Development of Genotoxic Impurities Control in Active Pharmaceutical Ingredient

Transcription

1 ( ) (active pharmaceutical ingredient API) R284.1 A (2015) DOI: /j.cnki.issn Development of Genotoxic Impurities Control in Active Pharmaceutical Ingredient WANG Ping, XU Caihong, CHEN Xian, HU Ailing, LOU Chao, JIN Xiufang, GONG Junqiang, CHEN Yiqun(Zhejiang Huayi Pharmaceutical Co., Ltd., Yiwu , China) ABSTRACT: OBJECTIVE To introduce the background of regulatory guidance, valuation and control strategy of genotoxic impurities in active pharmaceutical ingredient(api). METHODS Based on the understanding of regulatory expectations on the control of genotoxic impurity by studying of the history of European and US regulations, propose methods for assessing & controlling genotoxic impurities in drug substance. RESULT & CONCLUSION The most effective way to achieve the regulatory expectations is to establish control strategies based on a combination of semi-quantitative assessment, allied to analytical results and data from appropriate purging studies. Such an approach should ensure that any actual genotoxic impurity related risk is clearly identified and managed. KEY WORDS: genotoxic impurities; API; risk assessment DNA DNA DNA DNA (active pharmaceutical ingredient API) PharmEuropa [1] EMEA (Safety Working Party SWP)(Committee for Proprietary Medicinal Products CPMP Committee for Human Medicinal Products CHMP) [2] ICH Q3C(R5) Tel: (0579) pwang@zhp.com.cn Chin J Mod Appl Pharm, 2015 January, Vol.32 No.1 119

2 [3] (as low as technically feasible ALATF) 2004 () (as low as reasonably practical ALARP) ALATF (threshold of toxicological concern TTC)(1.5 µg d 1 ) [4] (70 ) 1.5 µg (<1/ ) (ppm)=ttc (µg d 1 )/ (g d 1 ) TTC [5] 50% TD TD 50 TD DNA TTC TTC TTC 1.5 µg d 1 TTC (Pharmaceutical Research and Manufacturers of America PhRMA) Lutz Mueller PhRMA [6] TTC 1 1 GTIs Tab. 1 Proposed allowable daily intake for genotoxic impurities during clinical development depending on the duration of exposure /µg d 1 ( ) a 0.5% c >1~3 40 a 0.5% c >3~6 20 a 0.5% c >6~12 10 a 0.5% c > bc a % b % 70 c ( ) Note: a Probability of not exceeding a 10 6 risk is 93%; b Probability of not exceeding a 10 5 risk is 93%, which considers a 70-year exposure; c Other limits (higher or lower) may be appropriate and the approaches used to identify, qualify, and control ordinary impurities during developed should be applied. 12 1/ TTC 1/ Tab. 2 Clarification of genotoxic impurities () () 2 - TD 50 (MTD) () NOEL (LOEL) DNA(DNA DNA ) TTC API ( ) Ames API Ames API ppm API () API API API 120 Chin J Mod Appl Pharm, 2015 January, Vol.32 No

3 EMEA [7] 2008 CHMP (CHMP Safety Working Party, SWP) Q&A [8] TTC SWP TTC Lutz Mueller TTC 3 3 TTC Tab. 3 A staged TTC approach /µg >1~3 20 >3~6 10 >6~12 5 > SWP EDQM 4 4 Tab. 4 EDQM decision table for use during elaboration or revision of monographs CHMP CHMP CHMP ( ) CHMP CHMP CHMP ( ) SWP ( )1.5 µg d 1 TTC ALARP SWP Q&A ICH ICH SWP ICH Q3a ICH Q3a Chin J Mod Appl Pharm, 2015 January, Vol.32 No.1 121

4 1.2 FDA EMEA Q&A FDA EMEA 2008 FDA FDA [9] FDA EMEA TTC SAR FDA ICH EMEA Q&A ALARP FDA EU TTC FDA 120 µg d 1 ( 14 d) ICH ICH M [10] TTC API GTIs EDQM 2006 [11] EDQM TOP EDQM [12] Tab. 5 Top three deficiencies for new application for CEP (2011) [12] 0.10% 3 <30% TTC 2.2 EMEA 122 Chin J Mod Appl Pharm, 2015 January, Vol.32 No

5 API ( API ) API ( API ) ( ) API API 2.3 EMEA FDA DEREK Mcase Ashby Tennant [13] 1 1 Fig. 1 Structural alerts 2.4 Lutz Mueller 5 2 SAR SAR (Ames ) TOXNET (Hazardous Substances Databank HSDB) (Chemical Carcinogenesis Research Information System CCRIS) (Integrated Risk Information System IRIS) Berkeley TTC Chin J Mod Appl Pharm, 2015 January, Vol.32 No.1 123

6 2 Fig. 2 Reaction scheme example 6 6 Tab. 6 Genotoxic Compounds Classified based on Reactivity a / / // / N S /Michael / / a Note: a Susceptible to attack by a wide range of potential nucleophiles ( ) / API ph () 4- [14] API ( ) ( ) Bandichhor [15] 5 -HT 0.01% ph 124 Chin J Mod Appl Pharm, 2015 January, Vol.32 No

7 ppm 40~80 ppm( >95%) API API (spiking) (purging) Liu [16] / 5 3( ) ( 5%) ppm ii 2 23 ppm 3 API API 1.7 ppm( ii) 3 EMEA FDA ICH M7 REFERENCES 3 5 Fig. 3 Five potential genotoxic impurites in the process of pazopanib HCl [1] European Directorate for the Quality of Medicines and Healthcare Alkyl mesilate (methane sulfonate) impurities in mesilate salts [S]. Pharmeuropa, 2000, 12(1): 27. [2] Safety Working Party. Position paper on the limits of genotoxic impurities (CPMP/SWP/5199/02/ draft 2) [S]. London: Committee for Proprietary Medicinal Products, [3] ICH Expert Working Group. Impurities: Guideline for Residual Solvents Q3C, (R5) step 4 version [S]. European Union, Japan and USA: ICH HARMONISED TRIPARTITE (ICH), 2011: 6-7. [4] MUNRO I C, RENWICK A G, DANIELEWSKA-NIKIEI B. The threshold of toxicological concern (TTC) in risk assessment [J]. Toxicol Lett, 2008, 180(2): [5] KROES R, RENWICK A G, CHEESEMANN M, et al. Structure-based thresholds of toxicological concern (TTC): Chin J Mod Appl Pharm, 2015 January, Vol.32 No.1 125

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