Automated Systems for Bioprocessing

Abstract

An automated system for performing bioprocessing includes an incubation system configured to house at least one incubation chamber for incubating a cell culture chamber to which flexible tubing is fluidly connected, and a storage system configured to store at least one fluid-containing consumable product to which the tubing is fluidly connected, wherein the incubation system and the storage system are arranged together to enable a robotic device to operate tube welds between the flexible tubing of the cell culture chamber being incubated and the tubing of the stored consumable product, whereby the tube welds form a sterile fluid connection between the cell culture chamber and the consumable product such that a closed system is maintained.

Description

[Technical Field]

[0001] The present disclosure relates to automated bioprocessing. More particularly, the present disclosure relates to automated systems that can be configured to perform multiple bioprocessing steps or operations in parallel while maintaining a closed system. [Background technology]

[0002] An increasing number of therapeutics use cells rather than small molecules as a starting point. Approaches to manufacturing these products are rapidly evolving to keep up with the constantly emerging new therapies. In recent years, we have seen an increase in the use of many new types of cell therapy. One type is autologous cell therapy.

[0003] Autologous cell therapy is a promising type of therapy with great clinical and commercial potential, ranging from treating cancer to repairing genetic defects. These therapies involve harvesting cells from a patient, manipulating them over days to weeks, and then reintroducing them into the patient's body to produce a therapeutic effect. The steps performed during autologous cell therapy are often complex; for example, a typical CAR-T process may involve a series of steps, starting with cryopreserved Leukopacks, thawing, washing to remove DMSO, enriching, activating, transducing, expanding, and concentrating T cells, filling the formulation into IV bags, and cryopreservation, along with several other intermediate washing steps.

[0004] Bioprocessing systems have been developed to perform the above steps. In such bioprocessing systems, multiple different consumables (e.g., fluid-containing bags) may be required throughout the cell therapy process, for example, to supply media, reagents, and / or cellular materials to a growth chamber (e.g., a cell culture chamber). Similarly, one or more consumables (e.g., output or waste bag consumables) may receive fluid samples from the growth chamber. The term "consumable" may therefore be used to refer to a "single-use" element or component of the system.

[0005] Some of the processes discussed above, such as activation, transduction, and proliferation, can be carried out in a cell culture chamber, which can be incubated in a bioreactor (i.e., "incubation chamber"). During one or more of these processes, various functions need to be performed, such as perfusion, gas and nutrient delivery, reagent mixing, medium conditioning, and heat exchange. Summary of the Invention [Problem to be solved by the invention]

[0006] However, due to the need to maintain a closed system when handling cells, reagents, and other fluids, conventional consumables (e.g., media bags) include a complex network of external flexible tubing to interface with the incubation chamber. This network of flexible tubing can be difficult to handle, especially by automated means such as robotic devices. Additionally, storing such consumables in a space-efficient manner for easy access and use within a bioprocessing system can be complicated.

[0007] The ability to simultaneously store and operate multiple bioreactors, including supplying each bioreactor with the necessary fluids from consumables when required, can be difficult due to the need for specialized equipment to interface with each consumable, thus making it difficult and expensive to run multiple incubation processes in parallel. Furthermore, typical bioprocessing systems have limited capacity for bioreactors and a corresponding limit on the number of growth chambers (e.g., cell culture chambers) that can be accommodated at one time. [Means for solving the problem]

[0008] Described herein is an automated system for performing bioprocessing, comprising an incubation system configured to house at least one incubation chamber for incubating a cell culture chamber fluidly connected by flexible tubing, and a storage system configured to store at least one fluid-containing consumable product fluidly connected by tubing, wherein the incubation system and storage system are arranged together to enable a robotic device to operate tube welds between the flexible tubing of the cell culture chamber being incubated and the tubing of the stored consumable product, whereby the tube welds form a sterile fluid connection between the cell culture chamber and the consumable product such that a closed system is maintained.

[0009] During use, one or more incubation chambers and / or one or more fluid-containing consumables can be housed or stored by the automated system, although it will be understood that these chambers and consumables are removable and replaceable from the automated system. The incubation system can have one or more features that hold the incubation chambers in place in the incubation system, such as at least one incubator base with dimensions corresponding to the incubation chambers. The storage system can include multiple consumable holding positions or slots, each configured to receive and store a consumable. Each slot can be configured to receive a cartridge containing the consumable. Each slot can have one or more engagement features that releasably hold the consumable (e.g., in a respective cartridge) within the slot.

[0010] The system can be configured as a bioreactor system for a bioprocessing system, and thus can form part of a larger bioprocessing system.

[0011] The incubation system can further be configured to store the cell culture chambers in a predetermined orientation in each incubation chamber, optionally with a portion of the flexible tubing held outside the incubation chamber, for example by one or more tubing clips. In this way, the tubing can be manipulated and connected to different consumables without opening the incubator and risking affecting the incubator temperature.

[0012] The storage system may further be configured to store each consumable with the consumable's tube held in a predetermined orientation, for example by one or more tube clips.

[0013] The incubation system can be configured to accommodate a single incubation chamber, or alternatively, the incubation system can be configured to accommodate multiple incubation chambers, each positioned to incubate an individual cell culture chamber in physical isolation from adjacent incubation chambers.

[0014] The incubation system can include a single incubation chamber for a single cell culture chamber, or a single incubation chamber for multiple cell culture chambers. Alternatively, or in addition, the incubation system can include multiple incubation chambers, each configured to receive a single cell culture chamber.

[0015] Each incubation chamber can be temperature controlled. Each incubation chamber can be gas controlled.

[0016] At least a portion of the storage system may be positioned to be elevated relative to the incubation system. Optionally, at least a portion of the storage system may be below the incubation system, thus inhibiting backflow of waste from the waste container into the incubation section.

[0017] The storage system may include a rack arrangement having one or more openings for receiving the consumables.

[0018] The system can further include a cell analysis unit, wherein the at least one robotic device is further configured to manipulate a fluid connection between the cell analysis unit and the incubating cell culture chamber.

[0019] At least one tube can be fluidly connected to the cell analysis unit, and the at least one robotic device can be further configured to manipulate the fluid connection between the tube fluidly connected to the cell analysis unit and a tube fluidly connected to an incubating cell culture chamber. The cell analysis unit (or "cell analyzer") can be a cell counter, a cytometer, or any other means of cell or media analysis.

[0020] Alternatively, the system can collect the sample by welding onto a vial that has a septum on one end and a tube on the other, the system then pumps the sample into the vial and then removes the tube, and since there is no requirement to close the sample analysis process, the robot transports the vial to the cellular analysis unit, which then pierces the septum with a needle.

[0021] One or more processing parameters of the system can be configured to be adjusted based on measurements by the cell analysis unit.

[0022] The system may further include an automated processing station in which processes and operations for bioprocessing are automated, for example, using one or more robotic devices. The automated processing station is preferably configured as a stand-alone processing station. The automated processing station may include a support surface or platform configured to form part of an incubation system. The storage system may be elevated relative to the support surface or platform.

[0023] The automation system may include robotic devices, and at least one robotic device may be provided on the processing station, i.e., the robotic device that operates the tube welding is part of the processing station.

[0024] The system (eg, processing station) can further include a movement system for the at least one robotic device configured to move the robotic device relative to at least one of the incubation system and the storage system.

[0025] The movement system can include at least one rail (e.g., on a processing station) to which at least one robotic device is movably mounted, and a drive system for moving the robotic device along the rail to one or more predetermined positions.

[0026] Alternatively, at least one robotic device may be separate from the processing station. According to another aspect of the present invention, a bioprocessing system is provided that includes an automated processing station as described above and herein and a separate robotic device configured to move independently relative to the automated processing station. In other words, the robotic device that operates the tube welding may be a separate robotic device. For example, the (at least one) robotic device may perform other functions in the bioprocessing system as well as the operation of sterile tube welding between flexible tubing in the processing station. Optionally, a robotic device may be provided as part of the processing station (e.g., in addition to at least one separate robotic device that can move independently relative to the processing station).

[0027] The robotic device can be configured to manipulate the fluid connection and thereby create a tube weld between the flexible tubing of the incubating cell culture chamber and the flexible tubing of the stored consumable, the tube weld being a sterile tube weld formed between the free ends of the respective tubes, to transfer fluid through the flexible tubing.

[0028] The robotic device can be configured to manipulate fluid connections to thereby disconnect flexible tubing of an incubating cell culture chamber and flexible tubing of a stored consumable.

[0029] The robotic device may be configured to manipulate the fluid connection, thereby sealing one or both of said flexible tubes, preferably before disconnecting the fluid connection.

[0030] The robotic device can be configured to manipulate the fluid connection, thereby pumping fluid between the consumable and the incubating cell culture chamber through said fluid connection.

[0031] The robotic device can be further configured to pump fluid by applying a peristaltic pumping action to at least one of the flexible tubes that form the fluid connection.

[0032] The robotic device can be configured to manipulate the fluid connection, thereby engaging and / or positioning at least one flexible tube of the incubating cell culture chamber and at least one flexible tube of the stored consumable relative to one another to form a fluid connection.

[0033] The at least one robotic device can be further configured to manipulate a fluid connection between the first incubating cell culture chamber and the second incubating cell culture chamber.

[0034] The robotic device can be configured to use interchangeable end effectors (e.g., for a robotic arm of the robotic device), and the system further includes an end effector storage system for storing one or more interchangeable end effectors for use by the robotic device.

[0035] The robotic device can include an end effector on the robotic arm, and the robotic device can further include at least one probe or sensor disposed on the end effector. The probe or sensor can be a Raman probe, an optical probe, a microscope, and / or any other suitable type of probe or sensor. It will be appreciated that such a probe is not required to directly contact the cells to collect data, thereby enabling cells to be monitored while maintaining a closed system.

[0036] The system may further include a movement system for the at least one robotic device configured to move the robotic device relative to at least one of the incubation system and the storage system.

[0037] The movement system can include at least one rail to which at least one robotic device is movably mounted, and a drive system for moving the robotic device along the rail to one or more predetermined positions.

[0038] The at least one robotic device can include a first robotic device and a second robotic device.

[0039] A first robotic device can be configured to create a sterile tube weld, and a second robotic device can be configured to manipulate the fluid connection, thereby at least one of pumping fluid through the fluid connection or, preferably, sealing the tube before disconnecting the fluid connection. In this manner, the second robotic device can be used to seal or pump fluid away from the weld, and if the weld fails, the first robotic device can be used to reweld the tube.

[0040] The system may further include a controller for controlling the automated sequence of operations of the system. The controller may be configured to control the automated sequence of operations according to one or more predetermined workflows. Preferably, the one or more predetermined workflows are reconfigurable workflows.

[0041] The controller can be configured to automatically schedule a sequence of actions for the system to follow. The system can further include a user interface configured to allow a user to program a predetermined workflow for the system to follow. The controller can be configured to simulate an automated sequence of operations before the system executes said sequence. The system can be attached to a computer network to allow remote monitoring and control of one or more systems. One or more systems can be controlled as a group of processing stations or as a subsystem within a more complex system.

[0042] The system can further include a fluid agitation system for agitating fluid contained within the incubating cell culture chambers. The fluid agitation system can be configured to agitate fluid within each incubating cell culture chamber prior to transferring the fluid from the cell culture chamber to the output vessel and / or the sample vessel.

[0043] The at least one robotic device can be configured to manipulate the fluid connections, thereby facilitating the transfer of fluid from the incubating cell culture chamber to a waste container, prior to agitating the at least one incubating cell culture chamber with the fluid agitation system.

[0044] The storage system may include a refrigeration or heating unit for regulating the temperature of one or more consumable items.

[0045] The system can include at least one of a probe or a sensor disposed on an end effector of the robotic arm.

[0046] The system may further include a tubing supply device arranged to provide auxiliary tubing to at least one of the cell culture chambers or the consumable, preferably the device including a tubing supply reel.

[0047] The system may further include means for identifying an identification mark on at least one of the consumable, the tube, and the cell culture chamber. The identification mark may be optical or non-optical. The identification mark may be a barcode, a QR code, an RFID, or an NFC code.

[0048] The system can include a self-contained processing station arranged to facilitate the transfer of fluids from consumables stored at the processing station to the incubating cell culture chambers.

[0049] Also described herein is a bioprocessing system that includes a plurality of the automated processing systems described above and herein.

[0050] Also described herein are methods that include carrying out (automated) bioprocessing using a system as described above and herein.

[0051] As used herein, the term "processing station" preferably refers to an apparatus, workstation, unit, module, or "standalone" system, which may form part of a larger system, such as an automated bioprocessing system. As used herein, the term "standalone" preferably means that the processing station is capable of operating independently as part of a larger system, as it can provide the necessary consumables, incubation chambers, cell culture chambers, and tubing required to perform the necessary processes and operations.

[0052] As used herein, the term "automated" preferably means a process or operation that, once initiated, can be performed entirely without human intervention. Preferably, the process or operation can also be started and finished without human intervention other than programming the equipment that performs the operation or process.

[0053] As used herein, the term "closed system" preferably means that there is no contamination to or from the ambient environment (e.g., transfer of materials from the cell culture chamber to the ambient environment and vice versa) during the operations or processes performed in the processing station. As used herein, the term "closed system" can also refer to a "functional" closed system, or more preferably, a completely closed system in which a physical barrier is maintained between the ambient and the contents of the cell culture chamber and consumables. In a functional closed system, for example, air can be supplied to the system through a sterile air filter, which, while not completely closed, is considered a "closed system" sufficient to prevent contamination.

[0054] As used herein, the term "tube welder" refers to any device configured to join (i.e., weld) a first tube to a second such tube (preferably at its free end), thereby providing a sterile (and preferably closed) fluid connection between the tubes. Briefly, a tube welder can include a first clamping unit and a second clamping unit. Each clamping unit can include a pair of jaws movable between an open position for receiving a flexible tube therebetween and a closed position for clamping the received tube. The clamping units can be located on a robotic arm. When the tube is clamped, the flexible tube is pinched closed, preferably inhibiting any flow of fluid through the flexible tube.

[0055] The clamping units can be operated to grip the tubing without clamping it closed, which can allow for engagement and placement of the tubing without restricting fluid flow. Once a first tube is clamped by the first clamping unit and a second tube is clamped by the second clamping unit, a cutting blade can be heated and moved across both clamped sections of the tubing. This cuts each tube into an upstream section that connects to the respective consumable and a downstream section that previously connected to the closed end of the tubing. Heat from the cutting blade is transferred to the tubing, causing each flexible tubing to at least partially melt at the newly formed cut end. The clamping unit is then moved to position the upstream sections of the tubing adjacent to each other. The downstream section can be discarded. When the blade is removed, the upstream sections are pressed together, thereby welding the tubing together to form a single tube. This joint can be referred to as a butt weld. At this stage, the joint between the tubes can remain pinched closed, and a pinch release mechanism can be operated to remove the pinched section, thereby establishing a fluid path through the joined tubing. Visual or mechanical quality assurance (QC) means may also be provided to ensure that the welds are properly welded together.

[0056] As used herein, the term "peristaltic pump" can refer to a rotary peristaltic pump or a linear peristaltic pump. A peristaltic pump is configured to compress a portion of flexible tubing and then move the compressed portion along the length of the tubing in a pumping direction, thereby forcing fluid through the tubing. Advantageously, a peristaltic pump allows for rapid pumping of fluid through the tubing with minimal wear on the tubing and minimal potential for contamination.

[0057] As used herein, the term "consumable" preferably refers to a container, such as a bag, that holds a fluid, including, for example, a cell sample (or cellular material), a reagent, or a fluid, that may be intended to be processed at a processing station, for example, as part of a cell therapy process. Thus, in the context of this disclosure, a cell suspension bag is an example of a consumable. Other types of consumables include media bags, sample bags, intermediate process bags, waste bags, and output bags. In the context of this disclosure, each consumable has an "upstream" end of tubing fluidly connected thereto, which provides a fluid conduit to a "downstream" (opposite) end of the tubing, the downstream end being fluid-sealed by pinching a portion of the tubing shut when not connected to another such (second) tubing.

[0058] As used herein, the term "growth chamber" is a specific type of cell culture chamber. Accordingly, it is noted that the term "cell culture chamber" can be interchanged with "growth chamber" within the scope of this disclosure, and processing stations can be used to perform the processes and operations described herein (e.g., fluidly connecting consumables) on different types of cell culture chambers, of which the growth chamber is just one example.

[0059] It will be understood by those skilled in the art that any apparatus feature described herein may be provided as a method feature, and vice versa. It will also be understood that specific combinations of the various features described and defined in any embodiment described herein may be implemented and / or provided and / or used independently.

[0060] It will also be understood that embodiments have been described herein purely by way of example and that modifications of detail may be made within the scope of the present disclosure. Furthermore, as used herein, any "means-plus-function" feature may alternatively be expressed in terms of its corresponding structure.

[0061] One or more embodiments will now be described, purely by way of example, with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0062] [Figure 1] FIG. 1 illustrates a first embodiment of an automated processing system. [Figure 2a] FIG. 2 shows an example of an incubation chamber for use in the processing system of FIG. 1. [Figure 2b] FIG. 1 shows the components of the incubation chamber in more detail. [Figure 2c] FIG. 1 shows the components of the incubation chamber in more detail. [Figure 3] 2A and 2B show an example of a consumable holder for use in the processing system of FIG. 1. [Figure 4A] FIG. 1 illustrates a second embodiment of an automated processing system. [Figure 4B] FIG. 1 illustrates a second embodiment of an automated processing system. [Figure 5A] FIG. 10 illustrates a third embodiment of an automated processing system. [Figure 5B] FIG. 10 illustrates a third embodiment of an automated processing system. [Figure 6A] FIG. 6 shows an example of a consumable holder for use in the processing system of FIGS. 4 and 5. [Figure 6B] FIG. 6 shows an example of a consumable holder for use in the processing system of FIGS. 4 and 5. DETAILED DESCRIPTION OF THE INVENTION

[0063] In the following description and accompanying drawings, corresponding reference numerals are preferably used to identify corresponding features to avoid the need to describe said common features in detail for every embodiment.

[0064] Generally speaking, an automated processing system is described herein, which can be configured to perform multiple processes or operations in parallel while maintaining a closed system. The processing system can form part of a larger automated bioprocessing system. Such an automated system can be configured to perform, for example, a cell therapy process. Operations and steps traditionally performed by a human operator are automated to improve the precision and accuracy, and therefore reproducibility, of the operations and processes. More specifically, the automated processing system can perform several operations and processes in parallel, particularly facilitating the incubation of cell culture chambers and the delivery of fluids containing reagents (or other materials, such as cellular materials) from consumables to the cell culture chambers while maintaining a closed system. In preferred embodiments, described in more detail below, the automated processing system can include processing stations (e.g., "apparatus") in which such processes and operations are automated using one or more robotic devices.

[0065] In a preferred embodiment, an automated robotic device can be used to maintain a closed system by manipulating (e.g., creating) fluid connections between fluid-containing consumables and incubating cell culture chambers at a bioprocessing station. The robotic device can also form sterile fluid connections between other consumables; for example, the robotic device can manipulate a fluid connection between two incubating cell culture chambers and / or manipulate a fluid connection between a cell culture chamber and an analysis chamber (or any other suitable container or consumable). The fluid connections created by the automated robotic device are tube welds formed between the (free ends) of sections of (typically) flexible tubing that are fluidly connected to the consumables and (typically) each of the incubation / cell culture chambers.

[0066] More specifically, the tube welds formed by the robotic device are sterile tube welds, and the sterile tube welds can be made by a tube welding apparatus or “tube welder.” This can be accomplished by a robotic device including a robotic arm with an end effector configured as a “tube welder” attached. For example, the end effector can be configured to engage an end of a tube that is fluidly connected to a consumable, clamp a portion of the tube at a location along the tube spaced from the end of the tube to form a pinched portion that fluidly seals the tube (and thus the consumable), remove an existing (free) end of the tube to form a new (free) end of the tube that was not previously in contact with another such tube, then bring the new end of the tube together with a correspondingly formed new end of another such tube that is fluidly connected to the cell culture chamber, and perform a tube weld to join the two tube ends together, thereby forming a fluid connection between the consumable and the cell culture chamber.

[0067] In other words, the robotic device can be configured to manipulate the fluid connection by engaging and / or positioning (the end of) a flexible tube of an incubating cell culture chamber and (the end of) a flexible tube of a stored consumable relative to one another to form a fluid connection, which is preferably created by the robotic device also performing tube welding to join the respective ends of the two tubes.

[0068] Once fluidly connected, fluid from the consumable can be transferred into the cell culture chamber. This can be achieved, for example, by a pumping mechanism (or means) configured to apply a peristaltic pumping action to the fluid-connected tubing to force fluid from the consumable through the tubing and into the cell culture chamber, the mechanism including multiple movable pressing elements arranged to sequentially contact portions of the tubing and repeat this movement. In other words, the pumping mechanism can include a peristaltic pump. The pumping mechanism can be provided by a robotic device including a robotic arm having attached thereto an end effector configured as such a pumping mechanism. Alternatively, the processing station can include a pumping mechanism configured to receive a portion of the fluidly connected tubing and apply a pumping action to the tubing to force fluid from the consumable through the tubing and into the cell culture chamber.

[0069] Once fluid transfer has occurred between the consumable and the cell culture chamber, the fluid connection formed between their respective flexible tubing can be disconnected. Once disconnected, the tubing is sealed to maintain a closed system. The tubing is preferably sealed before disconnecting the fluid connection. Disconnecting and sealing can be accomplished using a tube welder (e.g., further configured to seal and disconnect the tubing), or a separate tube sealer can be used for this purpose. The tube sealer can be provided on the same robotic device as the tube welder and / or the peristaltic pump. The tube sealer can seal the flexible tubing using heat and / or RF radiation.

[0070] As discussed below, one or more robotic devices can be attached to a processing station or can be provided as part of an autonomous mobile ("manipulator") unit / robotic device configured to move autonomously around a bioprocessing system (e.g., a system provided in an enclosed space) in which one or more such processing stations are located and to engage each processing station as required to manipulate fluid connections. Multiple robotic devices / arms can be provided, each with an attached end effector configured to perform a specific function, or a single robotic device / arm can be configured with interchangeable end effectors, which can be stored at the processing station and / or on the autonomous mobile unit.

[0071] A first embodiment of a closed processing system 10 is shown in Figure 1, which will now be described. The processing system 10 includes an automated processing station 100, which in turn includes an incubation system 102 configured to facilitate incubation of one or more cell culture chambers 104, and a storage system 106 configured to facilitate storage of one or more fluid-containing consumables 108. The storage system 106 is elevated relative to the incubation system 102.

[0072] Attached to each cell culture chamber 104 is one or more sections of tubing 104a through which fluids can be introduced into the cell culture chamber 104. Such tubing 104a can be seen more clearly in Figure 2. Similarly, attached to each consumable 108 is a section of tubing 108a through which the contents of the consumable 108 can be extracted. At least one of the tubing 104a, 108a, and preferably both, is flexible (i.e., not rigid) tubing.

[0073] The incubation system 102 and (consumable) storage system 106 are arranged together in the processing station 100 in a manner that allows a robotic device to operate sterile tube welds between tubing connected to stored consumables 108 and tubing 104a connected to incubated cell culture chambers 104, as previously discussed. In doing so, a sterile fluid connection is made between the cell culture chambers 104 and the consumables 108, thereby maintaining a closed system in the processing station 100.

[0074] In this embodiment, the processing station 100 includes a first robotic device 112 and a second robotic device 114, which together help automate the processing system 10. The robotic devices 112, 114 are attached to the processing station 100. The first robotic device 112 includes a robotic arm having a first end effector 112a configured to perform sterile tube welding, as generally discussed above. The second robotic device 114 includes a robotic arm having a second end effector 114a configured as a pumping mechanism, as generally discussed above. Either or both of the robotic devices 112, 114 can include a tube sealer. Alternatively, the tube sealer can be provided on a separate robotic device.

[0075] The processing station 100 includes a base unit 116 having a support surface 116a disposed on an upper side thereof. The base unit 116 is substantially box-shaped / cubic-shaped and has a generally rectangular bottom surface. One or more incubator bases 118 are disposed on the support surface 116a and rest on the support surface 116a. Each incubator base 118 is configured to receive an incubation chamber 110 configured to house a cell culture chamber 104. Such incubation chambers 110 are shown separately in FIG. 2 and will be described in more detail below. The support surface 116a and incubator bases 118 thus form part of the incubation system 102 in this embodiment.

[0076] The processing station 100 can include a fluid agitation system for agitating fluids contained within the cell culture chambers 110 being incubated. For example, the incubator base 118 can be configured to agitate the incubation chambers 110 mounted thereon, e.g., the incubator base 118 can be a rocker plate that rocks the incubation chambers 110 from side to side. Alternatively, or in addition, the incubator base 118 can include other means for agitating the incubation chambers 110 mounted thereon, such as an ultrasonic source, a vibration source, and / or an orbital shaker. The fluid agitation system can be configured to agitate fluids within the cell culture chambers 110 being incubated prior to transferring the fluids from the cell culture chambers to the output and / or sample vessels. In this way, the fluids contained within the output and / or sample vessels are representative of the contents of the cell culture chambers 110. Preferably, each incubator base 118 includes a separate means for agitation, allowing different cell culture chambers 110 to be independently agitated, e.g., at different times.

[0077] In this embodiment, the robotic devices 112, 114 are also mounted on a support surface 116a. Additionally, the base unit 116 is mounted on wheels 120, such as caster wheels, to allow it to be moved and positioned within the bioprocessing system.

[0078] Frames 122 extend vertically upward from both sides of the base unit 116 and form part of the storage system 106. The frame 122 is substantially rectangular, with a horizontal crossbeam connecting the upper ends of two opposing vertical members that are attached to opposite sides of the base unit 116 to form the frame 122. Support members (or rails) 124 extend across at least a portion of the width of the frame 122 and are provided for the purpose of supporting the consumables 108 (e.g., clips or tabs 154 on each consumable 108 hang from grooves in the rails), thereby forming part of the storage system 106. In this manner, at least a portion of the storage system 106 is positioned elevated relative to the incubation system 102. Optionally, the storage system 106 can have a portion below the incubation system that can be used to store waste containers. In this manner, backflow of waste from the waste containers into the incubation section is inhibited.

[0079] The consumables 108 are stored with their tubing 108a extending below the main bag portion (e.g., in situ) and can be engaged and / or manipulated by one of the robotic devices 112, 114 to, for example, create a fluid connection between the consumables 108 and the cell culture chambers 104 held within the incubation chamber 110, which is mounted on an incubator base 118 on a support surface 116a. The consumables 108 can be held by a consumable holder 150, which is configured to be removably attached to the frame 122 / support member 124. An example of such a consumable holder 150 is shown in FIG. 3 and described in more detail below. The tubing 104a, 108a, particularly the tubing 104a on the cell culture chambers 104, is typically longer than illustratively shown in FIG. 1.

[0080] In this embodiment, the cell culture chamber 104 and various consumables 108 are loaded onto the processing station 100 by a human operator (i.e., "manually") at the start of the process, although loading may be automated in the future, for example, by using a separate robotic device in the bioprocessing system configured to perform this function.

[0081] A power supply (not shown), controller / control unit (not shown), and / or motor drive mechanism (not shown) for each of the robotic devices 112, 114 may be provided in the base unit 116. Each of these components may be remotely controlled and / or programmed via a computer network (either wired or wireless) to enable the robotic devices 112, 114 to operate autonomously. The base unit 116 may also house one or more mass flow controllers for gas control. The base unit 116 may be configured to direct temperature-controlled air through or around the consumables 108 to keep them refrigerated. Other peripheral power, control, and communication components may also be provided and are well known to those skilled in the art.

[0082] Also attached to the frame 122 is a tube reel 126 configured to deploy similar (weldable) tubing that can be used to complement (e.g., extend) existing tubing 104a, 108a of the cell culture chamber 104 or consumable 108, respectively. For example, in the embodiment shown in FIG. 1 , additional tubing from the tube reel 126 can be used to join the consumable 108 to the cell culture chamber 104, or the tubing 104a and 108a can be configured so that their lengths overlap. Optionally, the tube reel 126 can include lengths of tubing made of multiple different materials in succession (e.g., PVC to Cflex) such that a cell culture chamber 104 with a portion of tubing 104a having ends made of Cflex can be fluidly connected to a consumable 108 with a portion of tubing 108a having ends made of PVC. Alternatively, or in addition, lengths of tubing (optionally comprising multiple different materials) can be provided on the frame that can be easily grasped by a robotic device, for example, as required. Preferably, the tubing on the reel and the tubes 104a, 108a of the cell culture chamber 104 and consumable 108 comprise a thermoplastic material.

[0083] The tubing reel 126 includes a housing attached to the frame 122 and contains a stored supply of tubing wound on a rotating reel (not shown) inside the housing. Here, two such tubing reels 126 are provided on the frame 122 in a spaced-apart configuration. In this way, the robotic devices 112, 114 can avoid handling long, flexible lengths of tubing that are difficult for a robot to handle. Furthermore, in this way, tubing does not have to be cleaned out when changing between different inputs pumped into the cell culture chamber 104, but can instead be swapped.

[0084] In this embodiment, each consumable 108 includes a fluid-containing bag with a section of flexible tubing 108a that allows fluid to be transferred from the bag. When not fluidly coupled to another tube 104a, the end of the consumable tubing 108a can be pinched shut to create a fluid seal. To unseal the tubing 108a, a portion of the bag-side of the tubing 108a can be clamped and sealed, the pinched end can be removed, and the clamped section can be released once the tubing 108a is fluidly connected to another tube 104a and fluid flow is established. This process can be performed by a robotic device, as previously discussed.

[0085] One embodiment of an incubation chamber 110 for incubating the cell culture chamber 104 is shown in Figures 2a-2c and will now be described. The illustrated incubation chamber 110 includes a generally cubic-shaped base 130 configured to be mounted on an incubator base 118 that forms part of the incubation system 102. As mentioned above, in this embodiment, the incubator base 118 is provided on a support surface 116a of the base unit 116 of the processing station 100.

[0086] The base unit 130 includes a plate 132 for receiving the cell culture chamber 104. The plate 132 can be seen more clearly in Figure 2b, i.e., without the cell culture chamber 104 mounted thereon. The plate 132 can be configured, for example, as a vented offset shaker base 132.

[0087] In this embodiment, the cell culture chamber 104 is in the form of a cell culture vessel having the general shape of a conical flask with an opening at the top. A removable cap 134 is attached (e.g., by screws) to the opening of the cell culture chamber 104 to seal its contents from the ambient environment. A plurality of tubes 104a extend through the cap 134 to allow for the introduction of fluids into the cell culture chamber 104, for example, from consumables 108 as described above, while maintaining a closed system within the cell culture chamber 104. This is possible because the cap 134 seals around the tubes 104a, the ends of which are pinched shut and sealed (similar to the method described above for consumables 108) before a robotic device makes aseptic fluid connections via sterile tube welds, as previously described.

[0088] A cover 136 is positioned to fit onto the base 130 to enclose the cell culture chamber 104, thereby providing the incubation chamber 110 with a chamber 138 within which the cell culture chamber 104 can be incubated. The plate 132 can be heated, for example, via a heating element (not shown) positioned below the plate 132. A power supply (not shown) in the base 130 can provide power to the heating element, for example. In this manner, the incubation chamber 110 can be temperature controlled. Additionally, the incubation chamber 110 can be gas controlled, allowing gas (e.g., oxygen) to be introduced into the incubation chamber 110 via one or more gas ports (see below). A sterile air filter 144 can also be provided in the chamber 138.

[0089] In the embodiment of Figures 2a-2c, heating is achieved by heating air passing through a heating block 140 that extends into the chamber 138, as shown in Figure 2c. Arrows indicate the flow of air through the heating block 140 into the chamber 138, and the heating block 140 may house a heater 160, a heater fan 162, a CO2 sensor (board) 164, a CO2 sensor pump, a thermal sensor (board) 166, and one or more inlets 170, 172 for CO2 (or another gas mixture). One of the inlets 170, 172 may alternatively function as a sensor hole. A cable inlet 174 may also be provided to supply power and / or control the above-mentioned components in the heating block 140.

[0090] The incubator chamber 110 can have one or more openings or gaps that allow one or more tubes 104a from the sealed cell culture chamber 104 to pass through the cover 136 of the incubator chamber 110 in a predetermined orientation. In this way, a user can install the cell culture chamber 104 at the start of an operation (including clipping the tubes 104a into a tube path (not shown)) and close the cover 136, while the automated processing station 100 can still manipulate the tubes 104a without having to open the cover 136 and potentially losing temperature control of the chamber 138.

[0091] As shown in Figure 2b, air passages 142 are provided to deliver air beneath and around plate 132. Air passages are particularly advantageous for ensuring that air reaches beneath a gas permeable cell culture chamber (or "bioreactor").

[0092] One embodiment of a holder 150 for a consumable 108 is shown in FIG. 3, which is described next. The consumable holder 150 includes a substantially rectangular frame 152 in which a consumable (bag) 108 is suspended by a clip / tag 154 attached to the frame 152. Legs 156 extend downward from one side of the frame 152 and then substantially across the width of the frame 152 to support the frame 152, for example, when the legs 156 are received within a correspondingly sized hole or bore in the device. The frame 152 and legs 156 can be formed from a metallic material, preferably stainless steel. A tube clip 158 is attached to the side of the frame 152 to hold a portion of the tubing 108a that is fluidly connected to the consumable 108. The tube clip 158 ensures that at least the portion of the tubing 108a is held in place and can be easily found and / or engaged, for example, by a robotic device.

[0093] A second embodiment of a closed processing system 20 is shown in Figures 4A and 4B, which are now described.

[0094] Similar to the first embodiment, this processing system 20 includes an automated processing station 200, which in turn includes an incubation system 202 configured to facilitate incubation of one or more cell culture chambers 204, and a storage system 206 configured to facilitate storage of one or more fluid-containing consumables 208. The storage system 206 is elevated relative to the incubation system 202.

[0095] The incubation system 202 and (consumable) storage system 206 are arranged together in a processing station 200 to allow a robotic device to operate sterile tube welds between tubing 208a connected to stored consumables 208 and tubing 204a connected to the cell culture chamber 204 being incubated, as previously discussed.

[0096] Similar to the first embodiment, the processing station 200 includes a first robotic device 212 and a second robotic device 214, which aid in automating the processing system 20. However, in this embodiment, the robotic devices 212, 214 are attached to a movement system including a movable platform 260 configured to move relative to the processing station 200. The processing station 200 includes a base unit 216 having a support surface 216a. One or more incubator bases 218 are disposed on the support surface 216a. The movable platform 260 is attached to a rail system 262 including one or more rails (not shown) extending along the underside of the support surface 216a of the base unit 216. Thus, more specifically, the movable platform 260 (and thus the robotic devices 212, 214 attached thereto) is positioned such that it can move relative to the incubator bases 218, allowing the robotic devices 212, 214 to individually engage each incubator base 218 as required.

[0097] As in the first embodiment, each incubator base 218 is arranged such that an incubation chamber 110 configured to house a cell culture chamber 104 is mounted on, on, or within the incubator base 218, as shown in Figure 2. Similarly, the support surface 216a and incubator base 218 form part of the incubation system 202 in this embodiment. Each incubator base 218 is separated from its neighbors by a partition wall 264.

[0098] The first robotic device 212 and the second robotic device 214 can include robotic arms with attached end effectors for manipulating the tubes, as discussed above for the first embodiment.

[0099] In this embodiment, the storage system 206 includes a plurality of slots 224 configured to receive and store the consumables 108. The consumables 108 are held in cartridges 50 that are configured to be placed into the slots 224 by a human operator, as shown. Such a consumable cartridge 50 is shown in Figures 6A and 6B and will be described in more detail below.

[0100] The consumable 108 is stored with its tubing 108a extending below the main bag portion of the consumable 108 and can be engaged and / or manipulated by either of the robotic devices 212, 214 to create a fluid connection, for example, between the consumable 108 and a cell culture chamber 104 held within an isolation chamber 210 attached to an incubator base 218 on a support surface 216a.

[0101] A user interface 266 is provided to control the autonomous operation of the mobile platform 260 and the robotic devices 212, 214. A power supply (not shown), a control unit (not shown), and / or a drive mechanism (not shown) for the mobile platform 260 and the robotic devices 212, 214 may each be provided in the base unit 216. Each of these components may be in communication with the user interface 266, which may include a touchscreen or similar programmable computing device, enabling the robotic devices 212, 214 to operate autonomously. Additionally or alternatively, one or more of these components may be remotely controlled and / or programmed via a computer network (either wired or wireless) to enable the robotic devices 212, 214 to operate autonomously. Other peripheral power, control, and / or communication components may also be provided and would be familiar to those skilled in the art.

[0102] Other peripheral power, control and communication components may also be provided and will be familiar to those skilled in the art.

[0103] In this embodiment, everything is forward facing so that it can be easily wiped clean. The individual incubation chambers 110 can be spaced apart with some spacing, and preferably also with dividing walls 264, between them so that if an individual incubation chamber 110 leaks, the area can be thoroughly cleaned while the other incubation chambers 110 continue to operate.

[0104] Having two robotic devices 212, 214 allows complex tasks to be performed in parallel, for example, a first robotic device 212 can manipulate several tubes 104a, 108a while a second robotic device 214 couples to the fluidly connected tubes 104a, 108a to pump fluid between the consumable 108 and the cell culture chamber 104. Additionally, if a weld fails, the second robotic device can fluidly seal the tubing upstream and downstream of the weld, allowing for a T-weld to be performed. Mounting the robotic devices 212, 214 on a movable platform 260 attached to a rail system 262 may allow the robotic devices 212, 214 to be shared with other processing stations or modules within a larger system. In another example (not shown), the robotic devices can be driven directly on the rail system 262 (e.g., using linear rails, etc.), or the rails can simply act as guides, with the robotic devices being mobile robots hooked to the rails and running on wheels. This latter option may be advantageous as it may be easier to daisy-chain more systems together while using the same robot, without having to deal with the complexities of a fully autonomous robot.

[0105] A third embodiment of a closed processing system 30 is shown in FIG. 5, which is now described. The processing system 30 includes an automated processing station 300 similar in all respects to the automated processing station 200 of the second embodiment (described above), except that the processing station 300 includes a single robotic device 312 mounted on a movable platform 360 to assist in automating the processing system 30. In this embodiment, the robotic device 312 is configured with interchangeable end effectors (not shown), which are stored in an exchange station 368 located behind a user interface 366. A robotic tool changer (not shown) can be hidden behind the user interface 366, allowing the robotic device 312 to select the appropriate tool as needed. The end effector can include a tube welder, a peristaltic pump, a tube sealer, and / or a tube disconnector (e.g., a heated cutting element such as a blade or wire). Advantageously, this "single robotic device" configuration should be cheaper than the "multiple robotic devices" processing station 200 of the second embodiment due to the cost of the robotic device. Also, because a single robotic device 312 takes up less space, the moveable platform 360 can be smaller than would be required for two robotic devices.

[0106] An exemplary embodiment of a cartridge 50 (or "device") for holding consumables 108 is shown in FIGS. 6A and 6B. In the example shown in FIG. 6A, the consumables 108 are connected to two flexible tubes 108a. The consumables 108 can be pre-installed in such a cartridge 50, which is configured to hold the tubes 108a in a predetermined orientation. The cartridge 50 includes a housing 70 configured to hold the consumables 108; in other words, the housing 70 provides a first portion of the cartridge 50 for holding the consumables 108. The cartridge 50 can also provide thermal insulation and / or thermal conduction with the consumables 108, allowing the temperature of each consumable 108 to be individually adjusted.

[0107] The housing 70 may have an upper surface and a lower surface separated by a pair of opposing side walls 73 a, 73 c (i.e., a first side wall 73 a and a second side wall 73 c), and at least one end wall 73 b, thereby forming a rectangular parallelepiped shape. The housing 70 may have a longitudinal axis with a first end 70 a and a second end 70 b.

[0108] The housing 70 may include a tray 70 with a cavity 71 shaped to receive the consumable 108 therein. The top surface of the housing 70 may be a removable cover 72 that substantially encloses the consumable 108 in the cavity 71, thus allowing the consumable 108 to be conveniently added and / or removed from the cartridge 50. Furthermore, this means that the cartridge 50 has a robust exterior that may protect the consumable 108 and may allow the cartridge 50 to be securely installed into the storage system 206, 306 of the processing station 200, 300, for example, into the slot 224, 324.

[0109] Preferably, the cavity 71 has dimensions comparable to the consumable 108 so that the consumable 108 fits snugly within the cavity 71, thereby holding the consumable 108 in place. This reduces the flexibility of the consumable 108 by holding the consumable 108 in a given shape. The housing 70 can be rigid and made of any suitable material, such as plastic or metal. In other examples, the housing 70 can include a material that has some flexibility, such as any material with elastic properties. In this way, the consumable 108 can be pressed into the cavity 71 by slightly stretching the cavity 71 during insertion. Once the consumable 108 is inserted, the housing 70 will then return to its original shape, thereby securing the consumable 108.

[0110] Advantageously, the use of cartridge 50 to house consumables 108, including bags, prevents the bags from expanding outward when full. Housing 70 may also include exterior insulation and a path for internal cool airflow to maintain the consumables contained within housing 70 at a specified temperature. A thermistor (not shown) may also be incorporated into housing 70 to monitor temperature.

[0111] The housing 70 can include at least one clamp 75 that holds the consumable 108 inside the cavity 71. In this example, the housing 70 has the clamp 75 toward the first end 70a of the housing 70, at the cavity 71. The clamp 75 can be a tab or a hook. The consumable 108 can be attached via a hanging opening provided in the bag of the consumable 108.

[0112] The housing 70 may include a means for engagement 76 provided on an exterior surface of the housing 70. In this example, the means for engagement 76 is a handle 76 attached to the first side wall 73 a. The handle 76 may allow the cartridge 50 to be manipulated and moved by a human operator and / or a robotic device.

[0113] For example, the handle 76 may allow for transport and placement of the cartridge 50 into the storage system 206, 306 of the processing station 200, 300, for example into the slot 224, 324.

[0114] The housing 70 is provided with one or more ribs 78 extending between the top and bottom surfaces of the housing 70 around its periphery. Identification markings, such as a barcode, QR code, RFID, or NFC code, may be provided on the cartridge 50 to facilitate easy loading of the cartridge 50 into the storage system 206 in a plug-and-play manner and / or to enable identification and tracking of the cartridge 50. For example, the cartridge 50 may be automatically identified upon insertion into the slot 224, 324 of the storage system 206, 306.

[0115] The housing 70 may include at least one recess (e.g., a gap or opening) 74 at an end (e.g., second end 70b) of the housing through which the tube 108a can pass. The recess 74 is preferably aligned with the portion of the consumable 108 that connects to the flexible tube 108a. Multiple recesses 74 may be present on the housing 70 for when the consumable 108 is fluidly connected to more than one tube 108a.

[0116] The cartridge 50 includes a second portion 80 configured to hold a flexible tube 108a connected to the consumable 108. The second portion 80 can extend from the second end 70b of the housing 70 and is preferably positioned adjacent to the recess 74. The second portion 80 can include multiple tube retaining elements 81 (e.g., tube clips) that hold the flexible tube 108a at multiple positions along a predetermined path. In this example, the second portion 80 includes a pair of tube retaining elements 81 that are spaced apart to hold a portion of the tube 108a in substantial tension therebetween, facilitating engagement by a robotic device. In this manner, a robotic device can engage the tube 108a at a position between the pair of tube retaining elements 81.

[0117] Tube 108a can be secured to each of the tube retaining elements 81 by applying a force to tube 108a to push it through the tube retaining elements 81, which then secure the tube 108a in a given position. Tube retaining elements 81 may alternatively include any suitable means for coupling a portion of tube 108a to second portion 80, such as a hook or clasp. The portion of tube 108a retained by tube retaining elements 81 may be permanently retained or removably secured.

[0118] The cartridge 50 may include means 77 for cooling the consumable 108 held within the housing 70. In this example, the means for cooling 77 is at least one air port 77 (or "air duct") in the first portion 70 and / or the second portion 80 of the cartridge 50, such that cool air can be supplied to the at least one air port 77 for cooling the consumable 108. Specifically, the cartridge 50 includes a first external air port 77a in communication with an internal air port 77b to facilitate the introduction of air into / from the cavity 71. A second external air port 77c is provided in the housing 70 in fluid communication with the cavity 71 to allow air to flow from / to the housing 70. Alternatively, a Peltier element and fan may be constructed within the consumable (not shown).

[0119] A single incubator base configured to mount a single incubation chamber or multiple incubation chambers on the support surface can be provided. Rather than each incubation chamber being configured to house a single cell culture chamber, a single incubation chamber can be configured to house (and thus incubate) multiple cell culture chambers.

[0120] The processing station can process multiple (e.g., patient) samples at a time, or alternatively, can distribute the contents of a single (e.g., patient) sample across multiple cell culture chambers (e.g., growth chambers) in which a design of experiment can be performed while adjusting conditions such as feed time / rate, reagent type, temperature, pH, etc. If the processing station includes a cell analyzer (e.g., a "cell analysis unit" or similar means), the incubation chamber (bioreactor) conditions or parameters (i.e., feed rate, etc.) can be automatically adjusted in response to measured parameters (e.g., cell number). The cell analyzer can be a cell counter, cytometer, or any other means of cell or media analysis.

[0121] As a further alternative, the pumping (and / or valving) means can be provided as separate devices or apparatus on the processing station (perhaps one pumping means per incubation chamber), and the robotic device can insert tubing that forms a fluid connection to the pumping means. In this way, control of the fluids can be maintained while the robotic device manages other incubation chambers.

[0122] While the processing station shown in the accompanying figures shows consumables (e.g., media / reagent bags) stored at room temperature within a storage system, portions of the storage system can instead be configured to refrigerate the consumables. This can be achieved, for example, by blowing cool air through air ducts on each consumable (allowing individual control of their temperature by varying the amount of air passing through each consumable), or by blowing cool air all around the consumables (similar to refrigerators found in supermarkets with open or sliding doors).

[0123] The processing station can transfer samples between different cell culture chambers (e.g., those already preloaded onto the processing station). For example, it may be desirable to perform activation in one chamber and transfection / expansion in a subsequent chamber coated with retronectin. Additionally or alternatively, it may be desirable to begin expansion in a small chamber and then transfer the culture to a larger chamber. The processes or operations performed in the processing station can be "reconfigurable," in the sense that a human operator can program the sequence of sampling, medium changes, when harvesting should occur, etc., for a particular application and then reprogram the processing station for another application.

[0124] The robotic device can also have probes capable of interrogating key analytes on individual cell culture chambers, enabling at-line monitoring of the analysis. For example, the robotic device could be equipped with probes for Raman spectroscopy (sensing metabolites such as glucose or lactate), optical probes for fluorescence lifetime (measuring pH and CO2 using a "presens" sensor), or microscopy (measuring cell morphology in adherent cell cultures), and move the probes between each cell culture chamber. Such an approach can be advantageous because the cost of the Raman system can be amortized over multiple patient samples. It will be appreciated that such probes do not require direct contact with the cells to collect data, thereby enabling cell monitoring while maintaining a closed system.

[0125] The processing system described herein may further include one or more cameras or sensors, such as a machine vision system, that enable tracking of all consumables 108 throughout a particular process. In other words, the system may include a means for maintaining traceability of the consumables 108. The one or more cameras or sensors may be located on a robotic device. The one or more cameras or sensors may be configured to identify identification marks on at least one of the consumables 108, the cell culture chambers 104, and the tubes 104a, 108a. The one or more cameras or sensors may be optical, such as to detect barcodes and / or QR codes, or non-optical, such as to detect RFID or NFC tags.

[0126] Bioprocessing systems containing one or more such processing stations are easy to adopt and expand. For example, the system may initially have a single processing station, but additional processing stations can be added as requirements grow. By incorporating multiple processing stations, a fully automated system can be achieved, optionally with robotic devices not located on the processing stations but instead located on autonomous mobile "operation" units / mobile robotic devices that can engage multiple processing stations as required.

[0127] A bioprocessing system can therefore incorporate multiple processing stations operating in parallel, as described herein, each processing station including: means for sterilely connecting a consumable (e.g., a cell bag) to a growth chamber (e.g., a cell culture chamber) and transferring cells to the growth chamber (i.e., seeding the cells); means for sterilely connecting a different consumable (e.g., a media bag) to the growth chamber and transferring fluid to the growth chamber (i.e., supplying the cells); means for agitating the growth chamber (e.g., so that the sample is representative) and taking a sample from the growth chamber; means for sterilely connecting another consumable (e.g., an output bag) to the growth chamber and transferring fluid to the output bag (i.e., harvesting the cells) and agitating the growth chamber before transfer to ensure all cells are dispensed; means for disconnecting consumables (e.g., cell bag, media bag, and output bag); and means for controlling the automated sequence of operations.

[0128] The means for controlling the automated sequence of operations can be provided by a processing and control unit (not shown). The processing and control unit can be part of the closed system or can be part of the bioprocessing system as a whole. The processing and control unit can be used to control multiple closed systems in parallel. The automated sequence of operations can be controlled according to one or more predetermined workflows, preferably one or more reconfigurable workflows. In this way, the particular method performed by the bioprocessing system can be easily changed or adapted without requiring modifications to the bioprocessing system itself.

[0129] The means for controlling the automated sequence of operations can be configured to automatically schedule the sequence of operations to be followed by the closed system. The sequence of operations can be automatically updated based on input received from at least one sensor of the bioprocessing system and / or the closed system. In this manner, multiple cell culture chambers can be processed simultaneously by the closed system while minimizing the risk of conflicts between their corresponding workflows. For example, the sequence of operations can be scheduled to minimize and preferably prevent either the robotic device or other parts of the closed system or bioprocessing system from being simultaneously required for separate workflows. If it is not possible to avoid a conflict, the means for controlling the automated sequence of operations can delay one of the conflicting operations based on a preprogrammed or user-configurable priority list.

[0130] The means for controlling the automated sequence of operations can be configured to simulate the automated sequence of operations before the bioprocessing system executes said sequence. The means for controlling the automated sequence of operations can communicate at least one result of the simulation to an operator. The at least one result can include an indication when a particular operation will occur, an indication when a manual step needs to be performed, and / or an indication that a conflict between two simultaneous operations may (or may not) occur. The bioprocessing system can further include a monitoring system that verifies that the automated sequence of operations has occurred. The monitoring system can be provided by the means for controlling the automated sequence of operations of the processing station.

[0131] The processing system can include a cell analysis device (e.g., a "cell analysis unit"), such as a cell counter / flow cytometer (or some other means of cell analysis / media analysis), and a means for transferring samples from the cell culture chamber into the cell analysis device. For example, a cytometer station configured to hold the analysis chamber (or analysis unit) can be mounted on a support surface of the base unit. Flexible tubing can be connected to the analysis chamber. A tube welder can form tube welds between corresponding tubing in the cell culture chamber and the analysis chamber, and a peristaltic pump can transfer a sample of the contents of the cell culture chamber into the analysis chamber for analysis. In response to measurements made by the cell analysis device, one or more processing parameters of the closed system can be adjusted. For example, the temperature of the incubation chamber can be changed and / or the feed rate into the incubation chamber can be changed.

[0132] It is also possible to sterilely connect a waste bag (i.e., consumables) to the cell culture chamber and remove waste medium from the top of the cell culture chamber at a processing station (i.e., to reduce medium volume without removing cells, either for concentration or medium exchange purposes).

[0133] Advantageously, the processing station may be capable of performing any of the following steps in the cell therapy process, i.e., activation, transfection, and expansion, in a single location (e.g., in a standalone station). Furthermore, the ability to run parallel processes simultaneously with automated sampling and cytometry may enable easy process development. Due to the automation of the processing station, samples can be taken 24 hours a day, every day. Additionally, the processing station can automatically maintain traceability between consumables (e.g., bags) and cell culture chambers (i.e., expansion chambers) in a space-efficient form factor.

[0134] While the foregoing relates to exemplary embodiments of the present invention, it will be understood that the invention is described herein purely by way of example and that modifications of detail can be made within the scope of the invention. Moreover, those skilled in the art will appreciate that the invention may not be limited to the embodiments disclosed herein or to any details shown in the accompanying drawings that are not specifically described herein or defined in the claims. Indeed, such superfluous features may be omitted from the drawings without detracting from the invention.

[0135] And other and further embodiments of the invention will become apparent to those skilled in the art from a consideration of the specification and can be devised without departing from the basic scope thereof as determined by the claims that follow. [Explanation of symbols]

[0136] 10 Processing System 100 Processing Stations 102 Incubation System 104 Cell Culture Chamber 104a tube 106 Storage System 108 Consumables 108a tube 110 Incubation Chamber 112 First Robotic Device 112a first end effector 114 Second Robotic Device 114a second end effector 116 Base Unit 116a Support surface 118 Incubator Base 120 wheels 122 frames 124 Support member 126 Tube Reel 130 base unit 132 Plates 134 Cap 136 Cover 138 Chamber 140 Heating Block 142 Air Path 144 Sterile Air Filter 150 holder 152 frames 154 clips / tags 156 Legs 158 tube clips 160 Heater 162 Heater Fan 164 CO2 sensor 166 Thermal Sensor 170, 172 entrance 174 Cable Entrance 20 Processing System 200 processing stations 202 Incubation System 206 Storage System 212 First Robotic Device 214 Second Robotic Device 216 base unit 216a Support surface 218 Incubator Base 224 Slots 260 Moving Platform 262 Rail System 264 Partition Wall 266 User Interface 30 Processing System 300 Processing Stations 306 Storage System 312 Robot Devices 324 Slots 360° Movable Platform 366 User Interface 368 Exchange Station 50 cartridges 70 Housing 70a first end 70b second end 71 Hollow 72 Cover 73a First side wall 73b End wall 73c Second side wall 74 recess 75 Clamp 76 Handle 77a First external air port 77b Internal air port 77c Second external air port 80 Second Part 81 Tube Retaining Element

Claims

1. An automated system for performing bioprocessing, An incubation system configured to house at least one incubation chamber for incubating a cell culture chamber with a flexible tube fluidly connected, A storage system configured to store at least one fluid-containing consumable with a tube fluid-connected, Includes, The incubation system and the storage system are arranged together such that a robotic device can operate a tube weld between the flexible tube of the incubated cell culture chamber and the tube of the stored consumables, thereby forming a sterile fluid connection between the cell culture chamber and the consumables so as to maintain a closed system, in an automated system.

2. The incubation system according to claim 1, wherein the cell culture chambers are further configured to store the flexible tubes of the cell culture chambers in each incubation chamber in a predetermined orientation, and optionally a portion of the flexible tubes is held outside the incubation chamber by, for example, one or more tube clips.

3. The storage system according to claim 1, further configured to store each consumable in such a state that the tube of the consumable is held in a predetermined orientation by, for example, one or more tube clips.

4. The system according to claim 1, further comprising a cell analysis unit, wherein at least one robotic device is further configured to operate a fluid connection between the cell analysis unit and a cell culture chamber incubating cells.

5. The system according to claim 1, further comprising an automated processing station, preferably configured as a standalone processing station, which includes a support platform configured to form part of the incubation system.

6. The system according to claim 5, wherein at least one robotic device is also provided on the automated processing station.

7. The automated processing station according to claim 5, A separate robotic device configured to move independently of the automated processing station, A bioprocessing system including [the specified element].

8. The system according to claim 6 or 7, wherein the robotic device is configured to operate the fluid connection and thereby create a tube weld between the flexible tube of an incubated cell culture chamber and the flexible tube of a stored consumable in order to transfer fluid through the flexible tube, the tube weld being a sterile tube weld formed between the free ends of the respective tubes.

9. The system according to claim 6 or 7, wherein the robotic device is configured to operate the fluid connection, thereby disconnecting the flexible tube of the incubated cell culture chamber from the flexible tube of the stored consumables.

10. The system according to claim 6 or 7, wherein the robotic device is configured to operate the fluid connection and thereby pump fluid between the fluid connection and the cell culture chamber incubating consumables.

11. The robotic device is configured to operate the fluid connection, thereby engaging and / or positioning at least one flexible tube of the incubated cell culture chamber and at least one flexible tube of the stored consumables toward each other to form the fluid connection, and / or The system according to claim 6 or 7, wherein the at least one robotic device is further configured to operate a fluid connection between a first incubated cell culture chamber and a second incubated cell culture chamber.

12. The robotic device is configured to use interchangeable end effectors, and the system further includes an end effector storage system for storing one or more interchangeable end effectors for use by the robotic device, and / or The system according to claim 6 or 7, wherein the robotic device includes an end effector on a robotic arm, and the robotic device further includes at least one probe or sensor disposed on the end effector.

13. The system according to claim 1, further comprising a controller for controlling the sequence of automated operations of the automated system.

14. A bioprocessing system comprising a plurality of the automation systems described in claim 1.

15. A method comprising the step of performing bioprocessing using the automated system described in claim 1.

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