(363d) Development, Scale-up and Control of a Continuous Flow Process of a Drug Substance Encompassing Multiple Reactions

An integrated continuous manufacturing process for generation of a drug substance encompassing a series of three reactions, crystallization, filtration and drying was established at lab scale and successfully scaled up to a commercial scale of 12 kg/h. This talk focuses on the process intensification and continuous process development of the reactions, wherein a series of three reactions - acetonide deprotection, hydrolysis and salt exchange - were all telescoped and intensified to an order of few minutes while achieving the desired purity.

First preliminary studies were conducted in batch mode to understand the scope for process intensification, followed by establishing feasibility of carrying out these reactions in flow reactors. The process was optimized at lab scale to identify the critical process parameters and the residence time distribution and reaction kinetics were also well-characterized. A detailed understanding of the flow process at the lab scale enabled selection of commercial equipment based on reaction requirements. As acetonide deprotection step was acidic in nature, required a high temperature and was sensitive to mixing, a silicon carbide reactor from Chemtrix® (Plantrix) was identified as the right choice. The hydrolysis was carried out in the Plantrix followed by a PFR to allow sufficient residence time and the salt exchange, which had some tendency to form precipitates, was carried out in a dynamic reactor from AM Technologies®. Next, the pilot scale feasibility and verification of design space were performed on these pilot scale equipment. Challenges faced during further scale-up to commercial equipment and their resolution will be discussed.

A control strategy comprising PAT and a diversion strategy based on residence time distribution and model-based sensitivity analysis was established for commercial operation. A greenfield facility capable of manufacturing 90 tons/annum of this API has been established.