Characterisation of non-compendial reference standards for impurities: How good is good enough?

Transcription

1 Characterisation of non-compendial reference standards for impurities: How good is good enough? Dr. Christian Zeine, Live webinar, Feb 1, 2017 Science for a safer world 1

2 Before we start 2

3 Impurity reference standards In contrast to API RS (see for example Ph.Eur. Chapter 5.12.), for impurity RS not much guidance from authorities ICH Q3A(R2) and Q3B(R2): Reference standards used in the analytical procedures for control of impurities (Q3B: degradation products) should be evaluated and characterised according to their intended uses. Outdated document of German authority BfArM (1996, Randnummerndokument *), translated: Impurity standards are used for purity tests and during method development and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. *Erläuterungen zum Antrag auf Zulassung eines Arzneimittels beim BfArM 3

4 Impurity reference standards, uses The intended use determines the analytical effort Two major types of uses Qualitative use System suitability Peak identification During analytical method validation (e.g. specificity) Quantitative use Limit test Quantification of impurity With the reference standard directly at each test With the help of relative response factors (RRFs) [POLL] During analytical method validation (e.g. accuracy) 4

5 Impurity reference standards, uses Impurity RS for qualitative use Identity must be secured Recommended combination of techniques: H-NMR IR CHN (free base resp. salt form) MS (from coupling with LC or GC) UV/VIS (from coupling with LC or GC) plus Purity estimation (from LC/GC, sometimes H-NMR possible, >85-90% should be the target, otherwise difficulties possible to interpret H-NMR and IR appropiately) 5

6 Impurity reference standards, uses Impurity RS quantitative use Accepted approach (in practice): Identity and assay to be determined Identity as aforementioned: H-NMR, IR CHN (free base resp. salt form, relevant for quantitative use) MS and UV/VIS (from coupling with LC or GC) 6

7 Impurity reference standards, uses Impurity RS quantitative use Accepted approach (in practice): Identity and assay to be determined Assay per 100%-method (aka mass balance; see also formula below): Water by Karl-Fischer/coulometry Residual solvent by H-NMR estimation, or GC/Headspace if necessary Subtract all absolute percentages (aka mass fractions or weight percentages) from 100% Multiply then with analyte s relative percent chromatographic purity (LC/GC) Or use another, sufficiently specific assay technique (e.g. qnmr) 7

8 Next slides: CofA, quant. impurity RS, regularly accepted by authorites 8

9 CofA: Impurity RS 9

10 CofA: Impurity RS 10

11 CofA: Impurity RS 11

12 CofA: Impurity RS 12

13 CofA: Impurity RS 13

14 CofA: Impurity RS 14

15 Points to consider during characterisation CHN analysis, an underestimated tool (1) Extremely helpful on issues concerning free base resp. salt form Relevant to know in case standard is used for quantification Common issue when user switches from one RS to another (see also next slide) O C H N Cl H 2 N O N H N O result [%] specified value [%] Hydrochloride [%] 53,25 53,25 47,74 6,85 7, ,07 13,31 11,93 Metoclopramide Imp. G (EP): Metoclopramide N-Oxide 15

16 Salt form issues during RS production N Cl HN x HCl Wanted: 1-(3-Chlorophenyl)piperazine Hydrochloride Literature data: Free base M= CAS liquid Hydrochloride M= CAS mp= C Dihydrochloride M= CAS mp= C Order from chemical trade: Molecular mass CAS Melting point Supply of Supplier 1 M= (free base) C (lit.) Dihydrochloride Supplier 2 M= C Dihydrochloride Supplier 3 M= C Hydrochloride 16

17 Points to consider during characterisation CHN analysis, an underestimated tool (2) Use of corrected values helpful, here water, residual solvent also possible C [%] H [%] N [%] value mean (n=3) 58,80 6,99 11,55 theoretical value 62,87 6,81 12,22 difference -4,08 0,18-0,67 Risperidone cis-n-oxide correction with 6,48% water; (RES <0,05%) C [%] H [%] N [%] corrected value 62,87 6,76 12,29 difference 0,00-0,05 0,07 17

18 Points to consider during characterisation Look for plausibility between other available results Example H-NMR and HPLC, case 1 Cl O OH 4-Chlorobenzoic acid, bezafibrate impurity A (EP), purity HPLC 99.3% HPLC 1 H-NMR 18

19 Points to consider during characterisation Look for plausibility between other available results Example H-NMR and HPLC, case 2 Nabumetone Imp D (EP): Imp of imp at 5.9 minutes O O 19

20 Points to consider during characterisation Look for plausibility between other available results Example H-NMR and HPLC, case 2 Nabumetone Imp D (EP): No corresponding result in H-NMR O Solvent DMSO-d6 O 0,17% RES Dichloromethane TMSH marker organic impurities < 0,5% 20

21 Points to consider during characterisation Look for plausibility between other available results Example H-NMR and HPLC, case 2 Nabumetone Imp D light sensitive HPLC O 0 h O h 1 h 24 h O O trans cis 21

22 Points to consider during use Can I use a qualitative impurity standard (research material) for quantitative applications? Depending on the angle from which you look on it: You can, but think twice! If purity indicated as for example >80%, or similar: With what value should I calculate? [QUESTION TO PARTICIPANTS!] Do not calculate with that value (i.e. 80%)! Material probably purer than that value, risk of underestimation of impurity If at all: Calculate with 100%! Risk of overestimation only! 22

23 Points to consider during use Can I use a qualitative impurity standard (research material) for quantitative applications? Risk of overestimation of imps Normally no regulatory issue, as patients not at risk to receive medicines with impurities really out of specs Economic risk however for pharmaceutical manufacturer Lot of outcomes possible that would generate hidden costs! False positive OOS results for imps: unnecessary investigations! Issues during validation studies possible During development of FDF (consideration of ICH Q3A/B): Risk of pushing yourself into unneccessary and expensive qualification studies (last resort animal tox studies) 23

24 Points to consider during use Can I use a qualitative impurity standard (research material) for quantitative applications? The less analytical details the higher the economic risk Depending on sources, qualitative standards often lacks correct identity with regard to salt forms Also water and residual solvents not checked Especially water in hydrates can make a considerable part of the substance on hand Salt form and water issues can lead to overestimation of 40% and more, i.e. assuming 100% assay when in fact 70% as is Even when chromatographic purity is quite high 24

25 Quantitative use: How good is good enough? For quantitative impurity standards: Do we need a second assay method, like for primary API RSs? We see these requests sometimes from clients Mainly due to requests from authorities My personal opinion: Not really With the 100%-method (or qnmr), risk of underestimation of assay of impurity RS is extremely low And then also underestimation of imps present in medicines => low risk for patients if at all Overestimation is minimised In backhand with our imp RS: carbon titration from CHN analysis Happy to discuss further please send me an ! 25

26 Closing remarks LGC Standards is part of LGC group Science & Innovation section of LGC acts as NMI for chemical and biochemical measurement in the UK (comparable to NIST in the US) 26

27 Closing remarks Manufacturing of pharmaceutical reference materials For impurities, APIs and excipients approx. 4,300 standards Constantly new developments (e.g. primary standards) Brochure of almost 500 impurity standards available with reference to the USP description, in most cases less expensive price-per-mg compared to USP, plus the CofA! ISO 34 and ISO accredited Customised services Production of solvents For HPLC applications in pharma industry Extremely pure for residue analysis Distribution Pharmacopoeial reference standards, phytochemicals CRMs/RMs from LGC, IRMM, NMIA, NIST etc. for all purposes 27

28 Service modules Process steps based on internal quality standards; ISO or ISO Guide 34 1 Sourcing 2 Quality Control 3 4 Packaging 5 6 RAWmaterial Characterisation Certification 7 Storage 8 Distribution Supplementary processes for stability monitoring and re-testing 28

29 Services for two pharmaceutical World Top 10 companies 1 Sourcing 2 Quality Control 3 4 Packaging 5 6 RAWmaterial Characterisation Certification 7 Storage 8 Distribution 1 Sourcing 2 Quality Control 3 RAWmaterial 4 Packaging 5 Characterisation 6 Certification 7 Storage 8 Distribution 29

30 Services over the whole chain 1 Sourcing 2 Quality Control 3 RAWmaterial 4 Packaging 5 Characterisation 6 Certification 7 Storage 8 Distribution + Stability Monitoring + QC Batch Monitoring For several top generic / ethical companies Depending on the extent of the service, price per unit can go down to less than 30 EURO 30

31 Join us April 6-7, 2017 in Potsdam! Main topics of seminar at Day One: Different kinds of reference standards and their intended application areas How to handle the details presented in a certificate of analysis that help you choose the right reference standard for your specific purpose Presented by experts from EDQM, Teva, LPU and LGC Day Two: Visit our production site in Luckenwalde Manufacture of impurity and primary reference standards Warehouse and dispensing facilities Bridge of Spies Source: Wikipedia You will receive further information with tomorrow s follow up ! 31

32 Thank you! Most of these slides were originally shown at the International Reference Standard Symposium at USP s headquarter on Nov 3, 2016: Thanks to the IRSS organisation team for the opportunity to speak there last year as a representative from LGC Thanks to my colleagues Dr. Andreas Sieg and Dr. Peter Weber for the analytical slides Join us for the seminar in April to see how we produce our reference standards! And thanks of course to you as the audience today! Please take the short survey after leaving the webinar! 32

33 QUESTIONS? Of course also per to Dr Christian Zeine, 2017, LGC. All rights reserved. LGC Ltd., Queens Road, Teddington, Middlesex, TW11 0LY, UK 33