1. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved The Ph. Eur. policy on impurities Dr Andrea Lodi Deputy Head, Laboratory Department, EDQM, Council of Europe Dr Andrea Lodi Deputy Head, Laboratory Department, EDQM, Council of Europe

2. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Impurities control Adapt to global trade Define practice for future monographs Reflect regulatory practice in monographs Harmonise the approach for different authors of monographs Define the needs for revision Adapt to global trade Define practice for future monographs Reflect regulatory practice in monographs Harmonise the approach for different authors of monographs Define the needs for revision

3. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Impurities control Impurities are either controlled or not by the test of the current Ph. Eur. monograph Older monographs may not have a test for related substances or use TLC Impurities are either controlled or not by the test of the current Ph. Eur. monograph Older monographs may not have a test for related substances or use TLC

4. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Impurities: key dates General monograph Substances for Pharmaceutical Use January 2002 General chapter 5.10 Control of impurities in substances for pharmaceutical use January 2005 General monograph Substances for Pharmaceutical Use January 2002 General chapter 5.10 Control of impurities in substances for pharmaceutical use January 2005

5. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved 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. ”

6. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved 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 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

7. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Basis for impurities control Specifications for approved products and batch analysis data for approved products Specified impurities are those normally found above identification threshold or those in the specifications for approved products Specified impurities are qualified at or above the level indicated in the monograph Specifications for approved products and batch analysis data for approved products Specified impurities are those normally found above identification threshold or those in the specifications for approved products Specified impurities are qualified at or above the level indicated in the monograph

8. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Requirements Limits for: Specified impurities Unspecified impurities Total impurities Impurities section Specified impurities Other detectable impurities If the Impurities section is not divided, all the impurities cited are specified Limits for: Specified impurities Unspecified impurities Total impurities Impurities section Specified impurities Other detectable impurities If the Impurities section is not divided, all the impurities cited are specified

9. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Impurities unusually potent or unusually toxic producing toxic or pharmacological effects at a level < the identification threshold  must be qualified and properly controlled producing toxic or pharmacological effects at a level < the identification threshold  must be qualified and properly controlled

10. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved PRODUCTION SECTION Normally gives limits but not methods case 1 Paroxetine anhydrous Impurity G: maximum 1 ppm, determined by LC, coupled with tandem mass spectrometry using a suitable, validated method.  not necessarily verifiable by an independent analyst  Examination of data, inspection Normally gives limits but not methods case 1 Paroxetine anhydrous Impurity G: maximum 1 ppm, determined by LC, coupled with tandem mass spectrometry using a suitable, validated method.  not necessarily verifiable by an independent analyst  Examination of data, inspection

11. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved PRODUCTION SECTION case 2 Pethidine hydrochloride Impurity B (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine)  for non-parenteral use maximum 10 ppm (method given)  for parenteral use maximum 0.1 ppm (method not given) case 2 Pethidine hydrochloride Impurity B (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine)  for non-parenteral use maximum 10 ppm (method given)  for parenteral use maximum 0.1 ppm (method not given)

12. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Other detectable impurities (ODI) Specific Ph. Eur. category Impurities sections in monographs may have a list of ODIs Analytical information only: the impurity is detected (not necessarily controlled) by the monograph method ODIs are limited in the monograph by the limit for “ unspecified impurities ” (or Substances for Pharmaceutical Use) Specific Ph. Eur. category Impurities sections in monographs may have a list of ODIs Analytical information only: the impurity is detected (not necessarily controlled) by the monograph method ODIs are limited in the monograph by the limit for “ unspecified impurities ” (or Substances for Pharmaceutical Use)

13. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Ph.Eur. texts to consult Specific monograph General monograph on Substances for Pharmaceutical Use General chapter 5.10 Control of impurities Any other relevant general monograph (for example Products with TSE Risk) General chapter 5.4 Residual Solvents Specific monograph General monograph on Substances for Pharmaceutical Use General chapter 5.10 Control of impurities Any other relevant general monograph (for example Products with TSE Risk) General chapter 5.4 Residual Solvents

14. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Substances for Pharmaceutical Use This monograph does not apply to herbal drugs, herbal drug preparations or extracts, which are the subject of separate general monographs [Herbal drugs (1433), Herbal drug preparations (1434), Extracts (0765)].

15. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Substances for Pharmaceutical Use Related substances Organic impurities in active substances are to be reported, identified wherever possible, and qualified as indicated in Table 2034.-1. Related substances Organic impurities in active substances are to be reported, identified wherever possible, and qualified as indicated in Table 2034.-1.

16. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Requirements do not apply to biological and biotechnological products oligonucleotides radiopharmaceuticals products of fermentation and semi-synthetic products derived therefrom crude products of animal or plant origin or herbal products peptides (*) (*) draft thresholds applicable to synthetic peptides published in Pharmeuropa 19.3 (July 2007) biological and biotechnological products oligonucleotides radiopharmaceuticals products of fermentation and semi-synthetic products derived therefrom crude products of animal or plant origin or herbal products peptides (*) (*) draft thresholds applicable to synthetic peptides published in Pharmeuropa 19.3 (July 2007)

17. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved 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. ” 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. ”

18. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Impurities Summary: Strategy for compliance Use state-of the-art methods for impurity control Know your product and its impurity profile Know your suppliers Request certificate of suitability to ensure smooth approval procedure Maintain liaison with Ph.Eur. Use state-of the-art methods for impurity control Know your product and its impurity profile Know your suppliers Request certificate of suitability to ensure smooth approval procedure Maintain liaison with Ph.Eur.

19. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Impurity Section Gives impurities 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 Gives impurities 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

20. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved How to use the general monograph “ Substances for Pharmaceutical Use ” to control impurities

21. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Substances for Pharmaceutical Use Use Maximum daily dose Reporting threshold Identification threshold Qualification threshold Human or human and veterinary ≤ 2 g / day > 0.05 per cent > 0.10 per cent or daily intake > 1.0 mg (whichever lower) > 0.15 per cent or daily intake > 1.0 mg (whichever lower) Human or human and veterinary > 2 g / day > 0.03 per cent > 0.05 per cent Veterinary only Not applicable > 0.10 per cent 0.20 per cent > 0.50 per cent

22. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved General chapter 5.10 Defines: Basis for monographs and impurities control Terminology Interpretation of related substances tests Other aspects of impurities control ESSENTIAL READING! Defines: Basis for monographs and impurities control Terminology Interpretation of related substances tests Other aspects of impurities control ESSENTIAL READING!

23. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved

24. Example no.1 Monograph has: Impurity A ≤ … (2 per cent) Impurity D ≤ … (1 per cent) Any other impurity ≤ … (0.5 per cent) Impurities section: Specified impurities A, B, C, D, E; Other detectable impurities F, G Monograph has: Impurity A ≤ … (2 per cent) Impurity D ≤ … (1 per cent) Any other impurity ≤ … (0.5 per cent) Impurities section: Specified impurities A, B, C, D, E; Other detectable impurities F, G

25. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved EXAMPLE 1

26. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Example no. 1 (continued) Impurities A and D are specified impurities with their own acceptance criteria (2%, 1%) “ Any other impurity ” refers to B, C and E as specified impurities (limit is above identification threshold) (0.5%) Apply Substances for Pharmaceutical Use for all other impurities (including F, G) (0.1%) Substance is an active ingredient for human use with maximum daily dose ≤ 2 g: identification threshold > 0.10%; qualification threshold >0.15% Impurities A and D are specified impurities with their own acceptance criteria (2%, 1%) “ Any other impurity ” refers to B, C and E as specified impurities (limit is above identification threshold) (0.5%) Apply Substances for Pharmaceutical Use for all other impurities (including F, G) (0.1%) Substance is an active ingredient for human use with maximum daily dose ≤ 2 g: identification threshold > 0.10%; qualification threshold >0.15%

27. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Example no. 2 Monograph has: Impurity A ≤ … (1 per cent) Any other impurity ≤ … (0.1 per cent) Impurities section: Specified impurities A, B, C, D, E; Other detectable impurities F, G Monograph has: Impurity A ≤ … (1 per cent) Any other impurity ≤ … (0.1 per cent) Impurities section: Specified impurities A, B, C, D, E; Other detectable impurities F, G

28. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved EXAMPLE 2

29. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Example no. 2 (continued) Any other impurity refers to B, C, D, E, F, G and any others (0.1%) => Specific thresholds to be applied to unusually potent or toxic impurities => 0.2 % of impurity G or of any other impurity not in the list must be qualified Any other impurity refers to B, C, D, E, F, G and any others (0.1%) => Specific thresholds to be applied to unusually potent or toxic impurities => 0.2 % of impurity G or of any other impurity not in the list must be qualified

30. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Example no. 3 The monograph has a TLC test: No spot more intense … (0.5 per cent) No impurities section The monograph has a TLC test: No spot more intense … (0.5 per cent) No impurities section

31. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved EXAMPLE 3

32. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Example no. 3 (continued) Apply Substances for Pharmaceutical Use Monograph ( => 0.5%) but General monograph 2034 (=> 0.1%) are  monograph needs to be revised Apply Substances for Pharmaceutical Use Monograph ( => 0.5%) but General monograph 2034 (=> 0.1%) are  monograph needs to be revised

33. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Example no. 4 Monograph: Impurity A ≤ … (2 per cent) Impurity D ≤ … (1 per cent) Any other impurity ≤ … (0.5 per cent) Impurities section: Specified impurities A, B, C, D, E; Other detectable impurities F, G Substance is a semi-synthetic product derived from a fermentation product: Monograph: Impurity A ≤ … (2 per cent) Impurity D ≤ … (1 per cent) Any other impurity ≤ … (0.5 per cent) Impurities section: Specified impurities A, B, C, D, E; Other detectable impurities F, G Substance is a semi-synthetic product derived from a fermentation product:

34. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved EXAMPLE 4

35. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Example no. 4 (continued) Impurities A and D are specified impurities “ Any other impurity ” refers to B, C and E as specified impurities and to all other impurities (including F, G) (0.5%) Impurities A and D are specified impurities “ Any other impurity ” refers to B, C and E as specified impurities and to all other impurities (including F, G) (0.5%)

36. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved Residual solvents Referred to in Substances for Pharmaceutical Use and General Chapter 5.4 Residual solvents Specific monographs do not include a test for residual solvents, except: –Where a product has been approved with a limit higher than the one indicated in 5.4, option 1. –Class 1 solvents Referred to in Substances for Pharmaceutical Use and General Chapter 5.4 Residual solvents Specific monographs do not include a test for residual solvents, except: –Where a product has been approved with a limit higher than the one indicated in 5.4, option 1. –Class 1 solvents

37. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved 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 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