This edition first published 2022
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Preface
Since the advent of the first book specifically focused on genotoxic (mutagenic) impurities that I authored and was released in 2010, a considerable amount of progress has been made in terms of management of such impurities. Indeed many of the concepts defined for the first time within the book have ultimately become enshrined in standard practice relating to mutagenic impurities. These include how to conduct a risk assessment, the use of SAR evaluation tools, compound‐specific limits, and the use of purge factors to assess carryover risk, to name a few. Indeed most if not all were ultimately captured within ICH M7, which was formalized in 2014.
As a result of this and continued advancement of the science pertaining to many of these and other concepts, it seemed timely to seek to update the book. Little did I or others foresee at the point where this was proposed the dramatic impact of N‐nitrosamines. By necessity, the book seeks to address not only the changes in general around management of mutagenic impurities, it also seeks to outline a holistic approach to management and control of N‐nitrosamines, covering all aspects of their management from a safety and quality perspective. As well as this new chapter has been added specifically seeking to examine side reactions that can result in mutagenic impurities, dramatically expanding on the work in the first book that was focused simply on sulfonate esters.
1
Historical Perspective on the Development of the EMEA Guideline and Subsequent ICH M7 Guideline
1.1 Introduction
To enable a thorough understanding of the current regulatory position relating to mutagenic impurities (regularly referred to as genotoxic impurities initially) as defined by ICH M7 [1], it is first important to consider the history behind the events that led up to this point and their context. Like many events, the exact point at which concerns relating to the potential presence of mutagenic impurities (MIs) in pharmaceuticals first emerged is difficult to determine. At the time that ICH Q3 guidelines were constructed, specifically ICH Q3A [2], only passing reference was made to compounds of “unusual toxicity” and the potential need for limits tighter than those defined by the guidelines. Although the term “genotoxic” or indeed “mutagenic” is not specifically mentioned, many have taken this to refer to impurities that are mutagenic.
The first public evidence of specific regulatory concern relating to genotoxic impurities was an article published within PharmEuropa in 2000 [3], which drew attention to the potential risk of formation of sulfonate esters resulting from the combination of sulfonic acids in alcoholic solution as part of a salt formation process. At this point this publication was merely a call for “further information,” it being part of an attempt to better understand the extent of any risk involved. The publication is now seen as a landmark event, signaling a new era of focus on genotoxic impurity risk assessment and control. It is interesting to reflect on the irony that the “start point” should indeed be sulfonate esters given the long‐standing concerns and investigations performed relating to such potential impurities over the subsequent years, much of which are described throughout the chapters within this book.
The first real attempt to generate some form of regulatory framework pertaining to MIs was a position paper relating to genotoxic impurities (GIs) published by the Committee for Proprietary Medicinal Products (CPMP1) on behalf of the European Medicines Agency (EMA) Safety Working Party (SWP) for comments in December 2002 [2]. Outlined below is an evaluation of this first draft position paper and an assessment of its later significance in the context of the finalized ICH M7 guideline.
1.1.1 CPMP – Position Paper on the Limits of Genotoxic Impurities –2002
1.1.1.1 Scope/Introduction
Within the introduction to the position paper, it was made clear that the need for such guidance was due to the fact that control over levels of genotoxic residues was not adequately addressed through existing ICH guidance.
The position paper consists of a series of sections that addressed the issue of genotoxic