Appropriate drug substance control strategy and specifications are best achieved when based on a understanding of the manufacturing process and a close collaboration of drug substance and product development teams.  For one of Amgen's clinical candidates, controlling genotoxic impurities in the drug substance and product presented a challenge to the chemistry, manufacturing and controls team responsible for developing the clinical candidate.  Control of one class of impurities, hydrazines, drove us to redesign the synthetic route to the drug substance.  This redesign included the development of a practical and highly regioselective, thiophene metalation procedure which eliminated N,N-dimethylhydrazine from one step and the need for excess hydrazine in a subsequent step.  The second genotoxic concern is an aniline intermediate in the synthetic route.  The aniline is also observed as a degradation product of the drug product, the formation of which has the potential to impact the shelf-life and/or storage conditions of the drug product.  Control over the aniline content in drug substance and product was established through a three-pronged approach.  First, a detailed mechanistic study of the final synthetic step, a SnAr with aniline as the nucleophile, led to the discovery that the step was autocatalytic.  Understanding this mechanism enabled us to develop reaction conditions to minimize carryover of the aniline to the freebase drug substance.  Second, the final salt-forming and crystallization process was optimized to reject the aniline within an established range and thereby set achievable specifications for aniline in the freebase.  Finally, we studied the mechanism of drug product degradation which led us to identify parameters leading to the formation of aniline and propose changes to both the drug product process and the DS attributes to achieve the target product profile.  This collaborative and 1st principles approach to developing a comprehensive genotoxic control strategy will be presented in detail.

Synthetic design and mechanistic studies as tools for the development of a genotoxic impurity control strategy

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.