Abstract
Real-time monitoring of product titers during process development and production of biotherapeutics facilitate implementation of quality-by-design principles and enable rapid bioprocess decision and optimization of the production process. Conventional analytical methods are generally performed offline/at-line and, therefore, are not capable of generating real-time data. In this study, a novel fiber optical nanoplasmonic sensor technology was explored for rapid IgG titer measurements. The sensor combines localized surface plasmon resonance transduction and robust single use Protein A-modified sensor chips, housed in a flexible flow cell, for specific IgG detection. The sensor requires small sample volumes (1–150 µL) and shows a reproducibility and sensitivity comparable to Protein G high performance liquid chromatography-ultraviolet (HPLC-UV). The dynamic range of the sensor system can be tuned by varying the sample volume, which enables quantification of IgG samples ranging from 0.0015 to 10 mg/mL, without need for sample dilution. The sensor shows limited interference from the sample matrix and negligible unspecific protein binding. IgG titers can be rapidly determined in samples from filtered unpurified Chinese hamster ovary (CHO) cell cultures and show good correlation with enzyme-linked immunosorbent assay (ELISA).
Highlights
Efficient and cost-effective production of biologics requires the ability to accurately monitor and control the production process
We explore a novel Localized surface plasmon resonance (LSPR)-based sensor technology that combines nanoplasmonic sensing with fiber optics that is possible to integrate for specific on-line/in-line biodetection in real-time
The flow cell was produced in medical grade stainless steel to tolerate both cleaning in place and high pressures
Summary
Efficient and cost-effective production of biologics requires the ability to accurately monitor and control the production process. Guidelines concerning process analytical technologies (PATs) released by the U.S Food and Drug Administration (FDA) in 2004 [1] initiated a large interest in development and implementation of technologies for near real-time or real-time monitoring of key performance indicators (KPIs) and critical quality attributes (CQAs) in bioproduction [2,3,4]. Therapeutic antibodies are currently the largest group of biopharmaceuticals. Until 2019, a total of 79 therapeutic immunoglobulin G (IgG) monoclonal antibodies (mAbs) had been approved by the U.S. FDA [5,6]. Techniques for process development and production of mAbs using mammalian cell cultures have been evolving rapidly, resulting in product titers ranging from about 1 to 10 mg/mL using CHO cell cultures [7,8,9,10]. Possibilities to monitor IgG titers are central for optimizing process conditions and Processes 2020, 8, 1302; doi:10.3390/pr8101302 www.mdpi.com/journal/processes
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