(667b) Data Rich Experimentation Methods Towards Immobilized Biocatalysis for Drug Substance Manufacture

Enzymes are increasingly used as highly specific and selective catalysts for small molecule API production. In many biocatalytic processes it is desirable to immobilize the enzyme on or within a solid support. Immobilization can improve enzyme stability, activity and catalyst loading and enables catalysis in environments which normally denature enzymes (e.g. extreme pH, high temperatures, and significant organic solvent). From a manufacturing perspective, immobilization greatly simplifies product isolation, reduces aqueous waste streams, and enables reactions to be telescoped into continuous flow processes.

Despite widespread use in chemical production, immobilized processes are generally developed by manually examining how the activity of a given enzyme varies when immobilized onto a small subset of resins. Here we discuss development of robust immobilized biocatalytic process at Merck. We focus on the development of flow-based reactors for characterizing enzyme immobilization on different resin classes and for monitoring biocatalytic processes in flow. We further discuss different biophysical methods and screening techniques which we are implementing to enable high throughput process development and improve our fundamental understanding of enzyme-resin interactions with an ultimate goal of developing robust, commercially viable manufacturing processes.