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  • Publisher:
    Elsevier
  • Publication Date:
    Oct 2013
  • Reference:
    Regulatory Toxicology and Pharmacology, 2013, 67(1), pp39-52
  • DOI:
    10.1016/j.yrtph.2013.05.001
  • PMID:
  • Publication Type:
    Paper
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Use of in silico systems and expert knowledge for structure-based assessment of potentially mutagenic impurities

Amberg A; Boyer S; Brigo A; Contrera JF; Custer LL; Dobo KL; Gervais V; Glowienke S; Greene N; Müller L; Muster W; Nicolette J; Reddy MV; Sutter A; Thybaud V; Van Gompel J; Vock E; White A;

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. 

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