An Automation Framework for Chromatography in Integrated Continuous Biomanufacturing

Abstract

Integrated continuous bioprocessing (ICB) is increasingly adopted in biopharmaceutical manufacturing due to its potential to improve process economics and enhance product accessibility. A critical barrier to broader adoption is the challenge of maintaining robust operation of the integrated downstream purification processes, particularly chromatography, under variability from upstream processes like dynamic perfusion bioreactors. Managing variability is difficult as bind-elute chromatography is inherently a semi-continuous process and standard commercial equipment offers limited sensing and control capabilities. This research addresses this challenge through two complementary innovations. First, an optimal scheduling and control framework is developed for single-column bind-elute chromatography integrated with a dynamic bioreactor harvest and surge vessel. A core innovation is the application of a mixed-integer nonlinear programming formulation within an open-loop rolling horizon scheme that simultaneously optimizes the chromatography loading flow rate and duration based on dynamic process models and feedforward upstream forecasts. Critically, this approach utilizes the surge vessel as a degree of freedom to effectively buffer upstream variability and enable a variable loading flow rate strategy by decoupling upstream and downstream operations. Complementing this control strategy, a multivariate wavelength selection method is applied for selective protein quantification using the limited UV-Vis absorbance wavelengths available on standard chromatography equipment. This method improves quantification accuracy of commercially available proteins on standard equipment compared to conventional approaches. Experimental validation using perfusion permeate containing monoclonal antibody demonstrates that the control system effectively adapts the chromatography process to dynamic upstream conditions and outperforms a naïve control strategy, improving performance metrics such as increased product throughput and reduced product losses compared to a naïve control strategy. Together, these contributions provide building blocks for more flexible and robust platforms to advance the transition toward fully continuous biomanufacturing.