Characterization of non-compendial reference standards for impurities: How good is good enough? Dr. Bernard Olsen, Webinar Presentation

Transcription

1 Characterization of non-compendial reference standards for impurities: How good is good enough? Dr. Bernard Olsen, Webinar Presentation

2 Our brand for pharmaceutical reference standards Over 5,000 Impurity, Active Pharmaceutical Ingredient (API) and Excipient reference standards for more than 1,000 API families Suitable for qualitative and quantitative applications in method development, validation and routine quality control For API, excipient and finished dosage form production Extensive Certificate of Analysis (COA) COA for impurity standards COA for API reference standards produced under ISO guide Expert technical support Advice on technical applications for pharmacopoeial methods and internally developed protocols 5,000+ reference standards 4,000+ impurities for more than 1,000 API families 25 years experience Page 2

3 Characterization of non-compendial reference standards for impurities: How good is good enough? Dr. Bernard Olsen, Webinar Presentation

4 Impurity reference standards In contrast to API 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 Outdated document of German authority BfArM (1996, Randnummerndokument *), translated: Impurity standards are used for purity tests and during method development and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 Page 4

5 Impurityreferencestandards, uses The intended use determines the analytical effort Two major types of uses Qualitative use System suitability Peak identification Validation of specificity parameters Quantitative use Limit test Quantification of impurity Validation of accuracy parameters Page 5

6 Impurity reference standards Impurity RS for qualitative use Identity must be secured Recommended combination of techniques: H-NMR IR CHN (free base/acid vs. salt form) MS (from coupling with LC or GC) UV/VIS (from coupling with LC) plus Purity estimation (from LC/GC, sometimes H-NMR possible, >85% should be the target, otherwise difficulties possible in interpreting H-NMR and IR appropriately) Page 6

7 Impurity reference standards Impurity RS quantitative use Accepted approach (in practice): Identity and assay to be determined Identity as aforementioned: H-NMR, IR CHN (free base/acid vs. salt form, relevant for quantitative use) MS and UV/VIS (GC-MS or LC-DAD-MS) Page 7

8 Impurity reference standards Impurity RS quantitative use Accepted approach (in practice): Identity and assay to be determined Assay per 100%-method (aka mass balance; see also formula) 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) Page 8

9 COA, quantitative impurity RS, regularly accepted by authorities Page 9 9

10 Points to consider during characterization CHN analysis, an underestimated tool (1) Extremely helpful on issues concerning free base/acid vs. salt form Relevant if standard is used for quantification Common issue when user switching from one RS to another (see also next slide) Cl H 2 N O O N H Metoclopramide Imp. G (EP): Metoclopramide N-Oxide N O result [%] specified value [%] Hydrochloride [%] C 53,25 53,25 47,74 H 6,85 7, N 13,07 13,31 11,93 Page 10

11 Salt form issues during RS production Wanted: 1-(3-Chlorophenyl)piperazine Hydrochloride Literature data: Free base M= CAS liquid Hydrochloride M= CAS mp= C Dihydrochloride M= CAS mp= C HN N x HCl Cl Order from commercial sources: Molecular mass CAS Supplier 1 M= (free base) Supplier 2 Supplier 3 M= M= Melting point C (lit.) 210 C C Supply of Dihydrochloride Dihydrochloride Hydrochloride Page 11

12 Points to consider during characterization CHN analysis, an underestimated tool (2) Use of corrected values helpful; water, residual solvent also possible N N O N + F Risperidone cis-n-oxide O N O 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 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 Page 12

13 Points to consider during characterization Look for consistency with other available results Example H-NMR and HPLC, case 1 O HPLC Cl OH 4-Chlorobenzoic acid, bezafibrate impurity A (EP), purity HPLC 99.3% 1 H-NMR Page 13

14 Points to consider during characterization Look for consistency with other available results Example H-NMR and HPLC, case 2 Nabumetone Imp D (EP): Imp of imp at 5.9 minutes O O Page 14

15 Points to consider during characterization Solvent DMSO-d6 0,17% RES Dichloromethane TMSH marker Look for consistency with other available results organic impurities < 0,5% Example H-NMR and HPLC, case 2 Nabumetone Imp D (EP): No corresponding result in H-NMR Page 15

16 Points to consider during characterization HPLC Look for consistency with other available results O 0 h O 1 h 24 h O hυ O Example H-NMR and HPLC, case 2 Nabumetone Imp D light sensitive trans cis Page 16

17 Points to consider during use Can I use a qualitative impurity standard (research material) for quantitative applications? Depending on your perspective: You can, but think twice! If purity indicated as for example >80%, or similar: What value should I use for calculation (quick survey)? 80%? 90%? 100%? No idea? Do not calculate with the minimum 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! Page 17

18 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 False positive OOS results for imps: unnecessary investigations! During development and consideration of ICH Q3A/B: Risk of pushing yourself into unneccessary and expensive qualification studies (e.g., animal tox studies) Page 18

19 Points to consider during use Can I use a qualitative impurity standard (research material) for quantitative applications? The fewer analytical details the higher the economic risk Depending on sources, qualitative standards often lack correct identity with regard to salt forms Also water and residual solvents not checked Especially water can be a considerable percentage of the substance in hydrates, see next slide Page 19

20 Points to consider during use Can I use a qualitative impurity standard (research material) for quantitative applications? The fewer analytical details the higher the economic risk 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 Would mean you report a 0.12% impurity as being 0.17% 200 Above ICH qualification limit of 0.15% 50 unnecessary, 0 expensive toxicity studies % Error assuming 100% assay True Assay, % Page 20

21 Quantitative use: How good is good enough? For quantitative impurity standards: Do we need a second assay method, as for primary API RSs? LGC gets these requests sometimes from clients Mainly due to requests from authorities In my opinion: Not really With the 100%-method (or qnmr), risk of underestimation of assay of impurity RS is extremely low Therefore, with low chance of underestimation of imps present in medicines the safety risk for patients is low Overestimation is minimized with appropriate identification and assigned value Page 21

22 Thank you! To LGC for the opportunity to present this webinar To Dr. Andreas Sieg and Katrin Tänzler for the case study slides And of course to you for your attention Page 22

23 QUESTIONS? Also via to Page 23