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

ElsevierVolume 1682, 25 October 2022, 463496Journal of Chromatography AHighlights•

Variability in cell culture titer is a key challenge for continuous downstream processing.

All downstream steps require dynamic adjustment to compensate for titer variations.

A real-time automated control strategy is developed for the downstream train from 1–12 g/L.

The number of capture and polishing chromatography columns is varied automatically.

A wide range of titers can be processed on a single integrated setup without manual inputs.

Abstract

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.

Keywords

Monoclonal antibody

Continuous processing

BioSMB

Real-time control

Variable titer

Data availability

Data will be made available on request.

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