Continuous concentration and diafiltration tangential flow filtration with scalable dual membrane technology

Abstract Intensified, integrated, and continuous bioprocessing are key trends in current biologics biomanufacturing. They model more efficient and economical production in upstream and downstream processes. Continuous or single‐pass (SP) tangential flow filtration (TFF) and particularly diafiltration (buffer exchange) are key applications needed in downstream processing. This work presents a novel flat sheet membrane cassette for TFF diafiltration with optional simultaneous ultrafiltration (concentration). It enables effective buffer exchange of feed streams in a single‐pass, without dilution and with reduced shear stress to the valuable product. Contaminants such as salts, media components, or any small molecules smaller than the respective membrane cut‐off are continuously removed while the needed buffer volume is comparable to conventional diafiltration processes with recirculation. The flat‐sheet membrane cassette design resembles classic TFF cassettes and can therefore be scaled up and down and handled analogously. In addition, the design allows for a closed configuration, suitable for aseptic or bioburden‐controlled conditions. To introduce the buffer, only one additional external connection port is required. This allows continuous diafiltration without significant increase in operator or process control complexity. This work presents ultrafiltration and diafiltration application data using bovine serum albumin (BSA) as a model protein and real antibodies processed with an automated lab‐scale process system for reproducible data collection. The process performance was evaluated based on buffer exchange efficiency, transmembrane pressure (TMP) and permeate flux rates under varying process parameters, namely feed protein concentration, feed flow rate and diafiltration volumes. Buffer consumptions similar to conventional recirculation diafiltration have been observed with even reduced buffer consumptions at diafiltration volumes below 3. Buffer exchange values ranged over a broad range depending on the process parameters while relevant settings achieved a ~97 to >99% buffer exchange at, for example, 3, 5 or 7 diafiltration volumes at relatively low TMP between 50 and 350 mbar using both BSA and mAb. Typical permeability values and feed flow rates ranged from 10 to 60 L/(m 2 h) and 1 to 7 L/(m 2 h), respectively, using BSA and mAb protein concentrations from ~3 to 80 g/L and were significantly depending on the set process parameters. The data demonstrates how this new SPTFF concept can contribute to intensified and continuous biomanufacturing.