This work highlights ongoing efforts in the development of a biocatalytic route to a key advanced intermediate in support of an active clinical development program. At the forefront of this development, the team was tasked with identification and characterization of scale-appropriate reactors to perform the reaction. The biocatalytic transform is a hydroxylation, and as such requires oxygenation of the aqueous medium during the course of the reaction. Complicating the matter, the reaction requires catalytic quantities of iron which is susceptible to background oxidation, creating a need for a careful balance between adequate chemical reaction rate, and over-oxidation of iron, ultimately leading to a stalled reaction.
In this work, we discuss the initial reactor design and characterization as well as preliminary demonstration of the system at scales from 10 to 1000 ml. In particular, this work highlights development and application of novel reactor designs and experimental strategies towards the establishment of a robust manufacturing process. Furthermore, advanced experimentation techniques, including integrated data capture and analysis, have been employed to build process understanding as rapidly as possible, especially considering the complex reactor design requirements this chemistry poses. Additionally, we have repurposed an AMBR15, a parallel micro bioreactor commonly employed for mammalian cell culture, to enable rapid screening of a wide variety of experimental parameters. This experimental strategy has enabled deep insight into the suspected mode of catalyst deactivation, and offers an opportunity for robust operation and parameter optimization moving forward.