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The Ph. Eur. policy on impurities

The Ph. Eur. policy on impurities. Dr Andrea Lodi Deputy Head, Laboratory Department, EDQM, Council of Europe. Impurities control. Adapt to global trade Define practice for future monographs Reflect regulatory practice in monographs

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The Ph. Eur. policy on impurities

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

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

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

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

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

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

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

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

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

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

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

  12. 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” (orSubstances for Pharmaceutical Use) © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved

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

  14. 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)]. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved

  15. Substances for Pharmaceutical Use Related substances Organic impurities in active substances are to be reported, identified wherever possible, and qualified as indicated in Table2034.-1. © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved

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

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

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

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

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

  21. Substances for Pharmaceutical Use © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved

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

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

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

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

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

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

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

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

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

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

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

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

  35. 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%) © AL IPA/EDQM/IDMA Symposium 2007, All rights reserved

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

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

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