Continuous Precipitation of Biotherapeutics: A Review

Abstract The increasing efficiency of upstream production of biotherapeutics exposes significant challenges in downstream purification. Chromatography, the traditional gold standard, offers high purity and yield but faces limitations such as restricted mass transfer, limited capacity, and scalability issues, especially with high‐titer strains. As biomanufacturing moves toward fully continuous production, interest grows in alternatives beyond chromatography. Precipitation has emerged as a versatile, scalable, and titer‐independent technique that achieves yields and purities comparable to chromatography while offering simpler and more adaptable processing. It can be operated continuously, enabling seamless bioprocessing. Despite its potential, continuous precipitation remains less explored for biotherapeutics due to biomolecular complexity. Effective design requires deep understanding of thermodynamics, process modeling, hardware, and real‐time monitoring. This review discusses these critical factors, key design elements, and application examples, highlighting precipitation as a promising purification technology and exploring future research directions.