Abstract
The integration of real time release testing into an advanced process control (APC) concept in combination with digital twins accelerates the process towards autonomous operation. In order to implement this, on the one hand, measurement technology is required that is capable of measuring relevant process data online, and on the other hand, a suitable model must be available to calculate new process parameters from this data, which are then used for process control. Therefore, the feasibility of online measurement techniques including Raman-spectroscopy, attenuated total reflection Fourier transformed infrared spectroscopy (ATR-FTIR), diode array detector (DAD) and fluorescence is demonstrated within the framework of the process analytical technology (PAT) initiative. The best result is achieved by Raman, which reliably detected mAb concentration (R2 of 0.93) and purity (R2 of 0.85) in real time, followed by DAD. Furthermore, the combination of DAD and Raman has been investigated, which provides a promising extension due to the orthogonal measurement methods and higher process robustness. The combination led to a prediction for concentration with a R2 of 0.90 ± 3.9% and for purity of 0.72 ± 4.9%. These data are used to run simulation studies to show the feasibility of process control with a suitable digital twin within the APC concept.
Highlights
Innovations in biologics manufacturing are accelerating and driving towards continuous operation to cope with increasing titers and the multitude of new entities such as antibody fragments, virus-like particles (VLPs), exosomes and messenger ribonucleic acid [1,2]
Recent works have shown that selective precipitation [4,7,8,9,10,11,12,13,14,15] is a suitable alternative to protein A chromatography, which was identified to be the bottleneck in monoclonal antibody (mAb) manufacturing
It has been shown that precipitation as a unit operation is very robust and achieves a high depletion of the side components due to the mode of operation
Summary
Innovations in biologics manufacturing are accelerating and driving towards continuous operation to cope with increasing titers and the multitude of new entities such as antibody fragments, virus-like particles (VLPs), exosomes and messenger ribonucleic acid (mRNA) [1,2]. The underlying process for this study is a monoclonal antibody manufacturing (mAb) in CHO cells (Chinese hamster ovary) [3,4,5,6], which is still the typical workhorse to present innovations. Recent works have shown that selective precipitation [4,7,8,9,10,11,12,13,14,15] is a suitable alternative to protein A chromatography, which was identified to be the bottleneck in mAbs manufacturing. Precipitation can be achieved differently, e.g., with cold ethanol [14,16], polyethylene glycols (PEG) of different sizes (3350–8000 g/mol) [4,7,8], with a combination of PEG and salts [11,17] or even with salts alone [10]
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