Potential impurities in drug substances: Compound-specific toxicology limits for 20 synthetic reagents and by-products, and a class-specific toxicology limit for alkyl bromides.

Autor: Bercu JP; Gilead Sciences, 333 Lakeside Drive, Foster City, CA, USA. Electronic address: jbercu@gilead.com., Galloway SM; MRL, Merck & Co., Inc., W 45-316, West Point, PA, USA., Parris P; AstraZeneca, Drug Safety and Metabolism, Innovative Medicines and Early Development, United Kingdom., Teasdale A; AstraZeneca, Silk Road Business Park, Macclesfield, Cheshire, SK10 2NX, United Kingdom., Masuda-Herrera M; Gilead Sciences, 333 Lakeside Drive, Foster City, CA, USA., Dobo K; Pfizer Worldwide Research and Development, Genetic Toxicology, Eastern Point Road, Groton, CT, USA., Heard P; Pfizer Worldwide Research and Development, Genetic Toxicology, Eastern Point Road, Groton, CT, USA., Kenyon M; Pfizer Worldwide Research and Development, Genetic Toxicology, Eastern Point Road, Groton, CT, USA., Nicolette J; AbbVie, Inc., 1 North Waukegan Road, North Chicago, IL, USA., Vock E; Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str., 88397 Biberach, Germany., Ku W; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA., Harvey J; GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, SG12 0DP, United Kingdom., White A; GlaxoSmithKline R&D, Park Road, Ware, Hertfordshire, SG12 0DP, United Kingdom., Glowienke S; Novartis AG, NIBR, Klybeckstrasse, CH-4057 Basel, Switzerland., Martin EA; AstraZeneca, Drug Safety and Metabolism, Innovative Medicines and Early Development, United Kingdom., Custer L; Bristol-Myers Squibb, 1 Squibb Dr, New Brunswick, NJ, USA., Jolly RA; Eli Lilly and Company, Indianapolis, IN, USA., Thybaud V; Sanofi, Vitry-sur-Seine, France.
Jazyk: angličtina
Zdroj: Regulatory toxicology and pharmacology : RTP [Regul Toxicol Pharmacol] 2018 Apr; Vol. 94, pp. 172-182. Date of Electronic Publication: 2018 Feb 09.
DOI: 10.1016/j.yrtph.2018.02.001
Abstrakt: This paper provides compound-specific toxicology limits for 20 widely used synthetic reagents and common by-products that are potential impurities in drug substances. In addition, a 15 μg/day class-specific limit was developed for monofunctional alkyl bromides, aligning this with the class-specific limit previously defined for monofunctional alkyl chlorides. Both the compound- and class-specific toxicology limits assume a lifetime chronic exposure for the general population (including sensitive subpopulations) by all routes of exposure for pharmaceuticals. Inhalation-specific toxicology limits were also derived for acrolein, formaldehyde, and methyl bromide because of their localized toxicity via that route. Mode of action was an important consideration for a compound-specific toxicology limit. Acceptable intake (AI) calculations for certain mutagenic carcinogens assumed a linear dose-response for tumor induction, and permissible daily exposure (PDE) determination assumed a non-linear dose-response. Several compounds evaluated have been previously incorrectly assumed to be mutagenic, or to be mutagenic carcinogens, but the evidence reported here for such compounds indicates a lack of mutagenicity, and a non-mutagenic mode of action for tumor induction. For non-mutagens with insufficient data to develop a toxicology limit, the ICH Q3A qualification thresholds are recommended. The compound- and class-specific toxicology limits described here may be adjusted for an individual drug substance based on treatment duration, dosing schedule, severity of the disease and therapeutic indication.
(Copyright © 2018. Published by Elsevier Inc.)
Databáze: MEDLINE
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