Continuous manufacturing of monoclonal antibodies: Automated downstream control strategy for dynamic handling of titer variations

Handling long-term dynamic variability in harvest titer is a critical challenge in continuous downstream manufacturing. This challenge is becoming increasingly important with the advent of high-titer clones and modern upstream perfusion processes where the titer can vary significantly across the course of a campaign. In this paper, we present a strategy for real-time, dynamic adjustment of the entire downstream train, including capture chromatography, viral inactivation, depth filtration, polishing chromatography, and single-pass formulation, to accommodate variations in titer from 1-7 g/L. The strategy was tested in real time in a continuous downstream purification process of 36 h duration with induced titer variations. The dynamic control strategy leverages real-time NIR-based concentration sensors in the harvest material to continuously track the titer, integrated with an in-house Python-based control system that operates a BioSMB for carrying out capture and polishing chromatography, as well as a series of pumps and solenoid valves for carrying out viral inactivation and formulation. A set of 9 different methods, corresponding to the different harvest titers have been coded onto the Python controller. The methods have a varying number of chromatography columns (3-6 for Protein A and 2-10 for CEX), designed to ensure proper scheduling and optimize productivity across the entire titer variation space. The approach allows for a wide range of titers to be processed on a single integrated setup without having to change equipment or to re-design each time. The strategy also overcomes a key unexplored challenge in continuous processing, namely hand-shaking the downstream train to upstream conditions with long-term titer variability while maintaining automated operation with high productivity and robustness.