(636d) Process Development and Scale-up of Depth Filters for Enzyme Removal in Small Molecule Drug Substance Manufacturing

Enzyme mediated reactions are a growing portion of the small molecule drug substance pharmaceutical pipeline. These enzymes are enabling greener chemistries to be employed, transforming the drug substance landscape. With these benefits comes the difficulty of removing the enzymes in the downstream process in order to isolate high quality intermediates and API. Having a tool box of options for enzyme removal is key since no one removal strategy will be optimal in all cases. In this talk we discuss the evaluation and scale-up of depth filtration as the enzyme removal unit operation for a complex, multiphase small molecule reaction system composed of immiscible organic and aqueous phases along with precipitated enzymes. Lab scale experiments were performed in a constant-flow mode to evaluate the loading capacity of different depth filter media (carbon impregnated cellulose based media versus media containing diatomaceous earth). The process was then scaled up to the pilot plant, where we switched to a constant-pressure mode of filtration. In this talk we will show how the process performed under these two modes of operation and how the filter loading capacity can be manipulated by having no agitation of the batch versus when the batch is well-mixed. The no agitation scenario allows the enzymes to settle, resulting in a portion of the enzymes remaining in the vessel on the walls and dish, thus decreasing the filter burden and ultimately reducing the amount of filter surface area needed per batch.