Читать книгу Mutagenic Impurities - Группа авторов - Страница 47

ICH M7 [1] was first introduced in June 2014, undergoing a first revision in July 2017. The guidance itself is a multidisciplinary guideline reflecting the fact that mutagenic impurities are both a quality and safety topic. It focuses on the control of mutagenic impurities and was introduced to address differences that existed between regional guidelines pertaining to genotoxic (mutagenic) guidelines, the principle regional guidelines being the European Medicines Agency (EMA) guideline [2], supplemented by its associated Question and Answer (Q&A) document [3] and the draft Federal Drug Administration (FDA) guideline [4]. No formal guidance was ever published by Pharmaceutical and Medical Devices Agency (PMDA), Japan. A comprehensive overview of the chronological development of the EMA and FDA draft guidelines is described in Chapter 1. These guidelines were introduced to address a perceived gap in existing impurity guidelines ICH Q3A [5] and Q3B [6] relating to management of DNA reactive mutagenic impurities that may arise during the synthesis of the active form and through degradation of either/both the drug substance (DS)/drug product (DP). Although broadly similar within their concept, there were nevertheless sufficient enough differences between the EMA and FDA guidelines to render a global approach challenging.

Clear within the ICH M7 concept paper [7] was a desire to harmonize these guidelines and to specifically address areas of uncertainty. Critical areas identified within the concept paper included:

1 Use of in silico structure activity relationship (SAR) tools for the assessment of mutagenic potential.

2 What are acceptable levels of genotoxic impurities during drug development?

3 What are acceptable levels of genotoxic impurities for marketing?

4 Should those impurities be regulated differently that are likely to have threshold effects?

5 Should levels of genotoxic impurities be regulated using a Threshold of Toxicological Concern (TTC) approach?

6 Structurally related genotoxic impurities are likely to have similar mechanisms of action. Should these be summed in calculating a TTC?

7 What process of qualification testing should be followed for impurities that are metabolites?

8 What additional data are needed to support having no special restrictions, or a higher acceptable daily intake (ADI) than the TTC, for a genotoxic impurity?

The following chapter will look in detail at the ICH M7 guideline, examining each aspect of the guideline, seeking in doing so to give a comprehensive overview of its practical implementation. It will also examine whether or not the guideline has succeeded in addressing the critical areas outlined in the concept paper.