title: A practical application of two in silico systems for identification of potentially mutagenic impurities.
abstract: The International Conference on Harmonization (ICH) M7 guidance for the assessment and control of DNA reactive impurities in pharmaceutical products includes the use of in silico prediction systems as part of the hazard identification and risk assessment strategy. This is the first internationally agreed guidance document to include the use of these types of approaches. The guideline requires the use of two complementary approaches, an expert rule-based method and a statistical algorithm. In addition, the guidance states that the output from these computer-based assessments can be reviewed using expert knowledge to provide additional support or resolve conflicting predictions. This approach is designed to maximize the sensitivity for correctly identifying DNA reactive compounds while providing a framework to reduce the number of compounds that need to be synthesized, purified and subsequently tested in an Ames assay. Using a data set of 801 chemicals and pharmaceutical intermediates, we have examined the relative predictive performances of some popular commercial in silico systems that are in common use across the pharmaceutical industry. The overall accuracy of each of these systems was fairly comparable ranging from 68% to 73%; however, the sensitivity of each system (i.e. how many Ames positive compounds are correctly identified) varied much more dramatically from 48% to 68%. We have explored how these systems can be combined under the ICH M7 guidance to enhance the detection of DNA reactive molecules. Finally, using four smaller sets of molecules, we have explored the value of expert knowledge in the review process, especially in cases where the two systems disagreed on their predictions, and the need for care when evaluating the predictions for large data sets.
authors.affiliation: Computational Sciences CoE, Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, USA.
authors.forename: Nigel
authors.initials: N
authors.lastname: Greene
authors.affiliation: Genetic Toxicology, Drug Safety Research and Development, Pfizer Worldwide Research and Development, Groton, CT 06340, USA.
authors.forename: Krista L
authors.initials: KL
authors.lastname: Dobo
authors.affiliation: Genetic Toxicology, Drug Safety Research and Development, Pfizer Worldwide Research and Development, Groton, CT 06340, USA.
authors.forename: Michelle O
authors.initials: MO
authors.lastname: Kenyon
authors.affiliation: Genetic Toxicology, Drug Safety Research and Development, Pfizer Worldwide Research and Development, Groton, CT 06340, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cheung
authors.affiliation: Genetic Toxicology, Drug Safety Research and Development, Pfizer Worldwide Research and Development, Groton, CT 06340, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Munzner
authors.affiliation: Genetic Toxicology, Drug Safety Research and Development, Pfizer Worldwide Research and Development, Groton, CT 06340, USA.
authors.forename: Zhanna
authors.initials: Z
authors.lastname: Sobol
authors.affiliation: Analytical R&D, Pharmaceutical Sciences, Pfizer Worldwide Research and Development, Groton, CT 06340, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Sluggett
authors.affiliation: Analytical R&D, Pharmaceutical Sciences, Pfizer Worldwide Research and Development, Groton, CT 06340, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Zelesky
authors.affiliation: Bayer Health Care, Investigational Toxicology, Müllerstr. 178, 13353 Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Sutter
authors.affiliation: Bayer Health Care, Investigational Toxicology, Müllerstr. 178, 13353 Berlin, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Wichard
mesh_terms: D000465:Algorithms; D003198:Computer Simulation; D004340:Drug Contamination; D009153:Mutagens / Q000032:analysis*; D018570:Risk Assessment; D012984:Software
chemical_list: D009153:Mutagens
keywords: Computational toxicology; Genotoxic impurities; ICH M7; Structure–activity relationships