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Cancer Drug Produced in Small Continuous-Flow Batches

Reactor for small-volume manufacturing

Gas/liquid reactor used in small-volume continuous drug manufacturing (Eli Lilly & Co.)

16 June 2017. A team from drug maker Eli Lilly & Company devised techniques for producing an experimental cancer drug in small quantities but with safe, economical methods used in continuous flow manufacturing. Researchers from Lilly’s labs in Indianapolis, Indiana and Dunderrow, Ireland describe their process in today’s issue of the journal Science (paid subscription required).

The Lilly team led by research scientist Kevin Cole sought to apply techniques developed in the chemical industry with continuous flow manufacturing to produce small quantities of pharmaceuticals, like those needed in clinical trials or on demand for smaller target populations, such as in precision medicine. Current manufacturing practices in the industry, in place for decades, are designed to produce large quantities of a single product using fixed, costly equipment.

Since health care is moving in the direction of precision medicine, say the authors, the pharmaceutical industry needs to follow suit, including its manufacturing practices. Cole and colleagues adapted processes used in the chemical industry among others, that make it possible to safely produce small batches of drugs that meet current good manufacturing practices required by regulators. Continuous flow manufacturing replaces the large batches produced with chemical reactions using a series of connected processing steps — e.g., heating, extraction, and filtration — that achieve the same result, but in smaller quantities.

Shifting to continuous flow processes faces economic and logistic hurdles, particularly in keeping down costs and scaling up to production quantities (even if smaller), while still meeting manufacturing standards required by FDA. To meet this goal, the Lilly team designed a 7-step process that replaces the usual single, large-batch production method.

The techniques developed by the Lilly team take advantage of the smaller quantities, such as lower safety risks from reducing amounts of potentially dangerous materials used at any one time, and performing production steps under fume hoods. The researchers also use transparent vessels, which provide better control of the process, and disposable fixtures that reduce cleaning steps and costs. In addition, online monitoring in real time makes it possible to quickly identify and fix problems.

As a test case, the team produced small quantities over several days of the experimental cancer drug prexasertib, a checkpoint inhibitor made by Lilly that improves the action of chemotherapies in attacking solid tumors. Prexasertib is currently in early- and intermediate-stage clinical trials combined with chemotherapy as a treatment for head and neck cancer and small cell lung cancer.

The researchers first demonstrated their process in Lilly labs in Indianapolis, then performed the techniques in the company’s manufacturing plant in Ireland that meets current good manufacturing practices. Their 8 reactors each turned out 3 kilograms (6.6 pounds) of prexasertib per day. The processes met current good manufacturing practices and prexasertib produced was deemed suitable in quality for clinical trials.

As reported in the industry newsletter Fierce Pharma, Lilly is not alone is adopting continuous flow manufacturing. GlaxoSmithKline, Vertex Pharmaceuticals, and Johnson & Johnson are at various stages in implementing these methods.

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