The Consultancy Activity on In Silico Models for Genotoxic Prediction of Pharmaceutical Impurities.
The toxicological assessment of DNA-reactive/mutagenic or clastogenic impurities plays an important role in the regulatory process for pharmaceuticals; in this context, in silico structure-based approaches are applied as primary tools for the evaluation of the mutagenic potential of the drug impurities. The general recommendations regarding such use of in silico methods are provided in the recent ICH M7 guideline stating that computational (in silico) toxicology assessment should be performed using two (Q)SAR prediction methodologies complementing each other: a statistical-based method and an expert rule-based method.Based on our consultant experience, we describe here a framework for in silico assessment of mutagenic potential of drug impurities. Two main applications of in silico methods are presented: (1) support and optimization of drug synthesis processes by providing early indication of potential genotoxic impurities and (2) regulatory evaluation of genotoxic potential of impurities in compliance with the ICH M7 guideline. Some critical case studies are also discussed.
S-IN Soluzioni Informatiche SRL, via Ferrari 14, Vicenza, 36100, Italy.
Manuela
M
Pavan
S-IN Soluzioni Informatiche SRL, via Ferrari 14, Vicenza, 36100, Italy. simona.kovarich@s-in.it.
Simona
S
Kovarich
S-IN Soluzioni Informatiche SRL, via Ferrari 14, Vicenza, 36100, Italy.
Arianna
A
Bassan
S-IN Soluzioni Informatiche SRL, via Ferrari 14, Vicenza, 36100, Italy.
Lorenza
L
Broccardo
Molecular Networks GmbH, Erlangen, Germany.|Altamira LLC, Columbus, OH, USA.
Chihae
C
Yang
S-IN Soluzioni Informatiche SRL, via Ferrari 14, Vicenza, 36100, Italy.
Elena
E
Fioravanzo
D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D004340:Drug Contamination; D017408:Guidelines as Topic; D009152:Mutagenicity Tests / Q000379:methods; D004364:Pharmaceutical Preparations / Q000032:analysis / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D000069436:Toxicological Phenomena
D004364:Pharmaceutical Preparations
(Q)SAR; Expert rule-based methods; Genotoxic impurities; ICH M7; In silico methods; Statistical-based methods