Given the increased reliance on multi-enzymatic cascades to manufacture biologically-inspired small molecule pharmaceuticals with high aqueous solubility, the pharmaceutical industry requires robust strategies to control immunogenic protein impurities in final drug substances. Due to similar solubility profiles with the pharmaceutical itself, protein rejection strategies relying on solubility differences (crystallization, extraction, etc.) often fail. Leveraging the rapid generation of modular acid-base pairs, we describe a pH-coupled extraction strategy relying on tertiary ammonium extractant switches for efficient purification and isolation of hydrophilic immuno-oncology drug candidate MK-1454 from an aqueous biocatalytic cascade containing crude E. coli cell lysates. We demonstrate this technique on &gt;300 g scale to isolate MK-1454 with no detectable protein impurities for human administration in clinical trials.

pH-switchable extractants for host cell protein rejection in the cascaded biocatalytic synthesis of an active pharmaceutical ingredient

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ACS Fall 2022

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