Abstract
Continuous manufacturing opens up new operation windows with improved product quality in contrast to documented lot deviations in batch or fed-batch operations. A more sophisticated process control strategy is needed to adjust operation parameters and keep product quality constant during long-term operations. In the present study, the applicability of a combination of spectroscopic methods was evaluated to enable Advanced Process Control (APC) in continuous manufacturing by Process Analytical Technology (PAT). In upstream processing (USP) and aqueous two-phase extraction (ATPE), Raman-, Fourier-transformed infrared (FTIR), fluorescence- and ultraviolet/visible- (UV/Vis) spectroscopy have been successfully applied for titer and purity prediction. Raman spectroscopy was the most versatile and robust method in USP, ATPE, and precipitation and is therefore recommended as primary PAT. In later process stages, the combination of UV/Vis and fluorescence spectroscopy was able to overcome difficulties in titer and purity prediction induced by overlapping side component spectra. Based on the developed spectroscopic predictions, dynamic control of unit operations was demonstrated in sophisticated simulation studies. A PAT development workflow for holistic process development was proposed.
Highlights
Innovation in biologics manufacturing urges toward continuous operations to cope with new entities in smaller volumes, such as antibody fragments, virus-like particles (VLPs), exosomes, and mRNA [1,2]
All spectra were preprocessed before a partial least squares regression (PLSR) was performed
Raman- and Fourier-transformed infrared (FTIR) spectra were trimmed to the relevant region for monoclonal antibody (mAb) and relevant side components, which was 1800–400 cm−1, and 1800–900 cm−1, respectively
Summary
Innovation in biologics manufacturing urges toward continuous operations to cope with new entities in smaller volumes, such as antibody fragments, virus-like particles (VLPs), exosomes, and mRNA (messenger ribonucleic acid) [1,2]. To demonstrate innovation, at first, monoclonal antibody manufacturing in Chinese Hamster Ovary (CHO) cells is the standard platform process [3]. Monoclonal antibody manufacturing in Chinese Hamster Ovary (CHO) cells is still the most widely used process for demonstrating new innovations, as it is well established in industry and academia. In contrast to documented lot deviations in batch or fed-batch operation, continuous manufacturing opens up new operation windows with improved constant product quality in combination with advanced process control (APC) [4].
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