Implementing PAT for single-pass tangential flow ultrafiltration for continuous manufacturing of monoclonal antibodies

Abstract

Control of single pass tangential flow ultrafiltration is crucial for continuous manufacturing of monoclonal antibodies. We propose a strategy to control the output concentration of a continuous ultrafiltration step regardless of variations in the volume or concentration of the feed material. Scheduling algorithms for the filtration runs and cleaning cycles are developed, accounting for the expected cycle times of different unit operations in the continuous train. The complete design space for the membrane module is characterized experimentally. An empirical model of the design space is developed to predict the logarithmic relationship between the feed flowrate and the maximum concentration factors achievable in a single pass for feed concentrations in the range of 1–50 g/L and feed flowrates in the range of 10–210 mL/min. The control strategy leverages in-line concentration, flowrate and pressure sensors, including near infrared spectroscopy (NIRS) flow cells to measure the concentration of mAb in the feed and retentate streams in the range 0.5–200 g/L. The control elements are the permeate pump and a variable control valve on the retentate line, which are used to obtain the desired concentration factor across the module in a single pass. Two case studies are designed to test the control system under conditions of high feed flow rate and low feed concentration, and low feed flow rate and high feed concentration, respectively. Successful control is demonstrated in both cases. The proposed system is the first complete approach that integrates process understanding, advanced monitoring sensors, and control strategies to consistently achieve concentration targets over long continuous campaigns for production of monoclonal antibodies.