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Use of the ‘purge tool’ in assessing mutagenic impurities

6 January 2016  •  Author(s): Dave Elder, GlaxoSmithKline and JPAG

David ElderThe International Conference on Harmonization M7 text provides guidance on establishing acceptable levels of mutagenic impurities (MIs) . It also outlines the safety and quality risk management processes that manufacturers need to undertake to control MIs that may potentially affect the drug substance or drug product. Over the past decade, some of the most significant challenges facing the pharmaceutical industry have been linked to performing genotoxic risk assessments (GRAs) and implementing a control strategy, including the analysis of these MIs and potentially mutagenic impurities (PMIs) at very low levels (ppm) in drug substances and products.

Historically, industry has responded to regulatory concerns by generating significant amounts of supporting analytical data. This approach exemplifies a quality by testing (QbT) paradigm – it is very resource-intensive (especially when applied to every PMI/MI that could occur in a synthetic process), it can be technically challenging, and it runs contrary to the underlying principles of quality by design (QbD). Tellingly, this QbT approach fails to acknowledge that these reactive MIs will likely be purged by prevailing downstream chemistry conditions. As a consequence, impurity fate mapping (or purging capability), analytical testing and control strategies for MIs/PMIs in drug substances and products have received significant focus during the evolution of this guidance.

One of the areas of particular interest to Industry is purging of MIs, because of the huge analytical resource burden required to support the current GRA process. Significant reduction in the analytical resource burden can be achieved by analysing the purge factor , i.e., the ability of a synthetic process to purge or remove a particular MI. The underlying principles supporting the purge factor are straightforward and involve identifying those intrinsic physicochemical factors affecting the processes’ capability to remove a specified MI. The most important parameters are reactivity, solubility, volatility, ionisability, as well as any other physical processes that remove impurities, e.g., preparative chromatography. These parameters are then allocated a relative weight (based on a pre-defined scoring system) in the overall purge factor…

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