Process analytical technology in continuous processing: Model-based real time control of pH between capture chromatography and viral inactivation for monoclonal antibody production.

ABSTRACT

A real time mechanistic model-based control strategy is demonstrated for in-line pH adjustment post-capture chromatography and prior to viral inactivation for continuous processing of monoclonal antibodies. At this point in the process, tight control of pH is essential, as pH fluctuations above 3.5 can result in incomplete viral inactivation, while fluctuations below 3.5 can lead to significant aggregate formation. The present approach predicts the pH profile during the transition phase between chromatography wash and elution steps by modelling the process stream at the column outlet as a mixture of two independent buffer systems. Control of pH in this transition phase is a critical consideration in capture chromatography as a significant amount of mAb material is eluted at this time. The model inputs are buffer concentrations, flow rates, and theoretical pKa values, along with cleaning step conductivity profiles which are readily available from a typical process chromatography equipment. The utilization of the most recent cleaning cycle data as an input to the model allows sensitive calibration to the individual process at hand on a column-to-column basis. The model is able to accurately predict the pH profile throughout the elution, as well as calculate the flow rate of the acid (titrant) required at each time point to maintain the pH consistently at 3.5±0.2. The strategy is demonstrated for various buffers, columns, operating conditions, and process deviations in a three-column continuous process, and is a useful and simple approach for achieving robust control of pH at this critical point in the continuous train.