title: Principles and procedures for implementation of ICH M7 recommended (Q)SAR analyses.
abstract: The ICH M7 guideline describes a consistent approach to identify, categorize, and control DNA reactive, mutagenic, impurities in pharmaceutical products to limit the potential carcinogenic risk related to such impurities. This paper outlines a series of principles and procedures to consider when generating (Q)SAR assessments aligned with the ICH M7 guideline to be included in a regulatory submission. In the absence of adequate experimental data, the results from two complementary (Q)SAR methodologies may be combined to support an initial hazard classification. This may be followed by an assessment of additional information that serves as the basis for an expert review to support or refute the predictions. This paper elucidates scenarios where additional expert knowledge may be beneficial, what such an expert review may contain, and how the results and accompanying considerations may be documented. Furthermore, the use of these principles and procedures to yield a consistent and robust (Q)SAR-based argument to support impurity qualification for regulatory purposes is described in this manuscript.
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Amberg
authors.affiliation: Toxicology Solutions, San Diego, CA, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Beilke
authors.affiliation: Gilead, Foster City, CA, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Bercu
authors.affiliation: Leadscope, Columbus, OH, USA.
authors.forename: Dave
authors.initials: D
authors.lastname: Bower
authors.affiliation: Roche Pharmaceutical Research & Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Brigo
authors.affiliation: Leadscope, Columbus, OH, USA.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Cross
authors.affiliation: Bristol-Myers Squibb, New Brunswick, NJ, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Custer
authors.affiliation: Pfizer, Groton, CT, USA.
authors.forename: Krista
authors.initials: K
authors.lastname: Dobo
authors.affiliation: Gilead, Foster City, CA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Dowdy
authors.affiliation: Genentech, South San Francisco, USA.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Ford
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Susanne
authors.initials: S
authors.lastname: Glowienke
authors.affiliation: Janssen, Beerse, Belgium.
authors.forename: Jacky
authors.initials: J
authors.lastname: Van Gompel
authors.affiliation: GlaxoSmithKline, Ware, Herts, UK.
authors.forename: James
authors.initials: J
authors.lastname: Harvey
authors.affiliation: Leadscope, Columbus, OH, USA.
authors.forename: Catrin
authors.initials: C
authors.lastname: Hasselgren
authors.affiliation: National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Honma
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Jolly
authors.affiliation: Vertex, Boston, MA, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Kemper
authors.affiliation: Pfizer, Groton, CT, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Kenyon
authors.affiliation: FDA Center for Drug Evaluation and Research, Silver Spring, MD, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Kruhlak
authors.affiliation: Bristol-Myers Squibb, New Brunswick, NJ, USA.
authors.forename: Penny
authors.initials: P
authors.lastname: Leavitt
authors.affiliation: Leadscope, Columbus, OH, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Miller
authors.affiliation: Roche Pharmaceutical Research & Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, Switzerland.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Muster
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: John
authors.initials: J
authors.lastname: Nicolette
authors.affiliation: KRKA, Novo Mesto, Slovenia.
authors.forename: Andreja
authors.initials: A
authors.lastname: Plaper
authors.affiliation: FDA Center for Drug Evaluation and Research, Silver Spring, MD, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Powley
authors.affiliation: Leadscope, Columbus, OH, USA.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Quigley
authors.affiliation: Merck Research Laboratories, West Point, PA, USA.
authors.forename: M Vijayaraj
authors.initials: MV
authors.lastname: Reddy
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Spirkl
authors.affiliation: FDA Center for Drug Evaluation and Research, Silver Spring, MD, USA.
authors.forename: Lidiya
authors.initials: L
authors.lastname: Stavitskaya
authors.affiliation: AstraZeneca, Macclesfield, Cheshire, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Teasdale
authors.affiliation: Janssen, Spring House, PA, USA.
authors.forename: Sandy
authors.initials: S
authors.lastname: Weiner
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Dennie S
authors.initials: DS
authors.lastname: Welch
authors.affiliation: GlaxoSmithKline, Ware, Herts, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: White
authors.affiliation: Bayer HealthCare, Berlin, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Wichard
authors.affiliation: Leadscope, Columbus, OH, USA. Electronic address: gmyatt@leadscope.com.
authors.forename: Glenn J
authors.initials: GJ
authors.lastname: Myatt
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods* / Q000592:standards; D003198:Computer Simulation; D004249:DNA Damage; D057225:Data Mining / Q000379:methods*; D016208:Databases, Factual; D019983:Guideline Adherence; D017408:Guidelines as Topic; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D016296:Mutagenesis; D009152:Mutagenicity Tests / Q000379:methods* / Q000592:standards; D009153:Mutagens / Q000737:chemistry / Q000145:classification / Q000633:toxicity*; D011050:Policy Making; D021281:Quantitative Structure-Activity Relationship; D018570:Risk Assessment; D014116:Toxicology / Q000331:legislation & jurisprudence / Q000379:methods* / Q000592:standards
chemical_list: D009153:Mutagens
keywords: (Q)SAR; Ames test; Expert review; ICH M7; Impurities; Mutagenic impurities; Toxicity databases