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.
We discuss the factors that influence the effectiveness of safeguards and security measures and the characteristics required of effectiveness evaluation methodologies. Within this context and from a utility standpoint, we review those effec¬ tiveness evaluation methodologies that have been developed. Our principal recommendation concerns the application and con¬ comitant validation of existing methodologies. This recommen¬ dation derives from our conclusion that there has been a gross imbalance between the effort spent on methodology develop¬ ment and the application of those methodologies. Only for those safeguards measures that do not seem to be covered by existing methodologies or that seem to be inadequately covered do we suggest development. This report presents our conclusions and recommendations resulting from a study, concluded in January 1980, of effectiveness evaluation methodologies for safeguards and security systems. The study' examined evaluation methodologies, either extant or being developed, and assessed the usefulness to the Department of Energy Office of Safeguards and Security (DOE/OSS) of such methodologies for performing an adequate and meaningful system evaluation. This report is structured as follows: first, we provide what we perceive to be factors that influence the effectiveness and effectiveness evaluations of safeguards and security systems; second, we briefly describe the review procedures used in our study; and last, we present our conclusions and recommendations. Appendixes A and B describe the methodologies we examined.
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