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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.