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Publication Date: 2016-Apr-25

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A system for sensing virus particles in complex environments such as a biomanufacturing stream of protein-based biopharmaceuticals is disclosed. The system uses a multivariable resonator sensor to reject bulk interferences in the biomanufacturing stream and to deliver broad dynamic measurement range. Further, bioreceptors are used to provide high selectivity and binding affinity of the bioreceptors with controlled ability for their sensor-immobilization, which eliminates the need for storage at low temperature. Furthermore, virus particles are actively transported to the sensor by centrifugation in a disposable fluidic cartridge, which significantly reduces detection time. Design of the disposable fluidic cartridge eliminates the requirement of assisting reagents and sample washing.

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The present disclosure relates generally to biomanufacturing and more particularly to sensors for virus detection in biomanufacturing streams.

As recommended by Food and Drug Administration (FDA), viral safety of biopharmaceuticals produced in animal cell culture require testing of cell lines and media components for the absence of viruses which may be infectious and/or pathogenic for humans. Several orthogonal viral clearance and inactivation steps are also recommended for downstream processing of the biopharmaceuticals and include hold time at low pH, solvent treatment for enveloped viruses, adsorption on chromatography media and ultrafiltration. However, non-enveloped Minute Virus of Mice (MVM) particles are resistant to physiochemical inactivation. In many instances, MVM infects and contaminates Chinese Hamster Ovary (CHO) cell-based production of biopharmaceuticals causing a significant disruption in downstream processing. Contaminated cultures are discarded despite huge expense and the contamination also results in several months of downtime for equipment decontamination.

Conventional virus counting methods are based on physical titer such as polymerase chain reaction and enzyme-linked immunosorbent assay, and biological titer such as cell culture methods. Such methods are time consuming, ranging from several hours to several days, and costly. These limitations prevent rapid and accurate detection of virus particles in numerous applications.

Further, virus detection in biomanufacturing streams, human body fluids, environmental samples, and other complex environments is a challenge. While some conventional technique sense single viral particles, most conventional virus sensing technologies suffer from various limitations.  These limitations include operating in vacuum or in solutions having minimized conductivity obtained on de-salting, addition of assisting reagents, and slow transport of viruses to the sensor. Therefore, these conventional technologies are difficult to implement outside of a laboratory. Also, these conventional techniques do not take into account the need for operation with a relevant sample volume for statistically valid measurements. Based on regulatory requirements, samples of several milliliters are required, which is a significant limitation of the sensor in terms of operation time and sample handling logistics.

It would be desirable to have an efficient virus sensing technique for complex environments.


Figure 1 depicts sampling-centrifugation-sensing process for quantitation of MVM particles in a biomanufacturing stream according to an embodiment of a technique for sensing virus particles. 

Figure 2 depicts a virus sensor based on radio-frequency resonant multivariable sensor:  (A) General view of the sensor integrated into a centrifuge tube.  (B) Distribution of electrical field in the sensor upon sensor excit...