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Process Chemistry

Flow chemistry reaches manufacturing milestone

Lilly chemists make chemotherapy drug candidate in a multistep continuous flow process using current Good Manufacturing Practices

by Bethany Halford
June 16, 2017 | A version of this story appeared in Volume 95, Issue 25

Although continuous flow chemistry—wherein molecules are made in a continuous process rather than in batches—has gained ground in academic labs, its adoption by industry and contract manufacturing labs has been comparatively slow. Now, chemists at Eli Lilly & Co. report a continuous manufacturing process for the chemotherapy drug candidate prexasertib monolactate monohydrate. Notably, the synthesis uses current Good Manufacturing Practices (cGMPs), linking each stage in the continuous manufacturing process to quality-control systems (Science 2017, DOI: 10.1126/science.aan0745).

Kevin P. Cole, the report’s lead author, explains that the chemists used continuous manufacturing because they needed to make only 24 kg of the compound. Making the drug candidate in batch equipment would have required an extensive cleanup afterward because the compound is potent and cytotoxic. The small flow setup can be dedicated to making this single compound and discarded, if necessary, at no great cost.

Also, the flow process included a step involving hydrazine—a compound used in rocket fuel—that would have been too dangerous to run in a batch reactor. Because flow chemistry uses a small amount of the reagent continuously instead of a large amount all at once in a batch process, the chemists could run the step safely at high temperature and pressure.

“Efforts like this are beginning to highlight the potential of continuous manufacturing in pharmaceuticals,” says Aaron Beeler, a Boston University chemist and cofounder of the continuous flow technology firm Snapdragon Chemistry. “In a cGMP setting, each of the continuous flow steps would have been noteworthy on their own. But as a multistep process this really is a substantial step forward.”

“Hopefully, this report will change the way that fine chemicals and pharmaceuticals are made,” Cole says, “by modernizing the manufacturing process and bringing it into the 21st century.”

CORRECTION: The structure in this story was updated on June 22, 2017, because of a production error. The hydrate was incorrectly represented as an H3O species.



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