title: Use of in silico systems and expert knowledge for structure-based assessment of potentially mutagenic impurities.
abstract: Genotoxicity hazard identification is part of the impurity qualification process for drug substances and products, the first step of which being the prediction of their potential DNA reactivity using in silico (quantitative) structure-activity relationship (Q)SAR models/systems. This white paper provides information relevant to the development of the draft harmonized tripartite guideline ICH M7 on potentially DNA-reactive/mutagenic impurities in pharmaceuticals and their application in practice. It explains relevant (Q)SAR methodologies as well as the added value of expert knowledge. Moreover, the predictive value of the different methodologies analyzed in two surveys conveyed in the US and European pharmaceutical industry is compared: most pharmaceutical companies used a rule-based expert system as their primary methodology, yielding negative predictivity values of ⩾78% in all participating companies. A further increase (>90%) was often achieved by an additional expert review and/or a second QSAR methodology. Also in the latter case, an expert review was mandatory, especially when conflicting results were obtained. Based on the available data, we concluded that a rule-based expert system complemented by either expert knowledge or a second (Q)SAR model is appropriate. A maximal transparency of the assessment process (e.g. methods, results, arguments of weight-of-evidence approach) achieved by e.g. data sharing initiatives and the use of standards for reporting will enable regulators to fully understand the results of the analysis. Overall, the procedures presented here for structure-based assessment are considered appropriate for regulatory submissions in the scope of ICH M7.
authors.affiliation: Bayer HealthCare, Investigational Toxicology, Müllerstr. 178, 13353 Berlin, Germany. Electronic address: andreas.sutter@bayer.com.
authors.forename: Andreas
authors.initials: A
authors.lastname: Sutter
authors.forename: Alexander
authors.initials: A
authors.lastname: Amberg
authors.forename: Scott
authors.initials: S
authors.lastname: Boyer
authors.forename: Alessandro
authors.initials: A
authors.lastname: Brigo
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Contrera
authors.forename: Laura L
authors.initials: LL
authors.lastname: Custer
authors.forename: Krista L
authors.initials: KL
authors.lastname: Dobo
authors.forename: Veronique
authors.initials: V
authors.lastname: Gervais
authors.forename: Susanne
authors.initials: S
authors.lastname: Glowienke
authors.forename: Jacky
authors.initials: J
authors.lastname: van Gompel
authors.forename: Nigel
authors.initials: N
authors.lastname: Greene
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Muster
authors.forename: John
authors.initials: J
authors.lastname: Nicolette
authors.forename: M Vijayaraj
authors.initials: MV
authors.lastname: Reddy
authors.forename: Veronique
authors.initials: V
authors.lastname: Thybaud
authors.forename: Esther
authors.initials: E
authors.lastname: Vock
authors.forename: Angela T
authors.initials: AT
authors.lastname: White
authors.forename: Lutz
authors.initials: L
authors.lastname: Müller
mesh_terms: D003198:Computer Simulation; D004249:DNA Damage; D004340:Drug Contamination; D004345:Drug Industry / Q000379:methods; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000737:chemistry* / Q000633:toxicity*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D009153:Mutagens
keywords: (Q)SAR; Genotoxic impurities; ICH M7; In silico; Mutagenicity