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traditional batch production, due largely to the overhead costs of the facility, so lend themselves well to continuous flow technology where capital costs tend to be much lower. Rather than converting a batch process into a continuous flow-based analogue, exploring flow synthesis in the early development stages allows for the subsequent steps to be streamlined, saving time and money in the long run, as previously noted. Multiple process steps in flow, such as reactions, work-up, extractions, crystallisations and distillations with different equipment requirements can be developed and connected in a small footprint facility as opposed to over several large assets in a production facility with the associated handling challenges and costs. Eli Lilly's highly potent oncology drug Prexasertib demonstrates the practice of employing continuous flow in early phase development, where the technology was adopted for the final four steps of the synthesis1 throughout clinical
scale manufacture, and now on to commercial production at a rate of three kilograms a day. Specific challenges that needed to be addressed, that have been published and discussed, included the use of hydrazine at elevated reaction conditions to drive purity and performance, as well as avoiding issues surrounding isolation and handling of potent toxic intermediates. Concurrent analytical monitoring also enabled rapid trouble-shooting during the manufacturing process. The recognised benefits of this process were numerous and allowed eight continuous operations to take place in series, within small continuous reactors, extractors, evaporators, crystallisers and filters. A continuous reactor type was developed and utilised, as was a method for in-process filtration and redissolution. The process included the ability to operate at high temperature in a low-boiling solvent, afforded improved safety for a hazardous reaction, better
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With continuous flow, all routes can be explored to find the most appropriate synthesis that can then be progressed through all the different stages of development.
yield and an improved impurity profile. The containment of highly potent materials was achieved through the use of dedicated and disposable equipment; and synthetic efficiencies were seen with enhanced product stability, the elimination of one isolation step, and the elimination of solids handling in another isolation step. The advantages described above and illustrated in the example from Eli Lilly demonstrate that continuous flow drastically minimises, if not eliminates, safety and quality complications that arise from inhomogeneity and it should therefore be regarded as a truly enabling technology and a powerful development tool.