By Dr. Stephen Born, Continuus Pharmaceuticals

The development of a continuous process to produce an antiviral drug for the treatment of influenza is presented.  The motivation behind this effort is to transition towards integrated continuous manufacturing (ICM) as a platform to create an agile and on-demand supply chain capability for a drug that has a highly variable market demand.  The work described herein includes an improved late-stage synthetic route to the API that: (1) reduced a four-step synthesis down to two-steps; (2) identified key diastereomeric crystallization conditions to reach required material specifications; and, (3) eliminated the use of N-methyl-2-pyrrolidone and N,N-dimethylacetamide in exchange for a more environmentally benign solvent mixture of acetonitrile and water.  After a full revision of the two-step synthetic route in batch mode, each unit operation was translated to continuous mode to evaluate their performance.  Together, this key synthetic route eliminated 16-unit operations, reduced lead time from 12 months to two days, and significantly simplified the process.