Abstract

Chromatography is widely used in biotherapeutics manufacturing, and the corresponding underlying mechanisms are well understood. To enable process control and automation, spectroscopic techniques are very convenient as on-line sensors, but their application is often limited by their sensitivity. In this work, we investigate the implementation of Raman spectroscopy to monitor monoclonal antibody (mAb) breakthrough (BT) curves in chromatographic operations with a low titer harvest. A state estimation procedure is developed by combining information coming from a lumped kinetic model (LKM) and a Raman analyzer in the frame of an extended Kalman filter approach (EKF). A comparison with suitable experimental data shows that this approach allows for the obtainment of reliable estimates of antibody concentrations with reduced noise and increased robustness.

Highlights

  • The application of spectroscopic techniques to monitor chromatographic processes in the frame of the so-called process analytical technology (PAT) initiative is very promising due to its potential for gathering important on-line process information in a non-invasive way [1,2,3,4,5]

  • Its predictions considerably improved with respect to the use of the single Raman-partial least squares (PLS) or the lumped kinetic model (LKM)

  • This was demonstrated for the case of a low titer harvest, which is typical for perfusion bioreactors

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Summary

Introduction

The application of spectroscopic techniques to monitor chromatographic processes in the frame of the so-called process analytical technology (PAT) initiative is very promising due to its potential for gathering important on-line process information in a non-invasive way [1,2,3,4,5]. Several applications of Raman spectroscopy have been reported in upstream processing [7,8,9], showing the potential of this technology, which often requires specific modeling techniques, such as partial least squares (PLS) regression, to extract the desired information from the measured spectra. A successful implementation of Raman spectroscopy for the on-line monitoring of monoclonal antibody (mAb) concentrations in downstream processing was reported by. In spite of these results, the use of this technology remains limited due to the intrinsic weakness of the Raman signal [11,12,13]

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