Small Volume Continuous Processing for the Manufacture of Active Pharmaceutical Ingredients

Eli Lilly has recently run a 3-step fully continuous process for the cGMP production of 200 kg API. The continuous reactions, separations, and purifications were inside laboratory fume hoods adjacent to the plant feed and intermediate vessels, providing safety and containment advantages. A silylation was run in a gas/liquid PFR designed to allow off-gassing without changing the liquid hold-up volume in the reactor, while maintaining low axial dispersion. Negishi coupling and acid deprotection reactions were accomplished in PFRs designed to handle solids because of insolubilities at end-of-reaction conditions. The reactors used inexpensive, consumable tubing to eliminate cross-contamination potential. A Grignard formation was run in a CSTR because of the solid Mg reagent. The Grignard reagent was an unstable intermediate, therefore it was continuously generated and immediately consumed in the downstream coupling reaction, which was an enabling aspect of continuous versus batch for the synthetic route. A zincate formation reaction was run in a CSTR to dampen out the stoichiometry fluctuations due to deliberate cyclic flow patters from the Grignard. A quench reaction was accomplished in a CSTR because of 2-phase liquid/liquid, the potential solids entering, and surging from the gas/liquid PFR. On-line HPLC was utilized downstream from the silylation, Grignard formation, and Negishi coupling reactions. Based on the on-line LC, flow rates were adjusted to maintain high conversion, and return from divert decisions were made. Continuous extraction and back-extraction were achieved in mixer-setters in series designed to handle small amounts of solids precipitates, and to facilitate ease of stop-restart and buffering capacity for stoichiometric flow fluctuations. The final API crystallization was done continuously because a key impurity was rejected kinetically. Continuous is superior to batch for kinetic rejection because the vessels are maintained in the kinetic regime with constant steady state supersaturation, consistent mean residence time with scale up, and immediate semi-continuous filter cake washing. Slurry milling, filtration and drying of the purified API were done batch. Surge vessels were an important aspect of the control strategy. They were used at 3 locations for decoupling, simplifying startups and automation, and forward processing decisions. Numerical modeling was used for residence time distribution, surge strategy, lot genealogy, and determining allowable disturbances and pump stops. Production rate was 8 kg/day, which is a sufficient production rate for future manufacturing of this specialized medicine because of the high potency and low annual demand.