Online control of the twin-column countercurrent solvent gradient process for biochromatography.

A new control concept for the twin-column MCSGP process has been developed. The controller is based on two independent PID controllers each of which affects one side of the product collection window. Accordingly, the two controllers, although independent, can together shift the product collection along the elution chromatogram. The product stream collected during one entire process cycle is analyzed with an at-line HPLC allowing a direct feedback of the measured purity values to the controller. The two set points are given by the purity values with respect to weak and strong impurities in the product stream. The controller performance was tested with two systems: In the first one, a three component protein model mixture was considered. The controller stability and reliability was tested in conditions of both set point tracking and rejection of feed composition and pump flow rate disturbances. The complete experiment ran for 112h during which the desired purity values were always kept within the set points. A more realistic example was the purification of a monoclonal antibody supernatant from fragments and aggregates. In this case, the process reached specifications after five cycles, and kept them for 20h of operation in spite of ongoing disturbances in pump flow rates and feed composition. A new general start-up procedure was developed and tested in this particular purification process. The procedure starts from very simple initial conditions and let the controller to identify conditions, particularly for the recycle streams, which lead to yield and purity values significantly better than the corresponding values achieved in batch chromatography in specs.