Ultrafiltration/diafiltration (UFDF) processes are used for final formulation of high value biotherapeutics like monoclonal antibodies. Membrane fouling and cleaning are both critical factors governing the performance of these processes, but there is very limited data on either of these phenomena, particularly at the high monoclonal antibody concentrations used in current UFDF systems. The objective of this study was to compare the effectiveness of different cleaning regimens for composite regenerated cellulose membranes in Pellicon 3 tangential flow filtration cassettes after UFDF of a monoclonal antibody product. The water permeability after UFDF was 20 +/- 5% smaller than the clean membrane permeability due to fouling. Membranes could be successfully cleaned with 0.5 N NaOH, but this caused an increase in permeability and a loss in solute rejection due to an opening of the membrane pores. Cleaning with DI water was not very effective under normal flow conditions but provided very good recovery of water permeability when the flow was into the retentate exit port and out through the feed port, without any damage to the membrane as seen with NaOH. These results demonstrate the potential of using a hydrodynamic cleaning cycle without any aggressive cleaning chemicals for antibody fouled membranes. port and