Increased titers from 2 to 10 mg/ml represents a major future challenge for recovery of desirable proteins during downstream processing. Pressure-driven microfiltration using synthetic membranes, due to its advantages such as speed, no phase change, no additives, selectivity and competitive economics, will be among several unit processes that will be considered to help attain this goal. Microfiltration in the biotechnology industry currently involves either removing soluble host cell protein while retaining larger insoluble particles like insoluble bodies or separating soluble recombinant protein from cells which are larger than the membrane pore-size. Such a step usually falls at the interface of upstream cell-culture/fermentation and downstream polishing steps. Hence, there is a need to rapidly optimize this step to meet time-lines for drug development and for new challenges such as those listed above. Using basic mass balance equations for batch concentration and diafiltration, we offer a simple and useful methodology to optimize a membrane filtration process. The process is similar to that used earlier for ultrafiltration. The main goals in any microfiltration application are high yield and low processing time, as enhancement in purity is implicit in the choice of membrane pore-size and chemical composition. An optimization diagram for predicting yield of the desired protein and processing time for microfiltration applications is developed by incorporating experimental parameters like observed sieving coefficient of protein, concentration factor and number of diavolumes. As a demonstration of the methodology, an optimization diagram was developed for the filtration of E. coil cell lysate containing inclusion bodies of a recombinant protein which enabled rapid determination of the two parameters (concentration factor and number of diavolumes) and optimization of membrane microfiltration processes for a given combination of sieving coefficient, membrane pore-size, and solute. (C) 2010 Published by Elsevier B.V.