(250e) Moving From Batch towards Continuous Organic-Chemical Pharmaceutical Production

Organic synthesis based production of pharmaceuticals has traditionally been done in batch reactors, and it is custom to tailor the synthetic routes to work well in these reactors instead of using reactor set ups designed to handle the relevant chemistry. A major problem of many batch reactions for pharmaceutical production is that the process is typically based on a long sequence of reactions, which thus results in time-consuming production processes that often need expensive storage of reaction intermediates as well. As such, batch production also implies that the full benefits of the Process Analytical Technology (PAT) initiative of the FDA cannot be realized in the pharmaceutical production process.

In contrast, a continuous production environment may potentially lead to improved safety against e.g. runaway reactions due to the reduced size of the reactors, higher productivity and reduced costs, and reduction or elimination of stocks. Furthermore, continuous production inherently implies an improved capability to react on process disturbances (e.g. changes in the quality of the raw materials used) via appropriate control loops, thus resulting in a more robust production process and a more consistent product quality.

In this paper the production of an active pharmaceutical ingredient (API) developed by Lundbeck A/S is studied, attempting to change the production from batch to continuous. This model reaction involves several unit operations which are typical of organic synthesis based pharmaceutical production, such as Grignard reaction, solvent exchange, liquid-liquid extraction, crystallization, etc. During the re-design of the existing process, opportunities are sought to obtain a less time-consuming and less complex production process. To this purpose, a systematic methodology for re-design is developed and applied. On the one hand, it is attempted to eliminate unnecessary intermediate production steps (in this case a crystallization step). On the other hand, a systematic solvent selection methodology is used to search for solvents which may further simplify the process and/or may lower its environmental impact. These objectives might be achieved by different routes, for example eliminating the need for solvent exchange between unit operations, or facilitating product purification or solvent recovery. Furthermore, the design of continuous operation units poses several engineering problems, e.g. processing hardly soluble compounds and highly viscous mixtures. Novel technological solutions are explored to carry out and if possible intensify these processes.

In this presentation the challenges and opportunities which arise when converting from batch towards continuous organic-chemical pharmaceutical production will be briefly discussed. The systematic methodology, the experimental and the computer-aided process design tools employed will be presented as well as results of applying the computer-aided tools to the model process.