Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions

TLDR

Advances in drug potency, tailored therapeutics, and progress in chemistry, engineering, analytical science, process modeling, and equipment design have driven pharmaceutical manufacturing toward flexible continuous processing, with technical and business drivers justifying the shift. The study develops a multistep continuous‑flow CGMP process that produced 24 kg of prexasertib monolactate monohydrate for clinical trials. The process uses eight continuous unit operations—small reactors, extractors, evaporators, crystallizers, and filters—to produce about 3 kg per day. The continuous process improves performance, safety, and containment of the potent compound compared to batch methods.

Abstract

Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.