Intermittent Flow and Practical Considerations for Continuous Drug Substance Manufacturing

Intermittent flow enables slurry flow out of continuous stirred tank crystallizers without solids plugging or clogging. It enables semi-continuous filtration, washing, and re-dissolving downstream from continuous crystallization. It allows solvent exchange distillation with strip to dryness in rotary evaporators to be a legitimate manufacturing unit operation for small-volume continuous processes. Intermittent flow back pressure regulation and vapor–liquid separation downstream from continuous high-pressure hydrogenation reactors tolerates a small amount of solids precipitate flowing out of the reactors without clogging or plugging, and they promote efficient pressure purge stripping of excess gas reagent. Intermittent flow stirred tank reactors are a practical alternative to plug flow reactors (PFRs) for heterogeneous reactions. Eleven examples of continuous reactions are given that have been run at manufacturing scale in PFRs. Mean residence time ranges from 0.7 to 24 h in the 11 examples; therefore, it is not necessary for a reaction to be extremely fast in order to be a viable candidate for flow chemistry. This chapter gives many general guidelines on how to design and operate a continuous process, avoiding many of the common operational, equipment, analytical, and process chemistry pitfalls. The continuous process checklist serves to help prevent common oversights.