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Interest of locally weighted regression to overcome nonlinear effects during in situ NIR monitoring of CHO cell culture parameters and antibody glycosylation

Abstract : Animal cell culture processes have become the standard platform to produce therapeutic proteins such as recombinant monoclonal antibodies (mAb). Since the mAb quality could be subject to significant changes depending on manufacturing process conditions, real time monitoring and control systems are required to ensure mAb specifications mainly glycosylation and patient safety. Up to now, real time monitoring glycosylation of proteins has received scarce attention. In this article, the use of near infrared (NIR) to monitor mAb glycosylation has been reported for the first time. Whereas monitoring models are mainly constructed using linear partial least squares regressions (PLSR), evidences presented in this study indicate nonlinearity relationship between in situ captured spectra and compound concentrations, compromising the PLSR performances. A novel and simple approach was proposed to fit non-linearity using the locally weighted regression (LWR). The LWR models were found to be more appropriate for handling information contained in spectra so that real time monitoring of cultures were accurately performed. Moreover, for the first time, the LWR calibration models allowed mAb glycosylation to be monitored, in a real time manner, by using in situ NIR spectroscopy. These results represent a further step toward developing active-control feedback of animal cell processes, particularly for ensuring properties of biologics. K E Y W O R D S in situ near infrared spectroscopy, locally weighted regression-LWR, monoclonal antibody-mAb glycosylation, partial least squares regression-PLSR, real time monitoring 1 | INTRODUCTION The production of biologicals, especially recombinant monoclonal anti-bodies (mAb), remains a challenge due to the structural complexity of these molecules and their sensitivity to changes in the manufacturing process. That is why strict quality control systems are required to ensure mAb specifications and patient safety. For that, regulatory agencies proposed the quality by design strategy, 1 which is rendered possible through the process analytical technology (PAT) approach. 2-4 The main objective is to real time monitor the concentrations of some process parameters, such as viable cell, nutrient, and metabolite concentrations, whose variability may have an impact on mAb quality attributes. 5
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Daniel Zavala‐ortiz, Bruno Ebel, Meng‐yao Li, Dulce Ma. Barradas‐dermitz, Patricia Hayward‐jones, et al.. Interest of locally weighted regression to overcome nonlinear effects during in situ NIR monitoring of CHO cell culture parameters and antibody glycosylation. Biotechnology Progress, Wiley, 2020, 36 (e2924), pp.1-10. ⟨10.1002/btpr.2924⟩. ⟨hal-02333228⟩



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