Economic Analysis of Integrated Continuous and Batch Pharmaceutical Manufacturing: A Case Study

Abstract

The capital, operating, and overall costs of a dedicated continuous manufacturing process to synthesize an active pharmaceutical ingredient (API) and formulate it into tablets are estimated for a production scale of 2000 t of tablets per year, with raw material cost, production yield, and API loading varied over broad ranges. Costs are compared to batch production in a dedicated facility. Synthesis begins with a key organic intermediate three synthetic steps before the final API; results are given for key intermediate (KI) costs of $100 to $3000/kg, with drug loadings in the tablet of 10 and 50 wt %. The novel continuous process described here is being developed by an interdisciplinary team of 20 researchers. Since yields are not yet well-known, and continuous processes typically have better yields than batch ones, the overall yields of the continuous processes with recycling were set equal to that of the batch process. Without recycling, yields are 10% lower, but less equipment is required. The continuous process has not been built at large scale, so Wroth factors and other assumptions were used to estimate costs. Capital expenditures for continuous production were estimated to be 20 to 76% lower, depending on the drug loading, KI cost, and process chosen; operating expenditures were estimated to be between 40% lower and 9% higher. The novel continuous process with recycling coupled to a novel direct tablet formation process yields the best overall cost savings in each drug loading/KI price scenario: estimated savings range from 9 to 40%. Overall cost savings are also given assuming the yield in the continuous case is 10% above and 10% below that of the batch process. Even when yields in the continuous case are lower than in the batch case, savings can still be achieved because the labor, materials handling, CapEx, and other savings compensate.

A Reaction Database for Small Molecule Pharmaceutical Processes Integrated with Process Information

“…This process related information is not available in the reaction databases listed in Table 1, but is needed for plant-wide design, process-operation simulation and optimization in studies related to sustainability and the economics of processes producing active pharmaceutical ingredients [39][40][41].…”

Design and additive manufacture for flow chemistry

“…It would also require huge research and development output, in order to develop effective flow processes which were capable of mimicking or improving upon established batch synthetic processes. 22 Multi-step reactions: chemical synthesis of fine chemicals and pharmaceuticals are often complex, involving multiple reaction and separation steps, each with alternate pathways and technical approaches. Reaction complexity in flow increases substantially as the potential number of reaction steps increases, making the production of many pharmaceutical targets incredibly complex.…”

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

“…2 Furthermore, moving to continuous processes in API production is expected to be economically beneficial. 3,4 However, these efforts are highly knowledge intensive 5 and putting them into practice is admittedly more difficult than in the case of batch processes. 6 To date, both laboratory and industrial scale API synthesis is conducted using classical organic synthesis methodologies, consisting of a sophisticated toolbox of reaction apparatus, analytical and work-up/purification techniques (Fig.…”