Abstract: A system for TFF filtration of a feedstock includes a feed vessel containing a solution comprising a target biomolecule, a filter membrane for filtering the solution, a feed pump for moving the solution from the feed vessel to the filter membrane, a buffer vessel coupled to the feed vessel by a buffer supply line, and a diafiltration pump disposed in the buffer supply line for delivering a buffer solution to the feed vessel. A variable path-length instrument is coupled to the feed line for determining, in real time, a concentration of the target biomolecule in the solution. A controller is coupled to the variable path-length instrument, the feed pump, and the diafiltration pump to control operation of the system based on the received information.