Described herein are novel systems and downstream protein purification (DSP) processes that provide high quality product rapidly, and on a large scale. Many of the processes enable one chromatography step to follow another chromatography step without an intermediate ultrafiltration/diafiltration (UFDF) step. These optimized processes allow for automation on the manufacture plant floor, permitting the use of a multi-cycling strategies that can utilize smaller, less expensive columns. The processes can provide considerable advantage on production efficiency, cost saving and on waste disposal.