Control of Potentially Genotoxic Impurities in Drug Products

Genotoxin is a substance capable of damaging DNA causing mutations (mutagen), cancer (carcinogen), or birth defect (teratogen).

The European and North American regulatory agencies recognized in mid 2000’s the importance of assessing the risk and subsequently introduced tight controls on the presence of genotoxic and potentially genotoxic impurities in drug substances and products. This resulted in multiple regulatory guidances for industry aimed at providing the industry with clear expectations regarding this aspect of drug product quality. The following guidance documents are currently in place:

1. Guideline on the Limits of Genotoxic Impurities, EME/CHMP/QWP/251344/2006, June 28, 2006.
2. ICH M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, Step 4 of ICH, July 15, 2014.
3. Genotoxic and Carcinogenic Impurities in Drug Substances and Products: Recommended Approaches; FDA Draft Guidance of December 2008.

Introduction of the requirements to control the quality of the pharmaceutical products constitutes a fundamental shift whereby the quantitative control of impurities has undergone a shift of orders of magnitude in terms of the required scrutiny of the overall production stream as well as the related analytical capabilities required.

Due to often complicated synthetic chemistry used to manufacture ever more and more structurally complex new chemical entities, the risk of formation of undesired toxic impurities is real. However the difficulty in developing a robust control strategy is multifold. Principally, these impurities are formed as undesired species and as such their formation typically occurs either through minor poorly understood chemical pathways or is related to the presence of other contaminating species (such as alcohols and reactive reagents such as various sulfonyl or phosphonyl species) or in many cases the actual drug intermediates have structural features with genotoxic potential.

Secondly, the control strategy cannot be developed and demonstrated to be robust and reliable without having the analytical methodology capable of detecting these impurities, often at the sub ppm level. Ultimately, whatever the analytical technique used, it must be validated by using the authentic reference standards of the potentially genotoxic impurities in question.

An emerging class of potentially genotoxic impurities, which are generated by metabolic pathways, are acyl glucuronides. Most drugs containing carboxylic acid moiety are metabolized and eliminated via acyl glucuronides. Acyl glucuronides require careful safety assessment due to their facile hydrolysis, rearrangements and reactions with plasma proteins.

Many acyl glucuronide drug conjugates have been associated with adverse effects of drugs and their toxicity. It is therefore not surprising that these molecules are under high scrutiny from the regulating agencies.