This document relates generally to the bioprocessing arts and, more particularly, to a bioprocessing vessel or an associated system providing enhanced resistance to noise by achieving equipotential with an associated liquid medium, thus improving the measurement of one or more process parameters by associated sensors.
Cell culture vessels such as bioreactors are frequently used for bioprocessing, such as for culturing cells for biologics research and manufacturing. A culture medium is added to the bioreactor to feed the cells being grown therein. A certain level of gas transfer between the gas phase and the liquid phase of the culture medium is also necessary to permit optimal cell growth.
In the course of cell culturing in particular, it is also necessary to obtain measurement of one or more process parameters in order to obtain data relating to the operating conditions of the bioreactor. One or more sensors or probes are often used for this purpose. For example, a temperature probe or sensor may be provided for sensing the temperature of the culture medium. Additional sensors, such as pH, oxygen, dissolved oxygen (DO), temperature, biomass/cell density, glucose, lactate, etc. may also be utilized for process control.
To optimize the signals such sensors provide, it is desirable for the liquid medium within the bioreactor to be at the same potential (equipotential) as the bioreactor and associated sensors or probes. The term equipotential relates to all conductive objects in a space having the same level of electrical charge or lack thereof. The lack of equipotential results in electromagnetic noise, which affects the accuracy of any sensor or probe measurements in proximity of the bioreactor.
Typically, stainless steel bioreactors do not suffer from such noise because they utilize ground connector(s) to eliminate potential differences among the liquid media, the bioreactor and the associated sensors or probes. On the other hand, as shown in
Accordingly, a need is identified for a bioprocessing arrangement, such as one involving a cell culturing vessel, bioreactor, or a system for bioprocessing, that is insulative to the liquid medium (in the case of a plastic, disposable vessel, for example), and yet adapted to reduce or eliminate signal noise caused by electrical interference in an associated sensor to achieve better measurement of process conditions.
According to one aspect of the disclosure, a system for bioprocessing comprises a bioprocessing vessel formed of a material insulative to a liquid medium when present therein. At least one sensor is provided for sensing a parameter of the bioprocessing vessel and generating a signal indicative of the parameter. At least one conductor is adapted to provide electrical communication between the liquid medium in the bioprocessing vessel and an external structure to achieve equipotential for reducing noise in the signal produced by the at least one sensor.
In one embodiment, the at least one conductor comprises a conductive material connecting the liquid medium with the external structure. For example, the at least one conductor may be a wire, cable, or pin made of a metal, such as stainless steel or copper.
The sensor may comprise a body connected (directly or indirectly) to the insulative material of the bioprocessing vessel, the body further including a conductive portion adapted to contact the liquid medium. In such case, the at least one conductor is adapted to electrically communicate with the conductive portion of the body. The at least one conductor may comprise a conductive liquid within the body in contact with the conductive portion of the body, as well as a solid conductor connecting the conductive liquid to the external structure.
The bioprocessing vessel may comprise a port for receiving the at least one sensor. The at least one sensor may be connected to a controller for monitoring one or more operating parameters of the system based on the signal from the at least one sensor. The one or more operating parameters may include any or all of liquid level, temperature, pH, oxygen, dissolved oxygen (DO), biomass/cell density, glucose, and lactate.
The system may also include a plurality of conductors for detecting a level of the liquid medium when present in the bioprocessing vessel. The plurality of conductors may comprise a plurality of pins extending into an interior compartment of the bioprocessing vessel at different heights.
The external structure may comprise a ground connection or a controller. The bioprocessing vessel may be selected form the group consisting of a bioreactor, a bioreactor having a fixed bed, a plastic bioreactor, a flexible bag, a bioreactor having a structured fixed bed, and a stirred tank bioreactor.
According to a further aspect of the disclosure, a system for culturing cells, includes a plastic bioreactor adapted to receive a liquid medium for culturing cells. At least one sensor is provided for sensing a parameter of the plastic bioreactor and producing a signal indicative thereof. At least one conductor is adapted to provide electrical communication between the liquid medium in the plastic bioreactor and a structure external to the plastic bioreactor to achieve equipotential for reducing noise in the signal from the at least one sensor.
The at least one conductor comprises a conductive pin or wire directly or indirectly connecting the liquid medium with the external structure. The at least one sensor comprises a body having a non-conductive portion connected to the plastic bioreactor, the body further including a conductive portion adapted to contact the liquid medium, the at least one conductor adapted to electrically communicate with the conductive portion of the body. The at least one conductor comprises a conductive liquid within the body in contact with the conductive body portion, as well as the at least one conductor further comprises a solid conductor connecting the conductive liquid to the external structure.
The plastic bioreactor may include a port for receiving the at least one sensor. The at least one sensor is connected to a controller for monitoring one or more operating parameters of the system based on the signal from the at least one sensor. The one or more operating parameters of the system is selected from the group consisting of liquid level, temperature, pH, oxygen, dissolved oxygen (DO), biomass/cell density, glucose, and lactate.
The system further includes a plurality of conductors for detecting a level of the liquid medium when present in the plastic bioreactor. The plurality of conductors comprise a plurality of pins extending into an interior compartment of the plastic bioreactor at different heights. The structure external to the plastic bioreactor comprises a ground connection.
The plastic bioreactor is selected from the group consisting of a plastic bioreactor having a fixed bed, a flexible plastic bag, a plastic bioreactor having a structured fixed bed, and a stirred tank plastic bioreactor.
According to a further aspect of the disclosure, an apparatus for use in connection with bioprocessing including a liquid medium and an external structure. The apparatus comprises a sensor for contacting the liquid medium, the sensor having a conductive material in electrical communication with the liquid medium. A conductor is adapted to provide electrical communication between the liquid medium via the conductive material of the sensor and the external structure to achieve equipotential.
In one embodiment, the sensor comprises a tubular body, and the conductive material comprises a portion of the tubular body. The conductor comprises a wire connected between the conductive material and the external structure. The conductive material comprises a liquid within the tubular body. The sensor may comprise a probe within the tubular body and in contact with the conductive material. The apparatus may form part of a bioprocessing vessel, which in turn may form part of a bioprocessing system.
A further aspect of the disclosure relates to a method of improving measurement of one or more process parameters by at least one sensor associated with a bioprocessing vessel formed of a material insulative to a liquid medium. The method comprises providing electrical communication between the liquid medium in the bioprocessing vessel and an external structure to achieve equipotential for reducing noise in a signal produced by the at least one sensor.
In one embodiment, the providing step comprises providing a conductor in electrical communication with the liquid medium and the external structure. The providing step may comprise providing a conductor in electrical communication with a conductive portion of the at least one sensor contacting the liquid medium and the external structure.
The method may further include the step of detecting a level of the liquid medium using a plurality of conductors extending into an interior compartment of the bioprocessing vessel at different heights. Still further, the method may include culturing cells in the bioprocessing vessel.
The accompanying drawings incorporated in and forming a part of the specification, illustrate several aspects of this disclosure, and together with the description serve to explain the principles of the disclosure. In the drawings:
Reference is now made to
One or more sensors 136 may also be associated with the bioreactor 110. The sensor(s) may include, for example pH, dissolved oxygen, temperature, liquid level, cell density/biomass, glucose, lactate, or any sensor for measuring other desirable parameters associated with bioprocessing. The system 100 may also include tubing 130, which may be connected to a reservoir, such as a bottle , for culture media circulation.
A controller (in this example shown integrated within system docking station) 134 may form part of the system 100 for providing process control functionalities and standard parameter monitoring. The controller 134 may be associated with the one or more sensors 136 for monitoring one or more process parameters, including but not limited to pH, DO, cell density, temperature, pressure, and/or fluid levels. The controller 134 may be connected to a display 150 for displaying parameters and other aspects for control of the system 100. The controller 134 may also be associated with a pump 160, such as a peristaltic pump, for circulating fluid via the tubing 130.
According to one aspect of the disclosure, and with reference to
While an elongated structure is shown, the conductor 140 may take any shape or form, and may comprise any electrically conductive material (e.g., metals, such as stainless steel or copper for example). As illustrated, the conductor 140 may extend through a portion of the vessel 110 to connect the culture media M with an external structure, such as a connection to the ground G, or possibly using controller 134. As one example shown in
Turning specifically to
The conductor 140 comprises a conductive material (such as a metal (e.g., stainless steel or copper) and may be inserted into the tubular body 136a from a position external to the bioprocessing vessel 110. For example, the conductor 140 may comprise an elongated structure, such as a solid wire or pin, having one end portion passed into the tubular body 136a and another end portion connected to an external structure (such as, for example, the ground or the controller 134). The conductor 140 may be placed in direct contact with conductive portion 136b via a screw or other mechanical fastener, or via welding, adhesive or other fastening arrangement.
The tubular body 136a may also be provided internally with a conductive material 142, such as a liquid (e.g., water or gel). This conductive material 142 serves to establish an indirect connection between the conductive portion 136b and the conductor 140 to ensure electrical communication is achieved. As can be appreciated, these arrangements serve to achieve equipotential between the sensor 136 and the liquid media in the bioprocessing vessel 110, thus potentially eliminating or significantly reducing the effects of electromagnetic noise on signals from the probe portion 138 indicative of process parameters.
When provided with a bioprocessing vessel (such as a bioreactor) 110, any conductors present may additionally be used to measure the level of liquid within the bioprocessing vessel 110 and/or detect the presence of foam. Specifically, with reference to
In such case, one skilled in the art can appreciate that the lowest conductor (148a) must remain submerged in order for this arrangement to work. As the levels of liquid or foam increase or decrease, the difference may be detected by the different levels in contact with the conductors 140 and thus provide an indication of the level of liquid or foam. Advantageously, this provides functionality to a bioreactor that both reduces the noise of the sensor probes and improves liquid level and foam detection thereby enhancing media level control without the need to use load cells. An example of such a level sensor arrangement that may be used in connection with the conductor 140 according to the disclosure is a CM-ENS liquid level relay, distributed by ABB Ltd. (e.g., three electrode version may provide the conductors 140 for liquid level sensing and grounding).
Various types of bioprocessing vessels with sensors in need of a reduction in signal noise as a result of the lack of equipotential may benefit from the foregoing teachings. As perhaps best understood with reference to
Liquid exiting the chamber 120 passes to a headspace formed by a chamber 124 on one (upper) side of the bed 122, where the liquid is exposed to a gas (such as oxygen). Liquid may then flow radially inwardly to a central chamber 126 to return to the lower entrance leading to the chamber 124 including the bed 122. This central chamber 126 can be columnar in nature and may be formed by an imperforate conduit or tube 128 or rather formed by the central opening of the bed 122 (which is illustrated as taking the form of a structured spiral bed). The chamber 126 returns the liquid to the first chamber 116 (return arrow R) for recirculation through the bioreactor 110, such that a continuous loop results (“bottom to top” in this version, but it could be reversed).
As shown in
While the foregoing embodiments illustrate so-called fixed bed bioreactors, it should be appreciated that the application of the disclosed concepts is not so limited. Rather, the aspects of this disclosure may readily be applied to other forms of vessels pertaining to bioprocessing, such as for example a media or harvest vessel, a rocking bioreactor or a stirred tank bioreactor. Such a stirred tank bioreactor 110 is shown in
The table in
This application claims the benefit of U.S. Provisional Patent Application Ser. No. 63/022,835, filed May 11, 2020, the disclosure of which is incorporated herein by reference.
Filing Document | Filing Date | Country | Kind |
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PCT/EP2021/062536 | 5/11/2021 | WO |
Number | Date | Country | |
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63022835 | May 2020 | US |