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Regul Toxicol Pharmacol. 2016 Jun;77:13-24. doi: 10.1016/j.yrtph.2016.02.004. Epub 2016 Feb 11.

Principles and procedures for implementation of ICH M7 recommended (Q)SAR analyses.

Author information

1
Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany.
2
Toxicology Solutions, San Diego, CA, USA.
3
Gilead, Foster City, CA, USA.
4
Leadscope, Columbus, OH, USA.
5
Roche Pharmaceutical Research & Early Development, Pharmaceutical Sciences, Roche Innovation Center, Basel, Switzerland.
6
Bristol-Myers Squibb, New Brunswick, NJ, USA.
7
Pfizer, Groton, CT, USA.
8
Genentech, South San Francisco, USA.
9
Novartis Institutes for Biomedical Research, Basel, Switzerland.
10
Janssen, Beerse, Belgium.
11
GlaxoSmithKline, Ware, Herts, UK.
12
National Institute of Health Sciences, Tokyo, Japan.
13
Eli Lilly and Company, Indianapolis, IN, USA.
14
Vertex, Boston, MA, USA.
15
FDA Center for Drug Evaluation and Research, Silver Spring, MD, USA.
16
AbbVie Inc., North Chicago, IL, USA.
17
KRKA, Novo Mesto, Slovenia.
18
Merck Research Laboratories, West Point, PA, USA.
19
AstraZeneca, Macclesfield, Cheshire, UK.
20
Janssen, Spring House, PA, USA.
21
Bayer HealthCare, Berlin, Germany.
22
Leadscope, Columbus, OH, USA. Electronic address: gmyatt@leadscope.com.

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.

KEYWORDS:

(Q)SAR; Ames test; Expert review; ICH M7; Impurities; Mutagenic impurities; Toxicity databases

PMID:
26877192
DOI:
10.1016/j.yrtph.2016.02.004
[Indexed for MEDLINE]
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