Evaluation and Control of Genotoxic Impurities in Active Pharmaceutical Ingredients

Transcription

1 modernmedicine.com/formulary-journal/news/user-defined-tag s/diabetes/diabetes-drug-canagliflozin-receives-fda-approval. [31] WASHBLUM W N. Development of the renal glucose reabsorption inhibitors: a new mechanism for the pharmacotherapy of diabetes mellitus type 2 [J]. J Med Chem, 2009, 52(7): [32] ZHANG W B, GONG N, WANG Y X. SGLT2 inhibitors: a novel category of oral anti-diabetes drugs [J]. Prog Physiol Sci( ), 2010, 41(6): * ( ) Pubmed Medline (European Medicines Agency EMA)(US Food and Drug Administratio U.S.FDA) (ICH) EMA U.S.FDA ICH M7 (threshold of toxicological concern TTC) 5 EMA U.S.FDA ICH M7 ICH M7 U.S.FDA EMA M7 R951 A (2014) DOI: /j.cnki.issn Evaluation and Control of Genotoxic Impurities in Active Pharmaceutical Ingredients ZHANG Huimin 1, LIN Jianqun 1, FENG Kangbiao 2, DU Yougong 1, WANG Hong 1, SUN Yuan 1* (1.Department of Pharmacy, Taizhou Hospital of Zhejiang Province, Taizhou , China; 2.Zhejiang Starry Pharmaceutical Co., Ltd., Taizhou , China) ABSTRACT: OBJECTIVE To provide a general overview of the regulatory guidelines on the control of genetoxic impurities in Active Pharmaceutical Ingredients, and provide some practical advices for following guidelines. METHODS Literatures about the topic of genotoxic impurities from databases such as Pubmed, Medline, websites of EMA, U.S.FDA and ICH were searched, then analysized and compared the current guidelines on this topic, and provided a controlling strategy for these impurities. RESULTS The guidelines of EMA, U.S.FDA and ICH (current step 2) maintained consistent in critical principles such as threshold of toxicological concern (TTC), risk assessment and the classification system for impurities. But the difference on other aspects between current guidelines of EMA and U.S.FDA would get them difficult to be implemented in a consistent manner for pharmaceutical manufacturers. and ICH M7, now the step 2 version, would provide a practical framework that could be applied for the control of genotoxic impurities. CONCLUSION The current guidelines can not provide a perfect strategy for the control of genotoxic impurities, and the ICH M7 that may replace the current guidelines of EMA and U.S.FDA, and will provide a better way for the pharmaceutical manufacturers to control the genotoxic impurities. KEY WORDS: genotoxic impurities; EMA; U.S.FDA; ICH M7 [1] DNA [2] 2000 (European Directorate for the Quality of Medicines and Health Care EDQM) Tel: fwz0805@163.com (0576) suny@enzemed.com * Tel: 1160 Chin J Mod Appl Pharm, 2014 September, Vol.31 No

2 (Pharm Europa) [3] ( ) EMA 2002 EMA [4] 1/ ( ) ICH Q3C [5] 2004 EMA (CHMP) [6] (threshold of toxicological concern TTC) TTC Munro 1996 Gramer [7] (US Food and Drug Administratio U.S.FDA) TTC [8-9] (structural alerts) TTC 0.15 µg d 1[10] TTC 1.5 µg d µg d 1 1/ ( ) EMA [6] 2 Q3C Note for Guidance on Impurities: Residual Solvents 2 TTC N- TTC 1.5 µg d 1 TTC [11] Chin J Mod Appl Pharm, 2014 September, Vol.31 No

3 TTC 1.5 µg d 1 (CPMP) (SWP) EDQM [12] (PhRMA) TTC [11,13] PhRMA 1 SWP 1 EMA TTC Tab. 1 Stage TTC values described in EMA guideline on the limits of genotoxic impurities /µg PhRMA PhRMA TTC 2006 (Regulatory Toxicology and Pharmacology) 2 [11] 2 TTC Tab. 2 Permision daily intake for genotoxic impurities in drug during clinical development based on stage TTC /µg d 1 0~1 120 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 identity, quantity, and control ordinary impurities during developed should be applied. TTC (SAR) SAR 1 Ames 3 TTC 1.3 U.S.FDA EMA FDA EMA TTC TTC SAR [14] U.S.FDA 3 10 ICH TTC U.S.FDA <14 d 120 µg d 1 U.S.FDA EMA 3 3 EMA U.S.FDA Tab. 3 Comparison of the guidelines of EMA and U.S.FDA U.S.FDA U.S.FDA TTC 1.5 µg d 1 U.S.FDA 14 d TTC 120 µg d 1 EMA U.S.FDA TTC 2 ICH ICH M7 [15] 1.4 ICH-M ICH ICH M7 [15] 2 [16] EMA U.S.FDA ICH M7 ICH M Chin J Mod Appl Pharm, 2014 September, Vol.31 No

4 ICH M7 EMA U.S.FDA Ames TTC ICH Q3A/3B [1,17] ICH M7 Ames DNA 5 (QSAR) 2 QSAR QSAR [18] 2 ( 5 5 ) ICH M7 EMA 1 TTC 120 µg d PhRMA TTC 5 ICH M7 4 Tab. 4 Current guidelines on the control of genotoxic impurities EMA Q&A EMA SWP EMA PhRMA U.S.FDA ICH PhRMA U.S.FDA ICH M7 DNA () TTC 2008 EMA EMA U.S.FDA 5 TTC Tab. 5 Compare of the staged TTC in different guidelines TTC /µg d 1 0~14 d >14 d~1 >1~3 >3~6 >6~12 >1~10 >10 PhRMA EMA U.S.FDA ICH M (Toxtree ) (PGI) Chin J Mod Appl Pharm, 2014 September, Vol.31 No

5 1 [11,17] Fig. 1 Risk evaluation decision tree for the control of genotoxic impurities (PDE) TD 50 A( A 1/2) 10 5 A TD mg kg 1 d 1 ( ) 63.7 mg kg 1 d 1 ( ) ( ) PDE PDE= 21.3 mg kg 1 d 1 /50 000=0.42 µg kg 1 d 1 PDE=0.42 µg kg 1 d 1 50 kg=21.3 µg d 1 ( 50 kg ) 21.3 µg 10 5 DNA DNA PDE (NOEL) (UF) PDE= NOEL (F1 F1 F2 F3 F4 F5 F2 F3 F4 F5 ) PDE 1 1 PDE= 50.7 mg kg d 50 kg = 4.22 mg d NOEL 50.7 mg kg 1 d 1 50 kg F1 12() F2 10( ) F3 5( 13 ) F4 1( ) F5 1( ) PDE [19] 6( ICH M7 step 2) 1.5 µg ( ) PDE= 6 ICH M7 TTC Tab. 6 Stage TTC in ICH M7 /µg d 1 0~ >1~ >1~ >10 ~ 1.5 TTC PDE TTC 7 7 Tab. 7 ICH M7 Limits for multiple genotoxic impurities in ICH M7 /µg d 1 0~1 120 >1~12 60 >1~10 10(30 1) ) >10 ~ 5 1) 3 Note: For clinical development up to 3 years, similar priciples could be applied to marketed products with justification Chin J Mod Appl Pharm, 2014 September, Vol.31 No

6 ( ) Tab. 8 Control strategy for genotoxic impurities based on the classification system 1 NOEL 2 PDE TTC 3 TTC DNA EMA U.S.FDA ICH M7 ICH REFERENCES [1] International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline: Imurities in New Drug Substances Q3A(R2) [S/OL] org/fileadmin/public_web_site/ich_products/guidelines/qua lity/q3a_r2/step4/q3a_r2 Guideline.pdf. [2] EMA (European Medicines Agency). Guidelines on the Limits of Genotoxic Impurities [S/OL] europa.eu/docs/en_gb/document_library/scientific_guideline/ 2009/09/WC pdf. [3] European Directorate for the Quality of Medicines and Health Care. Enquiry: Alkyl mesilate (methane sulfonate) impurities in mesilate salts [J]. Pharm Europa, 2000, 12(1): 27 [4] Committee for Proprietary Medicinal Products. Position Paper on the Limits of Genotoxic Impurities [S] CPMP/ SWP/5199/02/draft 2. [5] International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline: Impurities: Guideline for Residual Solvents Q3C(R) [S/OL] Guidelines/Quality/Q3C/Step4/Q3C_R5_Step4.pdf. [6] Committee for Medicinal Products for Human Use (CHMP). Guidelines on the Limits of Genotoxic Impurities [S/OL] library/scientific_guideline/2009/09/wc pdf. [7] MUNRO I C, FORD R A, KENNEPOHL E, et al. Correlation of structural class with no observed effect levels: a proposal for establishing a threshold of concern [J]. Food Chem Toxicol, 1996, 34(9): [8] MUNRO I C. Safety assessment procedures for indirect food additives: an overview. Report of a workshop [J]. Regul Toxicol Pharmacol, 1990, 12(1): [9] CHEESEMAN MA, MACHUGA E J, BAILEY A B. A tiered approach to threshold of regulation [J]. Food Chem Toxicol, 1999, 37(4): [10] KROES R, RENWICK A G, CHEESEMAN M, et al. Structure-based thresholds of toxicological concern (TTC): guidance for application to substances present at low levels in the diet [J]. Food Chem Toxicol, 2004, 42(1): [11] MULLER L, MAUTHE R J, RILEY C M, et al. A rationale for determination, testing and controlling specific impurities in pharmaceuticals that posses potential for genotoxicity [J]. Regul Toxicol Pharmacol, 2006, 44(3): [12] European Directorate on Quality of Medicines. Potentially genotoxic impurities and European pharmacopoeia monographs on substances for human use [J]. Pharma Europa, 2008, 20(3): [13] CHMP Safety Working Party. Question & answers on the CHMP Guideline on the Limits of Genotoxic impurities [S/OL] library/scientific_guideline/2009/09/wc pdf. [14] Center for Drug Evaluation and Research (CDER) of FDA. Guidance for Industry Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches Draft [S/OL] Drugs/.../ Guidances/ucm pdf. [15] ICH Steering Committee. Final Business Plan-ICH M7. Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk [S/OL] Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7 _Final_Business_Plan_June_2010.pdf [16] ICH Steering Committee. Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, Step 2 Version [S/OL] Chin J Mod Appl Pharm, 2014 September, Vol.31 No

7 Guidelines/Multidisciplinary/M7/M7_Step_2.pdf [17] International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use). ICH Harmonised Tripartite Guideline. Impurities in New Drug Products Q3 B(R2) [S/OL] fileadmin/public_web_site/ich_products/guidelines/quality/ Q3B_R2/Step4/Q3B_R2 Guideline.pdf. [18] Organisation for Economic Co-operation and Development. Report on the Regulatory Uses and Applications in OECD Member Countries of (quantitative) Structure-activity Relationship [(Q)SAR] Models in the Assessment of New and Existing Chemicals [S/OL] ehs/risk-assessment/ pdf. [19] FELTER S P, CONOLLY R B, BERCU J P, et al. A proposed framework for assessing risk from less-than-lifetime exposures to carcinogens [J]. Crit Rev Toxicol, 2011, 41(6): (unlabeled uses off-label uses out-of label usage or outside of labeling) 20% Chin J Mod Appl Pharm, 2014 September, Vol.31 No