Moving toward continuous manufacturing in the pharmaceutical industry offers new possibilities, such as reducing costs and improving flexibility and product quality. However, this paradigm change requires new small-scale continuous manufacturing technologies. Since drying is one of the crucial elements of pharmaceutical production, we performed an evaluation of existing drying technologies suitable for continuous production. We focused on small-scale equipment for handling preconcentrated slurries at the kg/h scale. Lactose (soluble) and ibuprofen (poorly soluble) suspensions were dried, first, in two fluidized bed spray dryers, second, in a small-scale spray dryer, third, in a spin flash dryer, fourth, in a paddle dryer, and, finally, in a corotating twin-screw extruder. During these trials we evaluated the performance of the equipment and its advantages and disadvantages with regard to pharmaceutical production. An analysis was performed to compare the different technologies. Our findings confirm that there is a need for improved continuous small-scale systems for drying crystalline products without causing agglomeration and/or attrition in order to preserve crystal properties originating from careful engineering during the crystallization phase. The aim of this study was to provide information regarding operational capabilities of continuous small-scale drying equipment.

Despite the many benefits that flow chemistry brings in the context of commercial manufacturing, a major issue for such continuous processing can be the clogging of flow equipment. In the case of verubecestat (MK-8931), the development of a flow chemistry process for the Mannich step greatly increased the reaction yield and the purity of the isolated product. However, in one of the plant-scale solvent runs in advance of process validation, an unforeseen and isolated clogging incident occurred. Herein, we report the methodical troubleshooting leading to the location of the clog, the structural elucidation of the solids, and eventual root cause analysis. The culprit was eventually tied to poly­(THF), which was present in extremely low levels in a specific lot of THF solvent used. An interesting observation with regards to the deposition of solids in the filter cartridge and static mixer element with respect to solvent flow led us to speculate that the precipitation of the solids is caused by a phenomenon known as hydrodynamic cavitation.

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The development of a robust manufacturing process to relebactam, a potent β-lactamase inhibitor, is described. The origin and control strategy of oligomer impurities formed during hydrogenolysis of benzyl urea intermediate 9 and deprotection of Boc-sulfate intermediate 11 have been thoroughly studied and developed. The optimal manufacturing process has been successfully implemented for commercialization, preparing relebactam (1) in >99% purity with a non-detectable level of oligomers.