related substances test, but may be other tests Not necessarily exhaustive Based on information obtained and verified during elaboration

12. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 12 Monograph Standard Requirements  Limits for: Specified impurities Unspecified impurities Total impurities Disregard limit  Impurities section (transparency list) Specified impurities Other detectable impurities  If the impurities section is not divided, all the impurities cited are specified

13. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 13 Specified Impurities  Specified impurities are those in specifications for approved products  Specifications for approved products and batch analysis data for approved products  Specified impurities are qualified at or above the level indicated in the monograph

14. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 14 Other Detectable Impurities (ODIs) Specific EP category  Impurities sections in monographs may have a list of ODIs  Analytical information only: the impurity is detected by the monograph method  ODIs are limited in the monograph by the limit for “unspecified impurities” (or Substances for Pharmaceutical Use )

15. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 15 Transparency List Bromazepam

16. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 16 General Chapter 5.10 Control of Impurities in Substances for Pharmaceutical Use Defines:  Basis for the elaboration of monographs with regards to the control of impurities  Terminology  Interpretation of related substances tests  Other aspects of impurities control ESSENTIAL READING!

17. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 17 Control of Impurities in Substances for Pharmaceutical Use The tests are intended to cover organic and inorganic impurities that are relevant in view of the sources of active substances in authorised medicinal products. Control of residual solvents is provided by the general monograph “Substances for pharmaceutical use” and general chapter 5.4 “Residual solvents”. Instructions for the control of impurities may be included in the Production section of a monograph, for example where the only analytical method appropriate... is to be performed by the manuf. since the method is technically too complex for general use...

18. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 18 Specified impurities: A, B, C, D, E, F, G, H, I, J Example: Anhydrous Paroxetine HCl

19. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 19 Interpretation of The Related Substances Test A specific monograph on a substance for pharmaceutical use is to be read in conjunction with the general monograph on substances for pharmaceutical use. Where a monograph has no related substances test (or equivalent) but only specific tests, the user of a substance must nevertheless ensure that there is suitable control of organic impurities. Where an impurity other than a specified impurity is found in an active substance, it is the responsibility of the user of the substance to check whether it has to be identified / qualified

20. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 20 Acceptance criteria for the related substances test presented in different ways in existing monographs. Decision tree given to be used as an aid in the interpretation of the general acceptance criteria and their relation with the Impurities section of the monograph. General acceptance criteria for “other” impurities are currently expressed in various ways in the monographs: “any other impurity”, “other impurities”, “any impurity”, “any spot”, “any band”, etc. Pending editorial adaptation of already published monographs, the decision tree may be used to determine the acceptance criteria to be applied. Interpretation of Related Substances Test

21. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 21 Revision Needs  Replace TLC by LC, GC or CZE  Add a limit for total of impurities  Allow unambiguous peak identification  Bring general acceptance criterion in line with “Substances for pharmaceutical use“  Introduce impurity section (transparency list)

22. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 22 Directive 2003/63/EC “ However, where a starting 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. ”

23. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 23 Monograph Revision Impurities control has to be updated for newly authorised products/sources: “ [Where] a monograph … [may] be insufficient … the competent authorities shall inform the European Pharmacopoeia. The marketing authorisation holder shall provide the European Pharmacopoeia with the details of the alleged insufficiency and the additional specifications applied. ” (Directive 2003/63/EC)

24. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 24 Residual Solvents Dealt with in Substances for Pharmaceutical Use and general chapter 5.4 Residual solvents Specific monographs do not include a test for residual solvents, except:

25. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 25 Residual Solvents: Class 1 solvents are always named and limited in monographs Class 3 solvents are only named and limited in monographs when they exceed 0.5% (impact on assay results) Class 2 solvents are NOT named and limited in monographs: chapter 5.4 applies

26. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 26 Genotoxic Impurities CHMP Guideline on the limits of genotoxic impurities in effect 1.1. 2007 Applicable to 1.New active substances 2.New applications for existing active substances where assessment of the route of synthesis, process control and impurity profile does not provide reasonable assurance that no new or higher levels of genotoxic impurities are introduced as compared to products currently authorised in EU containing the same active substance.

27. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 27 Challenges for the Pharmacopoeia What about existing substances covered by an EP monographs ? Transparency lists may contain structures of potentially genotoxic substances Structural alert does not automatically imply genotoxicity Sometimes production section to flag up PGIs

28. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 28 PGIs in Transparency Statements (1) Classified as « other detectable impurities » This is analytical information only This does not necessarily confirm the occurrence of the impurity at relevant levels Rarely adequate control of such substances EP monographs may relate to several routes of synthesis The PGI may be irrelevant for certain routes of synthesis

29. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 29 PGIs in Transparency Statements (2) In many cases, introduction of regular testing would not be helpful Analytical challenge: sensitivity, specificity Problem for authors of monograph revisions, new monographs and users

30. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 30 Solution Policy paper on GTI adopted by European Pharmacopoeia Commission in March 2008 EMEA QWP and SWP have been consulted Comments were approved by CHMP and CVMP

31. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 31 Products Authorised Before Issuance of the Guideline Monograph based on approved specifcations Structural alert only does not trigger follow-up Action for monographs only needed when study data demonstrate genotoxicity of the PGI New synthetic routes giving rise to new PGIs or higher levels of previously recognised PGIs => apply Guideline

32. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 32 Products Authorised After Issuance of The Guideline Monographs will be based on specifications of the Marketing Authorisations

33. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 33 Consequences Monographs (limit and tests) will be updated if relevant information is submitted from stakeholders (in particular National Competent Authorities) The existence/use of a monograph does not release the user from his responsibility to review the synthetic route, the process control and the impurity profile as regards PGIs Certification Unit applies the Guideline

34. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 34 Update on Mesilates Working party has been created to work on methanesulfonic and benzenesulfonic acid Possible introduction of tests and limits for lower alkylesters Work on alkylesters of the mentioned acids in mesilate and besilate monographs Currently covered by production sections Await action by regulatory authorities Development of general methods may be considered at a later stage

35. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 35 Heavy Metals – State of Play Lack of sensitivity of general test Positive results rarely reported Ph.Eur. Commission recognised the need for a review Working party appointed in 2009 Important factors to be addressed: –Class/source/ origin of the material –Focus on metals which are likely to be present –Focus on priority metals (toxicity, quality) –Allow flexibility in analytical methods –Consider general method approach similar to residual solvents

36. Dr. Susanne Keitel, 03/2010 ©2010 EDQM, Council of Europe, All rights reserved 36 Heavy Metals – State of Play (2) Oct. 2009: ICH Steering Committee decided to establish expert working group to cover metal residues (ICH Q3 D) Scope: to elaborate limits for metal residues, based on CHMP guideline, using similar approach as for residual solvents. Not limited to elements covered in CHMP guideline! First meeting to take place in June 2010. Representatives of EP, JP and USP to participate as observers.

37. Thank you!