Overview of genotoxic impurities in pharmaceutical development

International Journal of Toxicology

Volumn 28, Issue 6, 2009, Pages 468-478

  Bercu, Joel P ^a   Dobo, Krista L ^b   Gocke, Elmar ^c   Mcgovern, Timothy J ^d  

^a ELI LILLY AND COMPANY   (United States)

^b PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United States)

^c F HOFFMANN LA ROCHE LTD   (Switzerland)

^d SciLucent LLC   (United States)

Author keywords

Drug substance; Ethyl methanesulfonate; Genotoxic; Impurities; Quality

Indexed keywords

HYDRAZINE; MESYLIC ACID ETHYL ESTER; NELFINAVIR;

BONE MARROW TOXICITY; CARCINOGENICITY; CHROMOSOME DAMAGE; CONFERENCE PAPER; DNA DAMAGE; DOSE RESPONSE; DRUG IMPURITY; DRUG SYNTHESIS; EUROPE; GENOTOXICITY; HUMAN; MAXIMUM ALLOWABLE CONCENTRATION; MICRONUCLEUS; MUTAGENICITY; MUTATION RATE; NUCLEOTIDE SEQUENCE; RISK ASSESSMENT; RISK MANAGEMENT; TOXICITY TESTING; UNITED STATES;

ANIMALS; CARCINOGENS; CHEMISTRY, PHARMACEUTICAL; DNA; DNA DAMAGE; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG CONTAMINATION; DRUG DISCOVERY; ETHYL METHANESULFONATE; EUROPEAN UNION; HUMANS; LEGISLATION, DRUG; MUTAGENS; PHARMACEUTICAL PREPARATIONS; RISK ASSESSMENT; UNITED STATES;

EID: 73549085864     PISSN: 10915818     EISSN: 1092874X     Source Type: Journal    
DOI: 10.1177/1091581809349195     Document Type: Conference Paper

References (45)

1. International Conference on Harmonisation. Q3A (R2) : impurities in new drug substances. 2006. http://www.ich.org/LOB/media /MEDIA422.pdf. Accessed September 25, 2009.
2. International Conference on Harmonisation. Q3B (R2) : impurities in new drug products 2006. http://www.ich.org/LOB/media /MEDIA421.pdf. Accessed September 25, 2009.
3. International Conference on Harmonisation. Q3C (R4) : impurities: guideline for residual solvents. 2009. http://www.ich.org/LOB /media/MEDIA5254.pdf. Accessed September 25, 2009.
4. Committee for Medicinal Products for Human Use, European Medicines Agency. Guideline on the limits of genotoxic impurities. 2006. EMEA/CHMP/QWP/251344/2006. http://www.emea.eu.int /pdfs/human/swp/519902en. pdf. Accessed September 25, 2009.
5. United States Food and Drug Administration: Center for Drug Evaluation and Research. Guidance for industry: genotoxic and carcinogenic impurities in drug substances and products: recommended approaches. 2008. http://www.fda.gov/ downloads /Drugs/GuidanceComplianceRegulatoryInformation/Guidances /ucm079235.pdf. Accessed September 25, 2009.
6. Kroes R, Renwick AG, Cheeseman M, et al. Structure-based thresholds of toxicological concern (TTC) : guidance for application to substances present at low levels in the diet. Food Chem Toxicol. 2004;42:65-83.
7. Munro IC, Kennepohl E, Kroes R. A procedure for the safety evaluation of flavouring substances. Joint FAO/WHO Expert Committee on Food Additives. Food Chem Toxicol. 1999;37:207-232.
8. Rulis AM. Establishing a threshold of regulation. In: Bonin JJ, Stevenson DE, eds. Risk Assessment in Setting National Priorities. New York, NY: Plenum; 1989:271-278.
9. Cheeseman MA, Machuga EJ, Bailey AB. A tiered approach to threshold of regulation. Food Chem Toxicol. 1999;37: 387-412.
10. Munro IC. Safety assessment procedures for indirect food additives: an overview. Report of a workshop. Regul Toxicol Pharmacol. 1990;12:2-12.
11. Committee for Medicinal Products for Human Use, European Medicines Agency. Question & answers on the CHMP Guideline on the Limits of Genotoxic Impurities. 2008. EMEA/CHMP /SWP/431994/2007. http://www.emea.europa.eu/pdfs/ human/swp /43199407en. pdf. Accessed September 25, 2009.
12. Dobo KL, Greene N, Cyr MO, et al. The application of structurebased assessment to support safety and chemistry diligence to manage genotoxic impurities in active pharmaceutical ingredients during drug development. Regul Toxicol Pharmacol. 2006;44:282-293.
13. Müller L, Mauthe RJ, Riley CM, et al. A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity. Regul Toxicol Pharmacol. 2006;44:198-211.
14. Doak SH, Jenkins GJ, Johnson GE, et al. Mechanistic influences for mutation induction curves after exposure to DNA-reactive carcinogens. Cancer Res. 2007;67:3904-3911.
15. Swenberg JA, Fryar-Tita E, Jeong YC, et al. Biomarkers in toxicology and risk assessment: informing critical dose-response relationships. Chem Res Toxicol. 2008;21:253-265.
16. Müller L, Gocke E, Lave T, et al. Ethyl methanesulfonate toxicity in Viracept: a comprehensive human risk assessment based on threshold data for genotoxicity. Toxicol Lett. In press.
17. Gocke E, Muller L, Pfister T. EMS in Viracept: initial ("traditional") assessment of risk to patients based on linear dose response relations. Toxicol Lett. In press.
18. Gocke E, Ballantyne M, Whitwell J, et al. In vivo MNT and MutaTMmouse studies to define the dose response relations of the genotoxicity of EMS and ENU. Toxicol Lett. In press.
19. Johnson GE, Doak SH, Skibinski D, et al. Linear dose-response of DNA-reactive genotoxins: recommendations for analysis. Mutat Res. In press.
20. Gocke E, Wall M. In vivo genotoxicity of EMS: Statistical assessment of the dose response curves. Toxicol Lett. In press.
21. Lutz RW, Lutz WK. Statistical model to estimate a threshold dose and its confidence limits for the analysis of a sublinear dose response relationship, exemplified for mutagenicity data. Mutat Res. In press.
22. Müller L, Gocke E, Lavé T, et al. Threshold risk assessment for ethyl methanesulfonate toxicity, including susceptibility differences regarding tissue, species and individual age and predisposition. Toxicol Lett. In press.
23. Committee for Medicinal Products for Human Use, European Medicines Agency. Questions and answers on the follow-up to the contamination of Viracept (nelfinavir) with ethyl mesilate. 2008. EMEA/CHMP/375807/2008. http://www.emea.europa.eu /humandocs/PDFs/EPAR/Viracept/Q&A-Viracept- 37580708en. pdf. Accessed September 25, 2009.
24. McGovern T, Jacobson-Kram D. Regulation of genotoxic and carcinogenic impurities in drug substances and products. Trends Analyt Chem. 2006;25:790-795.
25. Humfrey CD. Recent developments in the risk assessment of potentially genotoxic impurities in pharmaceutical drug substances. Toxicol Sci. 2007;100:24-28.
26. United States Environmental Protection Agency. Guidelines for carcinogen risk assessment. 2005. EPA/630/P-03/001B. http:/ /www.cfpub.epa.gov/ncea/cfm/ recorddisplay.cfm?deid=116283. Accessed September 25, 2009.
27. Pierson DA, Olsen BA, Robbins DK, et al. Approaches to assessment, testing decisions, and analytical determination of genotoxic impurities in drug substances. Org Process Res Dev. 2009;13:285-291.
28. Peto R, Pike MC, Bernstein L, et al. The TD50: a proposed general convention for the numerical description of the carcinogenic potency of chemicals in chronic-exposure animal experiments. Environ Health Perspect. 1984;58:1-8.
29. Barlow S, Renwick AG, Kleiner J, et al. Risk assessment of substances that are both genotoxic and carcinogenic report of an International Conference organized by EFSA and WHO with support of ILSI Europe. Food Chem Toxicol. 2006;44:1636-1650.
30. Bos PM, Baars BJ, van Raaij MT. Risk assessment of peak exposure to genotoxic carcinogens: a pragmatic approach. Toxicol Lett. 2004;151:43-50.
31. Agency for Toxic Substance and Disease Registry. Toxicological profile for hydrazines. 1997. http://www.atsdr.cdc.gov/toxprofiles/tp100.html. Accessed September 25, 2009.
32. Bercu JP, Hoffman WP, Lee C, et al. Quantitative assessment of cumulative carcinogenic risk for multiple genotoxic impurities in a new drug substance. Regul Toxicol Pharmacol. 2008;51: 270-277.
33. An J, Sun M, Bai L, et al. A practical derivatization LC/MS approach for determination of trace level alkyl sulfonates and dialkyl sulfates genotoxic impurities in drug substances. J Pharm Biomed Anal. 2008;48:1006-1010.
34. Elder DP, Lipczynski AM, Teasdale A. Control and analysis of alkyl and benzyl halides and other related reactive organohalides as potential genotoxic impurities in active pharmaceutical ingredients (APIs). J Pharm Biomed Anal. 2008;48:497-507.
35. Yang Q, Haney BP, Vaux A, et al. Controlling the genotoxins ethyl chloride and methyl chloride formed during the preparation of amine hydrochloride salts from solutions of ethanol and methanol. Org Process Res Dev. 2009;13:786-791.
36. Teasdale A, Eyley SC, Delaney E, et al. Mechanism and processing parameters affecting the formation of methyl methanesulfonate from methanol and methanesulfonic acid: an illustrative example for sulfonate ester impurity formation. Org Process Res Dev. 2009;13:429-433.
37. Elder DP, Snodin DJ. Drug substances presented as sulfonic acid salts: overview of utility, safety and regulation. J Pharm Pharmacol. 2009;61:269-278.
38. Liu DQ, Chen TK, McGuire MA, et al. Analytical control of genotoxic impurities in the pazopanib hydrochloride manufacturing process. J Pharm Biomed Anal. 2009;50:144-150.
39. Laird T. Genotoxic impurities. Org Process Res Dev. 2009; 13:363-363.
40. Delaney EJ. An impact analysis of the application of the threshold of toxicological concern concept to pharmaceuticals. Regul Toxicol Pharmacol. 2007;49:107-124.
41. Gaylor DW, Kodell RL. Linear interpolation algorithm for low dose risk assessment of toxic substances. J Environ Pathol Toxicol. 1980;4:305-312.
42. United States Food and Drug Administration: Center for Drug Evaluation and Research. Guidance for industry and review staff: recommended approaches to integration of genetic toxicology study results. 2006. http://www.fda.gov/ downloads/Drugs/Guidance-ComplianceRegulatoryInformation/Guidances/ucm079257. pdf. Accessed September 25, 2009.
43. United States Food and Drug Administration: Center for Drug Evaluation and Research. Questions and answers regarding health concerns and potential shortage of nelfinavir (marketed as Viracept). 2007. http://www.fda.gov/cder/ drug/infopage/nelfinavir/qa.htm. Accessed September 25, 2009.
44. Berelowitz M. VIRACEPT (nelfinavir mesylate) 250 mg, 625 mg tablets, and powder for oral suspension: important information for prescribers. 2007. http://www.fda.gov/downloads/Safety /MedWatch/SafetyInformation/ SafetyAlertsforHumanMedical-Products/UCM154880.pdf. Accessed September 25, 2009.
45. Lewcock A. Viracept contaminant could be widespread, FDA says. in-Pharma. 2007. http://www.in-pharmatechnologist.com/Processing-QC/ Viracept-contaminant-could-be-widespread-FDA-says. Accessed September 25, 2009.