Enhanced cleaning strategies for UF/DF membranes in biopharmaceutical downstream processing

Membrane fouling during ultrafiltration/diafiltration (UF/DF) remains a major challenge for extending membrane lifetime in biologics manufacturing. Developing cleaning strategies that combine high efficiency with scalability is essential for robust downstream processing. In this study, different UF/DF membrane cleaning methods were assessed under bench-scale conditions with consideration for large-scale implementation. Permeate-closed cleaning (PCC), which temporarily closes the permeate port to enhance shear, effectively mitigated normalized water permeability (NWP) decline. Furthermore, forward and reverse PCC at elevated feed flux achieved comparable fouling control with fewer steps by leveraging hydrodynamic shear and localized backwashing. To simplify large-scale adoption, high-flux PCC was developed and demonstrated the ability to restore NWP and maintain stability over extended cycles. Quantitatively, high‑flux PCC reduced early NWP decay by ~ 18% over the first three cycles and recovered > 15% NWP in previously fouled membranes, stabilizing permeability over extended reuse. Backwashing under controlled negative transmembrane pressure (TMP) further improved pore-level cleaning and extended membrane usability. Additionally, combining sodium hypochlorite (NaClO) with sodium hydroxide (NaOH) provided strong oxidative and alkaline action; within the evaluated range (25-150 ppm NaClO), 50 ppm was identified as a practical lower limit for effective recovery, while 150 ppm restored NWP from ~ 70 to ~ 100% with residual NaClO < 0.02 ppm after final rinsing. Collectively, these findings present a portfolio of cleaning strategies-hydrodynamic, chemical, and combined approaches-that enhance cleaning efficiency, reduce chemical exposure, and support sustainable UF/DF operations in biologics manufacturing.