Modelling and optimization of single-pass tangential flow ultrafiltration for continuous manufacturing of monoclonal antibodies

Abstract Formulation of biotherapeutics using single pass tangential-flow filtration (SPTFF) is a critical step in continuous manufacturing processes for many drugs including monoclonal antibodies (mAbs). The concentration of the mAb in the final formulation is a critical quality attribute which affects safety and efficacy and is determined by the concentration factor achieved by the process material stream in a single pass through an SPTFF module. Modern SPTFF modules consist of multiple smaller membranes connected in different series and parallel configurations to increase the overall membrane area and residence time of the process material in order to achieve high concentration factors in a single pass. The present work leverages the gel polarization model of protein ultrafiltration to develop a model for the permeate flux vs. time profile of a single membrane inside an SPTFF module based on three key resistances, namely the boundary layer resistance, resistance of the deposited protein layer over time, and intrinsic membrane resistance. Correlations are developed to predict the key mechanistic parameters across the typical operating range of flow rate, bulk concentration and transmembrane pressure in downstream mAb processing steps. The single membrane model is then used as a building block to model complex SPTFF configurations with diverse tree structures, and to facilitate in-silico design of customized SPTFF configurations based on operating targets.