Research Article

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

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Science  16 Jun 2017:
Vol. 356, Issue 6343, pp. 1144-1150
DOI: 10.1126/science.aan0745

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Go with the flow in drug manufacturing

Although many commodity chemicals are manufactured using continuous flow techniques, pharmaceuticals are still mostly produced in large single batches. Cole et al. report a protocol for the small-volume continuous preparation of multi-kilogram quantities of a cancer drug candidate, prexasertib monolactate monohydrate, under current good manufacturing practices. Advantages of the approach include safer handling of hazardous reagents and intermediates, as well as yield and selectivity improvements in both the reaction and purification stages. Concurrent analytical monitoring also facilitated rapid trouble-shooting during the manufacturing process.

Science, this issue p. 1144

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.

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