(81c) Continuous Processing for the Manufacture of Drug Substance

Continuous processing has been used at Eli Lilly and Company for hybrid batch/flow processes at the 100 kg/day scale, and for fully continuous processes at the 3-10 kg/day scale. Safety, cost, and quality drivers for continuous versus batch, reactor designs, control strategies, automation and feedback control, on-line analytical, numerical modeling, and a new continuous processing facility will be discussed.

High pressure hydrogenation and Grignard formation reactions were run as hybrid batch/flow processes in batch manufacturing plants. The reactions were run continuously, and the workups and isolations were done in 2000 gallon batch tanks. Throughput was about 100 kg/day dissolved product in the continuous reactors. A 360 L vertical pipes-in-series continuous reactor was used for a reductive amination to make 2000 kg cGMP intermediate in a registration stability campaign. The manufacturing site had no high pressure hydrogenation capability prior to this campaign. The capital cost to install a continuous reaction system capable of 70 bar hydrogen pressure was about 1/10X the cost of batch. The continuous hydrogenation was deemed a low risk operation by the manufacturing plant because the volume of hydrogen headspace in the reactor was low and because the hydrogen source, reactor, and hydrogen stripping were all outside the building. A continuous Grignard formation reaction was run in a 50 L CSTR with sequestered Mg solids for reasons of safety and minimizing key impurities. Safety was improved because the Grignard reactor was about 100X smaller versus batch. Wurtz coupling impurity was minimized by maintaining higher stoichiometric ratio of Mg to aryl bromide starting material, proteo was minimized by minimizing water, and phenol was minimized by minimizing oxygen. All of these were easier to accomplish in a continuous reactor compared to batch.

A process was designed, developed and run in cGMP manufacturing with 8 continuous unit operations to produce a cytotoxic API at roughly 3 kg/day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. The results were published in Science. The continuous train was run in 3 separate segments one at a time, because there was not enough room in the 4-fume-hood facility to run it all simultaneously. A condensation reaction to form a pyrazole in step 1 used lower excess equivalents hydrazine in a superheated PFR compared to batch. The commercial scale PFR was only 1.5 L, and only about 20 g hydrazine was present in the reactor at any time. A counter-current multi-stage extraction removed residual hydrazine, acetic acid, and deprotected pyrazole product, while maximizing product yield. It also eliminated and isolation of step 1 product. Crystallization was needed after the step 2 S_NAr reaction to remove residual pyrazine, regioisomers, and low levels impurities. An “Isolation-Free Isolation” was done via continuous crystallization and intermittent-flow filtration and dissolve-off. This gave the impurity rejection benefits of a crystallization but avoided the isolation and handling of cytotoxic solids. A formate salt isolation was eliminated in step 3 by using intermittent flow distillation with strip to dryness to remove formic acid. The distillation results could not be replicated in batch mode because batch distillation times were longer, which led to elevated impurity formation. On-line HPLC was used downstream from every reaction to ensure that controlled operations were maintained. On-line refractive index probes were used for monitoring startup transitions, quantifying t and axial dispersion. The business reason for 3 kg/day to 10 kg/day production by fully continuous processing is that most of Lilly’s post-FHD portfolio is projected <1500 Kgs/year API. Therefore, a large portion of the portfolio may be delivered with the facility designed for fully continuous processing in laboratory fume hoods, which provide safety and containment advantages.

The successful lab hood continuous process led to the decision to invest in a new facility. In November 2017, Eli Lilly completed a 35 million euro facility for fully continuous processing at 10 kg/day throughput. The new facility was immediately used to run a 3-step fully continuous process for the cGMP production of 200 kg API. The process had an unstable Grignard reagent that was generated and used immediately in the next reaction in flow, which was a significant quality advantage over batch. Impacts of process holds were mitigated by on-line HPLC and divert valve, and the known kinetics of the impurity formations. Unreacted aryl bromide in a Negishi coupling reaction was to reject downstream, therefore accurate control of mass flow rates was necessary for maintaining stoichiometry. A combination of automated feedback control and manual feedback control was used throughout the continuous train. Strategically placed surge tanks were also important to the control strategy. Forward processing into the crystallization was approved via off-line analytical of drums that filled up about every 14 hours. Manual feed forward control based on the off-line analytical achieved the correct solvent ratio and API concentration in the downstream evaporator which fed continuous crystallization. Continuous crystallization proved superior for kinetic impurity rejection of a problematic dimer impurity. Numerical modeling with gPROMS was used for residence time distribution, surge strategy, lot genealogy, and determining allowable disturbances and pump stops. 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 inexpensive PFA tube reactors were disposable, eliminating cross-contamination potential. 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.

The presentation will cover manufacturing successes and failures. In GMP manufacturing, downtime and material loss events occurred because of improper pump selection, improper design of piping and manual valving systems, errors with positioning of manual valves, clogging because of restrictions in fittings and small bore valves, insufficient pressure relief downstream from positive displacement pumps, and air ingress due to in-line filters clogging and cavitating pumps.

Lab automation and on-line analytical were used to accelerate and enhance discovery and development. Continuous chemistry was used by the discovery scale up group to speed early phase material delivery using Newman Kwart and ortho-Claisen thermal rearrangements, imidazole cyclizations, and cryogenic lithiations. Automated intermittent flow stirred tank reactors were used for screening a wide range of conditions for hydrogenations and coupling reactions. Custom, in-house on-line HPLC systems have enabled tens of thousands of sample analyses on more than 50 different chemistries in development.