Reference standard

1. Primary / secondary standards in pharmaceutical QC Dr. Christian Zeine LGC Standards GmbH Webinar Series 2013 July 2013

2. Quick guide to the webinar tools Slide 2

3. Topics of today‘s talk • Close look on: • Close look on: Main reference standard types used in pharmaceutical analysis y – Primary reference standards – Secondary reference standards – Pharmacopoeial reference standards Impurity reference standards – Impurity reference standards 3

4. Reference standard types • Reference standards in general – Quote from ICH Q6A guideline (downloadable from www.ich.org) • 2.11 Reference Standard A reference standard, or reference material, is a substance prepared for use as the standard in an assay identification or purity test It should have a as the standard in an assay, identification, or purity test. It should have a quality appropriate to its use. It is often characterized and evaluated for its intended purpose by additional procedures other than those used in routine testing. g For new drug substance reference standards intended for use in assays, the impurities should be adequately identified and / or controlled, and purity should be measured by a quantitative procedure. 4

5. Reference standard types • Primary reference standards – Quote from ICH Q7 guideline (downloadable from www ich org) (downloadable from www.ich.org) • 11.17 Primary reference standards should be obtained as appropriate for the manufacture of APIs The source of each primary reference standard the manufacture of APIs. The source of each primary reference standard should be documented. Records should be maintained of each primary reference standard’s storage and use in accordance with the supplier’s recommendations. Primary reference standards obtained from an officially recognised source are normally used without testing if stored under conditions consistent with the supplier’s recommendations. • 11 18 Where a primary reference standard is not available from an officially • 11.18 Where a primary reference standard is not available from an officially recognized source, an “in-house primary standard” should be established. Appropriate testing should be performed to establish fully the identity and purity of the primary reference standard. Appropriate documentation of this testing should be maintained. 5

6. Primary/secondary reference standards • Recommended approach for primary RS (see also R EP General text 5.12., paragraph 4-1.) d d h f i RS ( l – Usually purity of >95% – Full characterization and documentation of • Identity (with several qualitative techniques: NMR, MS, IR, UV/VIS, Elemental analysis, where appropriate X-ray structure analysis) • Purity (with HPLC => impurity profile) Identify peaks with area percentage >0.1% Maybe check relative response factor of impurity behind peak continued ... continued 6

7. Primary/secondary reference standards • Recommended approach for primary RS (continued) Recommended approach for primary RS (continued) – Full characterization and documentation of • Residual solvents by GC-Headspace methods • Water content by Karl-Fischer titration • Loss on drying (sum of water and residual solvents) y g ( • Melting point (rough purity/identity information) • Sulphated Ash (inorganic impurities) ) • Assay, for primary RSs from purity calculation (with the results from all relevant examinations) plus at least one additional independent method (e.g. qNMR, titration) 7

8. Certificates – Primary y pharmaceutical reference standards 8

9. Certificates – Primary y pharmaceutical reference standards 9

10. Certificates – Primary y pharmaceutical reference standards 10

11. Certificates – Primary y pharmaceutical reference standards 11

12. Certificates – Primary y pharmaceutical reference standards 12

13. Certificates – Primary y pharmaceutical reference standards 13

14. Certificates – Primary y pharmaceutical reference standards 14

15. Certificates – Primary y pharmaceutical reference standards 15

16. Certificates – Primary y pharmaceutical reference standards 16

17. Certificates – Primary y pharmaceutical reference standards 17

18. Primary/secondary reference standards • Secondary reference standards – Quote from ICH Q7 guideline (downloadable from www.ich.org) (downloadable from www.ich.org) • 11.19 Secondary reference standards should be appropriately prepared, identified, tested, approved, and stored. The suitability of each batch of identified, tested, approved, and stored. The suitability of each batch of secondary reference standard should be determined prior to first use by comparing against a primary reference standard. Each batch of secondary reference standard should be periodically requalified in d ith itt t l accordance with a written protocol. 18

19. Secondary pharmaceutical y p reference standards – Certificates 19

20. Secondary pharmaceutical y p reference standards – Certificates 20

21. Secondary pharmaceutical y p reference standards – Certificates 21

22. Reference standard types • Pharmacopoeial reference standards (BP EP USP and others) (BP, EP, USP and others) – Are „special“ primary standards Are „special primary standards • From an officially recognised source • Can be used without further testing • Are widely accepted Are widely accepted – But ... • For claiming official status must be used according • For claiming official status, must be used according to the use mentioned in the monographs • Otherwise, responsibility lies with user, and pharmacopoeia commissions reject responsibility commissions reject responsibility 22

23. Reference standard types • Pharmacopoeial reference standards, Ph restricted use, quotations i l f d d – USP General Chapter <11> : • "They (USP Reference Standards) are explicitly required in many Pharmacopeial assays and tests and are provided solely for such use. Assessment of the suitability for use in other application(s) rests with the purchaser." – General text 5.12., Ph. Eur.: • „EPCRS. A substance (EP CRS) ... intended for use as stated in a monograph of the Ph Eur monograph ... of the Ph. Eur. ... Reference standards are ... suitable for their intended purpose; they are not necessarily suitable for other purposes. ... For any purposes other than that for which it has been established, its suitability ... has to be fully demonstrated." 23

24. Reference standard types • Impurity reference standards I it f t d d – Not much guidance from authorities here – Not much guidance from authorities here • ICH Q3A: Reference standards used in the analytical procedures for control of „Reference standards used in the analytical procedures for control of impurities should be evaluated and characterised according to their intended uses.” • German authority BfArM (“Randnummerndokument”), translated “Impurity standards are used for purity tests and during method development and validation of those tests. Identity must be ensured and purity and assay must be defined ” must be defined. – The following certificate of analysis is normally l t d ( always accepted (see also case study later) l t d l t ) 24

25. CofA: Impurity RS 25

26. CofA: Impurity RS 26

27. CofA: Impurity RS 27

28. CofA: Impurity RS 28

29. CofA: Impurity RS 29

30. CofA: Impurity RS 30

31. CofA: Impurity RS 31

32. Differences between reference standards and research materials • Recent case: Client informed us that authorities were accepting our impurity standard because of the CofA accepting our impurity standard because of the CofA – Client: German subsidiary of one of World‘s top 3 generic Client: German subsidiary of one of World s top 3 generic manufacturers – Also client information: Not all of their materials were accepted because of scarce analytical information were accepted, because of scarce analytical information on CofA • Be aware of the difference between impurity standard and research material, for example CofA 32

33. CofA: Research material 33

34. CofA: Research material 34

35. Differences between reference standards and research materials • Apart from client‘s experience, also to be aware p p of the following: , – CofA is relevant for the corresponding use • I.e. a research material with poor purity/assay information not suitable for quantitative purposes • Like determination of API‘s assay figures or impurity level • For both applications high risks of overestimation of analyte, can result in ... • ... releasing products of insufficient (API) quality into market • ... overestimating impurity => rejecting batches actually fine to be released 35

36. Summary of today‘s talk • Close look on: Main reference standard types used in pharmaceutical analysis analysis – Primary reference standards y • Very detailed characterisation – Secondary reference standards Compared to primary standards • Compared to primary standards – Pharmacopoeial reference standards • Special primary standards (for official applications) – Impurity reference standards • Detailed characterisaton relevant for exact impurity level • Be aware of the differences between a standard and a research material 36

37. Closing remarks g • LGC Standard is part of LGC group • LGC Standard is part of LGC group • S&T section of LGC acts as NMI for chemical and S&T section of LGC acts as NMI for chemical and biochemical measurement in the UK (comparable to NIST in the US) ) 37

38. Closing remarks g • Manufacturing of pharmaceutical reference materials • Manufacturing of pharmaceutical reference materials – For APIs and impurities, over 3,000 standards – Metal impurity materials (suitable eta pu ty ate a s (su tab e for ICP-OES and ICP-MS applications) – Constantly new developments L h f i t d d • Launch of primary standard catalogue products in October 2013! – ISO 34 and ISO 17025 accredited • Contract services Contract services – Custom synthesis (for RSs) – Custom analysis – Characterisation of customer material – Customised packaging and storage t l d t i O t b 2013! 38

39. Closing remarks • Further webinars in July/August, registration possible under http://pharma.lgcstandards.com/ p p g – On website, look under ‘Events’ Always on a Thursday, always 10.30 – 11.15 • 25thof July 2013: • 25thof July 2013: Seven truths of impurities and their reference standards, Part 1 • 1stof August 2013: Seven truths of impurities and their reference standards, Part 2 Seven truths of impurities and their reference standards, Part 2 39

40. QUESTIONS? Now, or to christian.zeine@lgcstandards.com @ g 40