Realization of a Manufacturing‐Scale Synthesis of Niraparib Using an Evolved Transaminase

The scale‐up of biocatalytic processes for pharmaceutical manufacture still presents key challenges. Here, we describe the development of a transaminase used in the manufacturing‐scale synthesis of niraparib, a small molecule poly(ADP‐ribose) polymerase (PARP) inhibitor. Realization of a commercial process began with the engineering of an improved enzyme variant over nine rounds of directed evolution. In tandem, process development was carried out, intensifying the substrate concentration and applying key insights on transaminase performance. The optimized process and enzyme were demonstrated over multiple batches at plant scale, and analysis of the CO 2 footprint per kilogram showed that the optimized process using the evolved enzyme had an 80% reduction in emission impact compared to pre‐evolution, highlighting the valuable improvements made through this multidisciplinary effort.