Fluid transfer systems, devices, and methods for bioprocessing

Abstract

1. A device for collecting a fluid sample from a fluid-containing consumable in a bioprocessing system, the device having a tubing fluidly coupled to the consumable, the device comprising: a fluid connection connected to the tubing of the fluid-containing consumable and configured to allow pumping of fluid or air through the device; an air input configured to allow supply of sterile air to the device; a sampling portion connected to the fluid connection, the sampling portion configured to receive a fluid sample from the consumable through the fluid connection while pumping it into the device; a bypass tube having a first end connected to the fluid connection and a second end connected to the air input, the bypass tube configured to receive air supplied from the air input and to direct the air from the device through the fluid connection without passing through the sampling portion, thereby purging fluid from the tubing connected to the consumable; and means for restricting fluid flow through each of the sampling portion and the bypass tube such that fluid pumped into the fluid connection flows only into the sampling portion and air pumped out of the fluid connection passes only through the bypass tube.

Description

[Technical Field]

[0001] The present invention relates to automated bioprocessing systems, such as bioprocessing systems for performing cell therapy. [Background technology]

[0002] Increasingly, cells, rather than small molecules, are being used as the starting point for therapeutics. Techniques for manufacturing these products are rapidly evolving to keep pace with the constantly emerging new treatments. In recent years, several new types of cell therapy have seen increased use. One type is autologous cell therapy.

[0003] Autologous cell therapies are a promising class of treatments with significant clinical and commercial potential, from treating cancer to repairing genetic defects. These therapies involve harvesting cells from a patient, manipulating them over days to weeks, and reintroducing them into the patient's body to deliver a therapeutic effect. The steps taken during autologous cell therapy are often complex. For example, a typical CAR-T process begins with cryopreserved leukopacks and may involve a series of steps: thawing, washing to remove DMSO, nutrient-rich T cell expansion, activation, transformation, expansion, concentration, formulation loading into IV bags, and cryopreservation, with several other intermediate washing steps.

[0004] Bioprocessing systems have been developed to perform the above steps. Within such bioprocessing systems, for example, multiple different consumables (e.g., fluid-containing bags) may be required to supply media, reagents, and / or cellular material to separate consumables called "growth chambers" (or "cell culture chambers") throughout a cell therapy process. Similarly, one or more consumables (e.g., output bag consumables or waste bag consumables) may receive fluid samples from the growth chambers. Thus, the term "consumable" is sometimes used to refer to "single-use" elements or components of the system.

[0005] Some of the above processes, such as activation, transformation, and proliferation, may be carried out in a cell culture chamber (or "bioreactor"), which may be incubated. During one or more of these processes, various functions need to be performed, such as medium addition and removal, harvesting and sampling, etc.

[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 for interacting with the incubation chamber, which can be difficult to handle, especially by automated means such as robotic devices.

[0007] An alternative approach is to connect each consumable to its own flexible tubing and individually make the necessary connections between consumables throughout the process. More specifically, tubing welding can be used to attach the flexible tubing to each other, a pump can transfer fluid through the connected tubing, and the tubing can be disconnected again to facilitate further connections between other consumables.

[0008] However, there are several reasons why tube welding may seem unsuitable for full (operator-independent) automation. For example, tube welding requires the handling of long lengths of flexible tubing, which are notoriously difficult to handle by automated handling means such as robots. For example, flexible tubing often does not stay in a well-defined, definite position when moved by a robot, making engagement, alignment, and orientation of the tube difficult.

[0009] When a sufficiently long piece of flexible tubing, constrained at one end, is manipulated at the other, the path defined by the tubing has some non-unique solution as to how the path between the constrained and manipulated ends will take shape depending on the internal stresses of the tubing. Such systems offer a high degree of flexibility. While ideal for humans, such applications present significant obstacles to automation and are therefore generally left to the human operator. Because weld strength is highly dependent on precise positioning and compression of the tubing, any error in the robot's engagement of the tubing can result in a failed weld. Avoiding kinking and / or entanglement of the tubing with other tubing and other components of the bioprocessing system is also a challenge. Furthermore, the tubing can apply unexpected tension to the robot or any attached consumables, reducing the likelihood of a successful weld or, in some cases, damaging the connection to the consumable.

[0010] An additional problem that can arise when using long flexible tubing is that when fluid is pumped between a first consumable and a second consumable, in some cases, a substantial amount of fluid may remain within the tubing itself when enough fluid reaches the second consumable. This volume of fluid is called "dead volume" and can waste fluid during a bioprocessing step, especially when long lengths of tubing are required to connect the consumables. This can be particularly problematic when only small samples need to be taken from the consumable, which may occur periodically during the bioprocessing step. Summary of the Invention [Problem to be solved by the invention]

[0011] Therefore, for at least the reasons stated above, to date it has been considered impractical to develop a bioprocessing system that utilizes flexible tubing connected by automated tubing welding. It is an object of the present invention to address the above-mentioned problems. [Means for solving the problem]

[0012] According to a first aspect described herein, there is provided a device for collecting a fluid sample from a fluid-containing consumable in a bioprocessing system, the device comprising: a fluid connection configured to connect to the tubing of the fluid-containing consumable and enable pumping of fluid or air through the device; an air input configured to enable supply of sterile air to the device; a sampling portion connected to the fluid connection, the sampling portion configured to receive a fluid sample from the consumable through the fluid connection while pumping it into the device; a bypass tube having a first end connected to the fluid connection and a second end connected to the air input, the bypass tube configured to receive air supplied from the air input and to direct the air from the device through the fluid connection without passing through the sampling portion, thereby purging fluid from the tubing connected to the consumable; and means for restricting fluid flow through each of the sampling portion and the bypass tube such that fluid pumped into the fluid connection flows only into the sampling portion and air pumped out of the fluid connection passes only through the bypass tube.

[0013] In this manner, fluid can be pumped from the fluid-containing consumable into the device (e.g., using a peristaltic pump on flexible tubing connected to the consumable) and then a fluid sample can be collected in the sampling section. This excess fluid can then be "purged" by reversing the pumping direction and returning the fluid to the consumable to prevent it from accumulating in the tubing attached to the consumable. The bypass tubing allows air to fill the tubing to replace the purged fluid, so the fluid sample remains in the device while the excess fluid is removed. Thus, the device allows a representative sample of fluid to be collected from the consumable without wasting a substantial amount of fluid. Alternatively, or additionally, the device can be used to perform fluid purging at other times during a bioprocessing step (e.g., at times other than when the sample is collected in the device). In at least one embodiment, the tubing connected to the fluid-containing consumable can be flexible (non-rigid) tubing; alternatively, in another embodiment, the tubing can be provided as or form part of a (rigid) fluid manifold of the fluid-containing consumable. Thus, the term "tube" can refer to any type of fluid conduit that functions as a tube, whether rigid or flexible.

[0014] The device may further include a sampling tube having a first end connected to the fluid connection portion and a second end connected to the air input portion, the sampling portion being disposed between the first and second ends of the sampling tube.

[0015] In this way, air displaced from the sampling portion when a sample is received is removed from the device via the air input. This allows the sampling portion to be formed from a substantially rigid material. Alternatively, the sampling portion can be a flexible bag that expands when a fluid sample is received, thereby accommodating an increase in the volume of the sampling portion without displacing air.

[0016] Preferably, the sampling portion is provided by a sample vessel disposed between the first and second ends of the sampling tube. Alternatively, the sampling tube itself may have a length sufficient to hold a fluid sample.

[0017] The sample vessel may have a tapered shape such that fluid may enter the sampling vessel at the narrow end of the taper and then fill toward the wider end of the taper, allowing the volume of the fluid sample to be determined with proportional precision for both small and larger fluid samples.

[0018] The sampling portion may include an extraction port for removing the fluid sample from the sampling portion, which may be a needleless sampling port or a luer lock capped port.

[0019] The means for restricting fluid flow through the device may comprise a first check valve for allowing fluid to flow (only) from the fluid connection into the sampling portion. The (first) check valve restricts drainage of the fluid sample from the sampling portion, for example, under gravity. Furthermore, when the sampling portion is formed by a sampling tube connected to the air input portion, the first check valve prevents air from purging the fluid sample from the sampling portion and instead forces air to flow from the air input portion to the fluid connection through the bypass tube.

[0020] Preferably, the check valve is located on the sampling tube between the sampling section and the air input section. In this way, the fluid sample can be collected in the sampling section without passing through the (first) check valve, thereby allowing the check valve to become an operating air valve when dried.

[0021] The means for restricting fluid flow through the device may comprise a second check valve for allowing air to flow (only) from the air input to the fluid connection through the bypass tube.

[0022] The second check valve restricts air from flowing through the bypass tube from the fluid connection toward the air input.

[0023] Preferably, one or both check valves are configured to prevent fluid from flowing through the valve (e.g., to allow only air to pass through the valve), so that fluid cannot pass through the device to reach the air input, and the device can be operated in any orientation within the bioprocessing system.

[0024] Alternatively, the means for restricting fluid flow through the device may comprise pinchable portions of tubing on both the sampling portion and the bypass tubing, such that either or both of the pinchable portions may be pinched closed to restrict fluid flow.

[0025] The fluid connection may comprise a length of (eg, flexible) tubing, allowing the device to be connected to the consumable tubing by tubing welding.

[0026] By using tubing welding to connect the fluid connections to the consumable, a closed system is maintained throughout the sampling process, thereby reducing the chance of contaminating the surrounding bioprocessing system. Tube welding can also be used for other connections within the bioprocessing system, so a separate connection process is not required for sampling.

[0027] The air input may be an air filter configured to supply sterilized air from the environment. Alternatively, the air input may comprise a container of sterile air. For example, the container may comprise a syringe or bag containing sterile air.

[0028] Preferably, the air input is a single air input connected to both the sampling unit and the bypass tubing. Alternatively, the sampling unit and the bypass tubing may be connected to separate air sources, such as separate air filters or separate containers of sterile air. Preferably, if the air input is a single air input, it is connected to both the sampling tubing and the bypass tubing by a single tube (e.g., via a y-connector or splitter).

[0029] The device may further comprise an external housing. In this manner, the device may be operated by a robotic device of the bioprocessing system. Additionally, the device may be attached to other parts of the bioprocessing system (e.g., bioprocessing equipment) via the external housing. The external housing may have one or more engagement features to facilitate installation of the device within the bioprocessing system and / or operation of the device by a robotic device. The external housing may hold portions of the device, such as fluid connections, air inputs, and / or extraction ports, in place to facilitate consistent engagement by the robotic device.

[0030] According to another aspect described herein, there is provided a sampling cartridge comprising a housing configured to hold one or more of the devices described above and herein. In this manner, a robotic device can engage the cartridge and move it around a bioprocessing system, and when a sampling operation is to be performed, the robotic device can engage one of the individual devices held within the housing.

[0031] According to another aspect described herein, there is provided a method of collecting a fluid sample using the device described above and herein, comprising the steps of connecting a fluid connection to tubing connected to a consumable; pumping fluid from the consumable through the fluid connection into a sampling portion of the device; and pumping any fluid remaining in the tubing back into the consumable, thereby drawing air from the air input portion into the tubing via a bypass tubing.

[0032] According to another aspect of the present invention, there is provided a consumable for a bioprocessing system, the consumable comprising: a container for a fluid; a tube having a first end connected to the container and extending to a second (e.g., free) end; and an air supply fluidly connected to the tube at a location between the first and second ends of the tube.

[0033] The air source allows sterile air to be supplied to the tubing. Advantageously, by providing the consumable with an air source connected to the tubing, air from the air source can be used to purge fluid from the tubing before performing any tube weld at (near) the second (free) end of the tubing. By removing fluid from the second end of the tubing, the tube weld is performed on dry tubing, which is generally more reliable than a "wet" weld (where fluid is still present), thereby improving the reliability of the connection with the consumable.

[0034] The air supply may include an air filter configured to supply sterilized air from the environment. The air supply may include a container of sterile air. The tube connected to the container may be a first tube, and the air supply may be connected to the first tube using a second tube, for example, by welding. The (e.g., three-way) connection between the tube and the air supply may include one or more valves for controlling the flow of fluid or air into the tube (e.g., from the container, the second end of the tube, and / or the air supply). For example, the one or more valves may be formed by a three-way valve or a stopcock. Alternatively, the one or more valves may include two pinch valves or a single pinch valve (to allow control of flow through either or both the tube and the air supply) and an (in-line) check valve. The one or more valves may be integrated into the consumable and preferably be externally actuable, for example, by a robotic device and / or an external solenoid.

[0035] Alternatively, control of the flow (of fluid or air) through the (e.g., three-way) connection between the tubing and the air source can be performed externally. For example, during use, a consumable can be mounted within the bioprocessing apparatus with the first tubing and / or the second tubing held by one or more valve seats. Thus, during use, the valve seats can be actuated to restrict the flow of fluid or air through either or both of the first tubing connected to the vessel and / or the second tubing connected to the air source.

[0036] Optionally, an air source may be provided using a device as described above and herein. The device may be connected to the tubing by a fluid connection of the device. Advantageously, using the device as an air source may allow both purging of fluid from the tubing and sampling of fluid by the device.

[0037] According to another aspect described herein, there is provided a fluid connection system for a bioprocessing apparatus, the fluid connection system comprising: a consumable storage section having a first subsection and a second subsection, each subsection configured to store at least one consumable containing a fluid to which a flexible tube is fluidly connected; a cell storage section configured to store consumables containing cells having at least a first flexible tube and a second flexible tube, each tube fluidly connected to the consumable containing cells; and a tube connection section disposed between the consumable storage section and the cell storage section, the tube connection section comprising: a first portion configured to hold a first flexible tube of the consumable containing cells and position the first flexible tube to be connected to a flexible tube corresponding to a consumable containing a fluid stored in the first subsection of the consumable storage section; and a second portion configured to hold a second flexible tube of the consumable containing cells and position the second flexible tube to be connected to a flexible tube corresponding to a consumable containing a fluid stored in the second subsection of the consumable storage section.

[0038] While the cell-containing consumables are described above as having a first flexible tube and a second flexible tube, it will be appreciated that the cell-containing consumables may have more than two flexible tubes fluidly connected to them, such as three or more flexible tubes. Similarly, the fluid-containing consumables may each have more than one flexible tube fluidly connected to them, such as two or more flexible tubes. Because there may be multiple (e.g., four) fluid-containing consumables in the consumable storage section and multiple (e.g., two) tubes connected to the cell-containing consumables, the fluid connection system replaces a complex many-to-many tubing connection configuration with two one-to-many tubing connection configurations, simplifying the connection process.

[0039] Furthermore, by having two subsections of the consumable storage section, each portion of the tubing connection section being positioned to connect one of the flexible tubings of the cell-containing consumable to the tubing in the corresponding subsection, it is possible to form a connection between the fluid-containing consumable and the cell-containing consumable without crossing the tubing. This reduces the likelihood of the tubing becoming tangled and also keeps the tubing substantially in a two-dimensional plane, thereby simplifying manipulation of the tubing by a robotic device. The cell-containing consumable may be referred to herein as a "cell consumable." The cell-containing consumable may be a cell culture chamber.

[0040] Preferably, the cell-containing consumable is a bioreactor and the cell storage section is a bioreactor platform arranged to receive the bioreactor. The bioreactor platform may include a shaker for agitating the bioreactor to resuspend the cells. Alternatively, the bioreactor platform may be a stationary platform.

[0041] Preferably, the tube connection section is further configured to arrange the first and second flexible tubes of the cell-containing consumable to be connected to an air supply source. In this manner, the air supply source can purge fluid from the first and second flexible tubes of the cell-containing consumable, thereby reducing wasted fluid / cells remaining in the tubes (e.g., from a sampling operation).

[0042] Preferably, the tubing connection section is further configured to arrange the first and second flexible tubing of the cell-containing consumable to be connected to a sample collection device, which may include at least one sample container into which fluid from the cell-containing consumable may be pumped to collect a representative sample.

[0043] Preferably, the tubing connection section is configured to place the first and / or second flexible tubing of the cell-containing consumable into a single device that constitutes both the air source and the sample collection device, preferably the single device being a device as described above and herein.

[0044] The consumable storage section may include a plurality of consumable holding locations, preferably arranged in a linear configuration. The consumable holding locations are preferably equally spaced apart. Preferably, each consumable holding location is formed by a slot, each slot configured to receive a fluid-containing consumable. Preferably, the fluid-containing consumables are contained within a cartridge, each slot including one or more engagement features for releasably retaining the cartridge within the slot. Accordingly, fluid-containing consumables may be referred to herein as "cartridge consumables." Alternatively, the fluid-containing consumables may be hung on a linear rack, with the consumable holding locations defined by adjacent positions along the rack.

[0045] Preferably, the plurality of consumable-holding locations includes an intermediate location included in both the first subsection and the second subsection of the consumable storage section. For example, if there are a total of five locations for fluid-containing consumables in the consumable storage section, the first subsection may include locations 1-3, and the second subsection may include locations 3-5. This configuration prevents crossing of tubing when a connection is made from the intermediate location to either the first flexible tubing of the cell-containing consumable or the second flexible tubing of the cell-containing consumable. Alternatively, the subsections may be separated from one another and not overlap, in which case a location for a fluid-containing consumable cannot exist in both the first subsection and the second subsection.

[0046] Preferably, the consumable storage section may include a third subsection configured to receive at least one fluid-containing consumable having a flexible tubing fluidly connected thereto, the third subsection including a consumable-holding position that is not part of either the first or second subsection. In other words, the consumable-holding position (e.g., a "buffer" position) of the third subsection is not used to hold a consumable to be connected to a cell-containing consumable. In this manner, the buffer position may be used to exchange a fluid-containing consumable held in the first subsection for a fluid-containing consumable held in the second subsection. This allows any of the fluid-containing consumables to be connected to any of the flexible tubing of the cell-containing consumable without crossing any tubing.

[0047] The tube connection section may include a first plurality of tube tips, each consumable holding location in the first subsection corresponding to at least one of the tube clips in the first plurality of tube clips, and each flexible tube connected to a consumable containing cells corresponding to at least one of the tube clips in the second plurality of tube clips.

[0048] In this manner, the flexible tubing can be held in a predetermined position within the tubing connection section by the tubing clips. Thus, the robotic device can consistently engage the tubing based on the known positions of the tubing clips within the tubing connection section. Preferably, the tubing clips hold the flexible tubing (within the first and / or second plurality of tubing clips) parallel to one another and / or are equally spaced apart from one another.

[0049] Preferably, each location in the consumable storage section corresponds to a pair of tube clips (or more tube clips) in the first plurality of tube clips, and / or each flexible tube connected to a cell-containing consumable corresponds to a pair of tube clips in the second plurality of tube clips. In this way, when one of the tubes is held by a pair of tube clips, the tube is held between the tube clips along a predetermined axis. Because a consistent length of the tube is held along the predetermined (linear) axis, the tube can be more consistently engaged by the robotic device. For example, if the robotic device includes a linear peristaltic pump, the pump can engage the tube along the predetermined axis of the tube between the pair of tube clips to pump fluid through the tube.

[0050] At least one of the tube clips may include a tubesheet having a contour shaped to receive a tube at a predetermined position on the tubesheet, a retaining element movable relative to the tubesheet between an open position to allow the tube to be received by the tubesheet and a closed position to hold the tube in place on the tubesheet, and an actuator configured to move the retaining element between the open and closed positions, the actuator controllable to move the retaining element among a plurality of intermediate positions, in each of which the retaining element exerts a different force on the tube against the tubesheet to thereby control fluid flow through the tube. The intermediate positions also allow tubes of different sizes to be properly retained and clamped in the tube clip for closure.

[0051] At least one of the tube clips may include at least one sensor for detecting one or more of the presence of a portion of the tube within the tube clip and / or whether the portion of the tube held within the tube clip contains fluid.

[0052] According to another aspect described herein, there is provided a bioprocessing apparatus comprising the fluid connection system described above and herein, wherein the consumable storage section, the cell storage section, and the tubing connection section can be configured by the bioprocessing apparatus.

[0053] The bioprocessing apparatus may further comprise one or more of a loading system, a storage system, an incubation system, and an unloading system.

[0054] According to another aspect described herein, there is provided a bioprocessing system comprising a fluid connection system as described above and herein, and / or a bioprocessing apparatus as described above and herein.

[0055] The bioprocessing system may further include a robotic device configured to manipulate fluid connections between one or more flexible tubes of the bioprocessing system. The robotic device may include a robotic arm having a robotic end effector. The robotic device may include a tube welder for forming sterile connections between tubes, a peristaltic pump for pumping fluid through the connected tubes, and / or a tube sealer for cutting and sealing the tubes. The robotic device may be provided as a device separate from the bioprocessing apparatus, such as a mobile manipulation unit that may move relative to the bioprocessing apparatus. Alternatively, the robotic device may be provided as part of the bioprocessing apparatus.

[0056] The robotic device is configured to form connections between tubes in the tube connection section. Preferably, the robotic device is configured to connect (only) a first flexible tube of the consumable containing cells to (only) a flexible tube of the consumable containing fluid in a first portion of the tube connection section, and to connect (only) a second flexible tube of the consumable containing cells to (only) a flexible tube of the consumable containing fluid in a second portion of the tube connection section. The robotic device only forms connections for tubes from a first subsection of the consumable storage section within the first portion of the tube connection section. The robotic device (for example) only forms connections for tubes from a second subsection of the consumable storage section within the second portion of the tube connection section.

[0057] In this way, the robotic device is operated to prevent the tubing from crossing when making connections, thereby reducing the likelihood of the tubing becoming tangled. The robotic device can be configured to perform a particular bioprocess workflow, which defines the steps (e.g., connecting, pumping, disconnecting, and / or sealing steps) to be performed by the robotic device in a particular sequence.

[0058] According to another aspect described herein, there is provided a method for connecting a first flexible tube attached to a first consumable item to a second flexible tube attached to a second consumable item, the method including: using a robotic device to engage the first flexible tube held in a first tube clip and pull the first flexible tube through the first tube clip to position the first flexible tube adjacent to a second flexible tube held in the second tube clip; engaging the second flexible tube while maintaining engagement of the first flexible tube with the robotic device; and welding the first flexible tube to the second flexible tube to form a (first) joined tube connecting the first consumable item to the second consumable item.

[0059] The robotic device includes a tube welder having a first pair of jaws and a second pair of jaws, whereby a first flexible tube can be engaged by the first pair of jaws while a second flexible tube can be (simultaneously) engaged by the second pair of jaws (or a second flexible tube can be engaged by the second pair of jaws while the first flexible tube can be (simultaneously) engaged by the first pair of jaws). After both tubes are engaged, the tube welder can clamp the tubes using the jaw pairs, heat and cut the tube along a cutting plane (e.g., using a heated blade to melt the tube during cutting), align the first flexible tube with the second flexible tube, and press the melted ends of the tubes together to form a joint tube. Preferably, the tube welder is provided on a robot end effector of the robotic device.

[0060] The method may further include removing the second tube from the second tube clip prior to welding and replacing the joined tube within the second tube clip after welding, which advantageously provides more space for the robotic device to manipulate the tube when welding the first flexible tube to the second flexible tube.

[0061] The method may further include sealing the joined tubing between a first tube clip and a second tube clip to divide the tubing into a first flexible tubing held by the first tube clip and a second flexible tubing held by the second tube clip; engaging a third flexible tubing held by a third tube clip and connected to a third consumable and pulling the third flexible tubing through the third tube clip to position the third flexible tubing adjacent to either the first flexible tubing or the second flexible tubing; engaging the first or second flexible tubing while maintaining engagement of the third flexible tubing with the robotic device; and welding the third flexible tubing to the first or second flexible tubing to form a second joined tubing connecting the first or second consumable to the third consumable.

[0062] In this way, subsequent connections can be made between flexible tubing, and the tubing is always held by either a tubing clip or a robotic device, so the placement and movement of all tubing is known at every stage as connections are made between consumables, thereby reducing the likelihood of making incorrect connections.

[0063] According to another aspect described herein, there is provided a tube clip for holding a portion of a flexible tube, the tube clip comprising: a tubesheet configured to receive the tube at a predetermined position; a retaining element movable relative to the tubesheet between an open position to allow the tube to be received by the tubesheet at the predetermined position and a closed position to hold the tube within the tubesheet; the retaining element movable relative to the tubesheet between the open and closed positions; and an actuator configured to move the retaining element between the open and closed positions, the actuator further configured to move the retaining element beyond the closed position to at least partially close and pinch the tube against the tubesheet, thereby controlling fluid flow through the tube. The tube clip may be provided within the fluid connection system described above. The tubesheet may be configured to receive the tube from a robotic device.

[0064] Thus, the actuator is controllable to move the retaining element among a plurality of intermediate positions, in which the retaining element applies a different force to the tube against the tubesheet, thereby controlling fluid flow through the tube and / or enabling the use of tubes of different diameters with the tube clip. Advantageously, the tube clip can pinch the tube (e.g., occlude the tube) to prevent fluid flow through the tube, hold the tube (tightly) to restrict fluid flow through the tube, hold the tube (lightly) without substantially restricting fluid flow through the tube, and / or release the tube completely from the tube clip. The tube clip can lightly hold the tube with sufficient force to prevent longitudinal movement of the tube through the tube clip, and can also lightly hold the tube to allow longitudinal movement through the tube clip.

[0065] The following preferred features may be provided in conjunction with either or both of the fluid connection systems described above and herein or the tube clips described above and herein.

[0066] Preferably, the actuator is controllable to provide a continuous range of intermediate positions for the retaining element. Optionally, the actuator is controllable to apply a continuous range of forces to the tubes in contact with the tubesheet.

[0067] The tubesheet profile may be semicircular or substantially C-shaped, rectangular, or have a generally V-shaped notch or groove. Thus, when a force is applied to a tube in contact with the tubesheet, the tube is urged toward a predetermined position, thereby facilitating consistent engagement of the tube in the tube clip by an external robotic device.

[0068] The retaining element may include a retaining arm configured to seal the tube within the tubesheet when the retaining element is in the closed position. The retaining arm may be a hook-shaped element, a bar element, or any other shape suitable for holding the tube against the tubesheet. One or more additional retaining arms may be used, such as two bar elements on two separate pivots.

[0069] The tubesheet may include first and second portions spaced apart by a gap in a direction parallel to the axis of the tubes, with the retaining arms positioned to contact the tubes within the gap, so that the retaining arms apply symmetrical forces to the tubes, thereby preventing the tubes from bending during engagement.

[0070] Preferably, the actuator is configured to rotate the retaining element during movement from the open position to the closed position. In other words, the retaining element may be attached to a pivot, and the retaining element rotates about the pivot. In this way, when the retaining element is in the open position, the tubesheet may be fully exposed, thereby allowing the tubes to be received unobstructedly in the tubesheet.

[0071] The tube clip may further include a cam element rotatably coupled to the actuator, whereby rotation of the cam element rotates and causes the retaining element to move laterally during movement from the open position to the closed position. Thus, during initial movement of the retaining element from the open position to the closed position, the retaining element may rotate to bring the retaining arms in front of the tubesheet. Thereafter, during subsequent movement of the retaining element, the cam element causes the retaining arms to move laterally toward the tube in a substantially linear direction. This may reduce shear forces applied to the tube (particularly if the tube is pinched when in the closed position), thereby reducing the risk of tube fracture.

[0072] Preferably, the retaining element is spring biased to counter the force applied by the actuator, thereby returning the retaining element to the open position when the actuator is disengaged. In this way, the actuator does not need to be controlled to actively rotate the retaining element towards the open position.

[0073] Preferably, the tube clip is configured to allow longitudinal movement of the tube therethrough. As used herein, longitudinal movement of the tube preferably refers to movement of the tube along the tube axis. By allowing longitudinal movement of the tube, the position of at least a portion of the tube remains known even when other portions of the tube are moved (e.g., to connect to other tubes). In this manner, the position of any tube can always be determined using at least one tube clip in the tube connection section. The tube clip may include rollers to allow longitudinal movement of the held tube. Preferably, the holding element is movable to a position where the tube is held within the tube clip but is not gripped or pinched by the holding element. In this manner, the tube does not necessarily have to contact the tube clip when in the closed position, thereby allowing the tube to be easily pulled longitudinally through the tube clip while still maintaining the tube in place within the bioprocess system (thereby enabling engagement by a robotic device). The tube-contacting surfaces of the holding element and / or tube sheet may include low-friction surfaces so as not to substantially impede longitudinal movement of the tube through the tube clip.

[0074] The tube clip may further include at least one sensor for detecting one or more of the presence of a portion of the tube within the tube clip and / or whether the portion of the tube held within the tube clip contains fluid.

[0075] At least one sensor may include an air bubble sensor. The sensor may comprise a capacitive sensor and / or an ultrasonic sensor. The sensor may comprise a force sensor for measuring the force or torque applied to the tube by the holding arm. Preferably, multiple sensors are provided.

[0076] The tube clip may further comprise a tube guide arranged to support the tube at a predetermined position along the tube's (longitudinal) axis offset from the tubesheet.

[0077] In this way, the position of the tube is not only known strictly at the tubesheet, but also along the length extending between the tubesheet and the tube guide. This may allow for more consistent engagement of the tube by an external robotic device. The tube guide may include tube fins positioned to extend along the tube's (longitudinal) axis. This allows for easy engagement of the tube by the robotic device, as the fins support the tube and are thin enough not to interfere with the closure of the jaws of the robotic device when they engage the tube. The tube guide may include a second tubesheet offset from the (e.g., first) tube along the longitudinal axis. In this way, the position of the tube is known at both the first and second tubesheets and the axis extending therebetween, thereby allowing for engagement of the tube by the robotic device without interference from either tubesheet.

[0078] Those skilled in the art will understand that any apparatus feature described herein may be provided as a method feature, and any method feature described herein may be provided as an apparatus feature. It will also be understood that specific combinations of the various features described and defined in any aspect described herein may be implemented and / or provided and / or used independently.

[0079] Furthermore, it will be understood that the present invention has been described purely by way of example and that modifications of detail may be made within the scope of the invention. Furthermore, in this specification, "means-plus-function" features may alternatively be expressed using corresponding structures.

[0080] One or more embodiments will now be described, purely by way of example, with reference to the accompanying figures. [Brief explanation of the drawings]

[0081] [Figure 1] FIG. 1 illustrates an example of a bioprocessing device forming part of a bioprocessing system. [Figure 2A] FIG. 10 shows a cartridge containing a cartridge consumable product with a tube connected thereto. [Figure 2B] FIG. 1 shows a cell culture chamber with multiple tubes connected thereto. [Figure 3] FIG. 1 shows a first example of a fluid connection system for connecting multiple cartridge consumables to a cell culture chamber. [Figure 4A] 1 shows a preferred example of a fluid connection system. [Figure 4B] FIG. 4B shows a tubing connection section of the fluid connection system of FIG. 4A. [Figure 5A] 4C shows steps in a method of connecting tubing using the fluid connection system in FIG. 4B. [Figure 5B] 4C shows steps in a method of connecting tubing using the fluid connection system in FIG. 4B. [Figure 5C] 4C shows steps in a method of connecting tubing using the fluid connection system in FIG. 4B. [Figure 5D] 4C shows steps in a method of connecting tubing using the fluid connection system in FIG. 4B. [Figure 6A] FIG. 1 illustrates an alternative fluid connection system. [Figure 6B] FIG. 1 illustrates an alternative fluid connection system. [Figure 6C] FIG. 1 illustrates an alternative fluid connection system. [Figure 6D] FIG. 1 illustrates an alternative fluid connection system. [Figure 7A] FIG. 10 shows an example of a sampling device that also allows for purging fluid from tubing in a bioprocessing system. [Figure 7B]FIG. 10 shows an example of a sampling device that also allows for purging fluid from tubing in a bioprocessing system. [Figure 7C] FIG. 10 shows an example of a sampling device that also allows for purging fluid from tubing in a bioprocessing system. [Figure 8A] 4C and 4D show examples of tube clips that can be used in the fluid connection system and tube connection section of FIGS. 4A and 4B. [Figure 8B] 4C and 4D show examples of tube clips that can be used in the fluid connection system and tube connection section of FIGS. 4A and 4B. [Figure 9A] FIG. 10 illustrates an alternative way in which a sample may be extracted. [Figure 9B] FIG. 10 illustrates an alternative way in which a sample may be extracted. [Figure 9C] FIG. 10 illustrates an alternative way in which a sample may be extracted. [Figure 9D] FIG. 10 illustrates an alternative way in which a sample may be extracted. [Figure 9E] FIG. 10 illustrates an alternative way in which a sample may be extracted. [Figure 9F] FIG. 10 illustrates an alternative way in which a sample may be extracted. [Figure 9G] FIG. 10 illustrates an alternative way in which a sample may be extracted. DETAILED DESCRIPTION OF THE INVENTION

[0082] overview FIG. 1 illustrates a bioprocessing apparatus 1. The bioprocessing apparatus 1 may be part of a broader bioprocessing system, such as a processing station of the bioprocessing system. The bioprocessing apparatus 1 may have multiple subsystems, such as a loading system, a storage system 20, a fluid connection system 30, an incubator system 40, and an unloading system. In the example shown in FIG. 1, the loading and unloading systems have been omitted. While FIG. 1 illustrates each system in a specific location on the apparatus 1, it will be appreciated that this location is purely exemplary and that the systems may be located in other locations.

[0083] The bioprocessing apparatus 1 is operable to receive a plurality of consumables and manipulate the consumables to perform a bioprocessing process, which may include steps such as, for example, transferring fluids between the consumables, incubating the consumables, and sampling from the consumables.

[0084] Each consumable has at least one flexible tube fluidly connected to it. As described in more detail below, fluid transfer between consumables is accomplished by connecting the consumables through their respective tubes before pumping the fluid between them. More specifically, a tube welder is used to weld the corresponding tubes together, a peristaltic pump is used to pump the fluid, and a tube sealer is used to resever each tube. When the tubes are not connected, the free ends of each tube remain sealed, thereby preventing exposure of each tube and the contents of the consumable to the environment. This provides a "closed system" and prevents contamination of the container contents or the environment.

[0085] The inputs of the bioprocess apparatus 1 can be consumables containing patient samples such as reagents, media, cytokines, and cells, as well as empty consumables for collecting samples for testing. The outputs from the bioprocess apparatus 1 after a bioprocessing step can be, for example, consumables containing cell cultures, waste consumables, or empty consumables.

[0086] The specific steps of a bioprocessing process may be defined by a "bioprocessing workflow." All of the steps of a bioprocessing process are preferably automated, whereby the manipulation of consumables (including fluid connections and transfers) is preferably performed by the robotic device 5 without operator intervention. The robotic device 5 may have at least one robotic arm including at least one end effector having components such as a tube welder for forming sterile connections between tubing, a peristaltic pump for pumping fluids through connected tubing, and / or a tube sealer for cutting and sealing tubing. These components may be provided on the same end effector or on separate end effectors or separate robotic devices.

[0087] The tube welder can have a first pair of jaws for gripping a first tube and a second pair of jaws for gripping a second tube. The peristaltic pump is preferably a linear peristaltic pump having a plurality of individual pushing elements that compress the retained tube to provide a peristaltic pumping action to force fluid through the tube. The tube sealer can comprise an RF sealer or a heat sealer; alternatively, sealing can be performed by the tube welder.

[0088] As shown in Figure 1, each of the sections is accessible from the front 1a of the bioprocess apparatus 1. This allows a robotic device 5 to manipulate the consumables. For example, as shown in Figure 1, the robotic device 5 can be independent of the bioprocess apparatus 1, such as a mobile manipulation unit that can move freely around the site where the bioprocess apparatus 1 is located. Alternatively, the robotic device 5 can be part of the bioprocess apparatus 1, for example, mounted on rails that extend adjacent to the front 1a.

[0089] The term "consumable" is used to refer to a component that directly contains and / or comes into direct contact with biological material and therefore cannot be reused. More specifically, the consumable may be a container such as a bag or a jar. To facilitate handling and manipulation of the consumable, the consumable may be located within a cartridge 100. Cartridge 100 is described in connection with FIGS. 2A and 2B.

[0090] FIG. 2A shows an example of a cartridge 100 for holding a consumable item 150. The consumable item 150 held within the cartridge 100 may be referred to as the "cartridge consumable item 150." The cartridge 100 includes a first portion 120 for holding the cartridge consumable item 150 and a second portion 130 for holding a flexible tube 155 at least partially along a predetermined path. More specifically, the first portion 120 is formed by a housing 120 within which the cartridge consumable item 150 (in the form of a bag 150) is located. The second portion 130 may include one or more tube clips 131 for holding the free end 155a of the tube 155 in a fixed position relative to the cartridge 100 (and thus relative to the slot). This allows the robotic device 5 to engage the tube 155 in a consistent position. For example, the tube 155 may be engaged at a position exactly between two tube clips 131. Alternatively, the cartridge 100 may have only a single passive clip 131. Preferably, the cartridge 100 is configured to extend and retract the tubing 155 connected to the consumable 150, and in this manner, the cartridge 100 can accommodate varying lengths of the tubing 155, 255 resulting from repeated connections.

[0091] FIG. 2B shows an example of a cell consumable 250 (e.g., cell culture chamber 250). The cell consumable 250 is sometimes referred to as a "bioreactor" 250. The cell consumable may be a gas-permeable cell culture vessel. In this example, the cell consumable 250 has the general shape of an Erlenmeyer flask with an opening at the top. However, this shape is merely exemplary. The cell consumable 250 may be any pot, flask, or container that contains cells. A removable cap 254 (e.g., a screw) is attached to the opening of the cell consumable 250. Multiple tubes 255 extend through the cap 254 to allow fluid to be pumped into and / or out of the cell consumable 250. For example, a first tube 255-1 may extend to the top of the cell consumable 250, and a second tube 255-2 may remain near the base of the cell consumable 250. This allows fluid to be easily added to the top of the cytological consumable 250 and removed from the base of the cytological consumable 250. Optionally, there may be additional tubes, such as a third tube 255-3. It will be appreciated that the tubes 255 may be configured differently from one another, and that there may be more or fewer tubes 255.

[0092] The tubing 255 extends from the cell consumable to allow access to the tubing 255 by the robotic device 5. In this manner, fluids can be added and / or removed from the cell consumable 250 via the tubing 255. The free end of the tubing 255a is positioned to have a fixed position relative to the cell consumable 250, for example, by using one or more passive clips (either on the cell consumable 250 or on the fluid connection system 30). In this manner, the tubing 255 can be engaged in a consistent position by the robotic device 5 when the bioreactor 250 is installed within the bioprocessing system 1. While the bioreactor 250 is shown in FIG. 2B as being located inside an external incubator with a base and cover, it will be appreciated that these components are not required.

[0093] As described later with respect to the fluid connection system 30, during a bioprocessing step, the flexible tubing 155 corresponding to the cartridge consumable 150 (referred to as "cartridge consumable tubing 155") may be welded to the flexible tubing 255 corresponding to the cell consumable 250 (referred to as "cell consumable tubing 255" or "bioreactor tubing").

[0094] Although not shown in FIG. 1 , an (optional) loading system will now be described. The loading system includes multiple loading slots. Each loading slot is configured to receive a cartridge 100 holding a cartridge consumable 150, such as a cartridge consumable 150 containing a patient sample or a reagent. The housing 120 of the cartridge 100 may have a standardized shape and / or one or more engaging components to facilitate consistent insertion of the cartridge 100 into one of the loading slots. The cartridge 100 may be loaded manually by a human operator or by an automated robotic device 5. The loading system also includes at least one bioreactor loading platform, where the cell consumable 250 may be initially loaded into the apparatus 1. As previously described, the cell consumable 250 has multiple flexible tubing 255 to transfer fluids to and from the cell consumable 250.

[0095] The apparatus 1 includes a storage system 20. The storage system 20 includes a plurality of storage slots 22. After the cartridge 100 is loaded into the loading slot, the robotic device 5 can transfer the cartridge 100 into the storage slot 22. Alternatively, the cartridge 100 can be loaded directly into the storage slot 22 (i.e., a loading system is not required). In this example, the storage slots 22 include a plurality of storage slots 22a for room temperature storage and a second plurality of storage slots 22b in a refrigerator 23. In this manner, multiple different types of cartridge consumables 150, such as cartridge consumables 150 containing different reagents, media, or patient samples, such as cells, can be stored within the bioprocess apparatus 1 in standardized cartridges 100, and as needed, any cartridge 100 can be removed from one of the storage slots 22 and moved to the fluid connection system 30 for fluid to be transferred. The storage system 20 may have other sections, such as a medium storage section 26 for larger medium bags (rather than the smaller bags of medium that must always be provided in the cartridge 100), which allows medium to be loaded into the device 1 in bulk and then transferred into the cartridge 100.

[0096] Next, the fluid connection system 30 will be described. During a bioprocessing step, it may be necessary to transfer fluid between consumables (e.g., from one or more of the cartridge consumables 150 into the cell consumables 250, or from one or more of the cell consumables 250 into the cartridge consumables 150). The fluid connection system 30 includes a consumables storage section 31 including a plurality of transfer slots 32. For a transfer step, the cartridge 100 can be moved from a storage slot 22 of the storage system 20 to a transfer slot 32 of the fluid connection system 30 by a robotic device 5. The fluid connection system 30 also includes a cell consumables storage section 34. The cell consumables storage section 34 may include a bioreactor platform 35. For a transfer step, the bioreactor 250 can be moved onto the bioreactor platform 35, for example, from a bioreactor loading platform of a loading system.

[0097] After the cartridge 100 is properly loaded into the fluid connection system 30, the tubing 155 corresponding to each cartridge consumable 150 is positioned in a predetermined position relative to each transfer slot 32. Similarly, once the cell consumable 250 is properly loaded into the fluid connection system 30, the tubing 255 connected to the cell consumable 250 is positioned in a predetermined position relative to the bioreactor platform 35. In this manner, the robotic device 5 can securely engage any of the tubing 155, 255 connected to any of the consumables 150, 250 to form a connection therebetween. Further features of the fluid connection system 30 are described below in conjunction with Figures 3-6.

[0098] The incubator system 40 will now be described in more detail. After various reagents have been mixed within the cellular consumable 250 (e.g., after fluid transfer has occurred in the fluid connection system 30), the cellular consumable 250 can be moved into the incubator system 40 for cell growth. Because the bioprocessing apparatus 1 can perform several bioprocessing steps (i.e., bioprocessing steps for different patient samples) in parallel, the incubator system 40 preferably includes several incubation platforms 45, each configured to support a respective cellular consumable 250. The incubator system 40 encloses the cellular consumable 250 within an incubation chamber 43 and maintains the cellular consumable 250 at a temperature higher than room temperature, such as approximately 37°C. The incubator system 40 can also be configured to agitate the contents of the cellular consumable 250, for example, by shaking or tilting the cellular consumable 250. In particular, each incubation platform 45 can be individually operable to agitate the cellular consumable 250 disposed on the incubation platform 45.

[0099] The cellular consumable 250 may be transferred from the incubator system 40 to the fluid connection system 30 at some point during the bioprocess workflow. For example, samples may be extracted from the cellular consumable 250 to monitor cell growth.

[0100] Although not shown in FIG. 1 , the (optional) removal system will now be described in more detail. The removal system includes multiple removal slots, which are similar to the loading slot, storage slot 22, and transfer slot 32 described above. The removal slots accept used cartridges 100, such as cartridges 100 containing cartridge consumables 150 containing waste medium, samples for testing, rich cell cultures, or empty cartridges. In this manner, used cartridges 100 may be easily removed from the device 1 via the removal system. Alternatively, cartridges 100 may be removed directly from the storage system 20 or the fluid connection system 30.

[0101] The unloading system also includes at least one bioreactor unloading platform, which may be similar to the bioreactor loading platform of the loading system. In this manner, used cellular consumables 250 may be easily removed from the device 1 via the unloading system 50. Alternatively, the cellular consumables 250 may be removed directly from the storage system 20 or the fluid connection system 30.

[0102] The bioprocess apparatus 1 includes a user interface 60. In this example, the user interface 60 is a tablet connected to the bioprocess apparatus 1. However, it will be appreciated that the user interface 60 may be located elsewhere, including remotely on the apparatus 1. The user interface 60 may be used by a human operator when loading the cartridge 100 into the loading system. For example, the operator may identify the contents of the cartridge 100 loaded into the loading slot. This information may be used by the apparatus 1 to track the location of the cartridge 100 as it is moved around the apparatus 1 (e.g., between slots 22, 32). The user interface 60 may allow a user to input a particular bioprocess workflow to be followed or to instruct the apparatus 1 to perform a sampling step.

[0103] Fluid Connection System The fluid connection system 30 will now be described in more detail. As generally described above, the fluid connection system 30 allows for a connection to be made between the tubing 155 corresponding to the cartridge consumable 150 and the tubing 255 corresponding to the cell consumable 250. Generally, there are four cartridges 100-1, 100-2, 100-3, 100-4 in the transfer slot 32, each holding a corresponding cartridge consumable 150-1, 150-2, 150-3, 150-4 connected to a corresponding tubing 155-1, 155-2, 155-3, 155-4. The cell consumable 250 has at least two tubings 255-1, 255-2.

[0104] Ideally, a fluid connection system should be able to:

[0105] First, the fluid connection system must be able to connect any of the tubing 155 corresponding to any of the cartridge consumables 150 to any of the tubing 255 corresponding to the cell consumables 250.

[0106] Second, the fluid connection system should measure the volume of fluid transferred between each of the consumables 150, 250 throughout the bioprocessing workflow.

[0107] Third, because the tube 155 generally extends downward from the cartridge 100, the fluid connection system must be able to prevent fluid from draining from the cartridge consumable 150 under gravity.

[0108] Fourth, the fluid connection system should allow for the transfer of samples from the cellular consumable 250 to a sample container, allowing for the progress of cell growth within the cellular consumable 250 to be monitored by taking representative samples throughout the bioprocessing method.

[0109] Fifth, the fluid connection system must be capable of purging fluid remaining in the tubing 155, 255 after the transfer step due to the length of tubing extending between the consumables 150, 250. For example, when fluid is pumped from the cartridge consumable 150 to the cell consumable 250 through the connected tubing, additional fluid initially remains in the connected tubing even after sufficient fluid has been transferred to the cell consumable 250. If this fluid is not removed and instead remains in the tubing for an extended period of time, the fluid may expire and contaminate other fluids in the closed system. Furthermore, purged fluid is preferably returned to the consumable from which it originated rather than being pumped into a waste container. If a sample is taken into a sample container, the tubing must be purged as well.

[0110] In practice, it is difficult to achieve a fluid connection system that can perform all of the above functions.

[0111] FIG. 3 shows a schematic diagram of a fluid connection system 30′. As shown, a cytological consumable 250 is connected to a first tube 255-1 and a second tube 255-2. Additionally, a sampling unit 90 is provided, which includes a plurality of sample containers 95. To enable connection of both tubes 255-1, 255-2 to the cartridge consumable 150 and the sampling unit 90, the fluid connection system 30′ requires the tubes 155, 255 to cross each other at several points. In fact, the fluid connection system 30′ of FIG. 3 requires a many-to-many connection configuration, which requires the tubes to cross at least one location.

[0112] However, crossing tubes becomes problematic when the bioprocess workflow is automated. First, when several connections and disconnections are performed, the same pairs of tubes may be repeatedly crossed, potentially causing the tubes to become tangled. Second, crossing tubes requires the tubes to exit a substantially two-dimensional plane, making it difficult for a robotic device to reliably engage the tubes (at a consistent position). Third, only the first cell consumable tube 255-1 can be connected to the sampling unit 90; therefore, sampling from the second cell consumable tube 255-2 is not possible.

[0113] To address the above-mentioned issues, FIG. 4A illustrates a preferred embodiment of a fluid connection system 30. The system 30 includes a consumable storage section 31 having a first subsection 31a and a second subsection 31b. Each subsection 31a, 31b is configured to store at least one fluid-containing consumable 150 having a flexible tube 155 fluidly connected thereto. More specifically, as already described above, the consumable storage section 31 includes a plurality of slots 32, each configured to receive a cartridge 100 holding a cartridge consumable 150. The slots 32 are preferably arranged in a linear configuration with the slots 32 evenly spaced apart. The slots 32 are divided into a first plurality of slots 32a and a second plurality of slots 32b, each corresponding to a respective subsection 31a, 31b of the storage section 31.

[0114] The fluid connection system 30 also includes a cell storage section 34 configured to store a cell consumable 250 (eg, a cell culture chamber 250) to which at least a first flexible tube 255a, 255b is fluidly connected.

[0115] The fluid connection system 30 also includes a tubing connection section 300 disposed between the consumables storage section 31 and the cell storage section 34. The tubing connection section 300 does not allow connection between any of the cartridge consumables 150 and any of the tubing 255-1, 255-3 connected to the cell consumables 250, but rather comprises a first portion 300a and a second portion 300b. The first portion 300a is configured to hold the first flexible tubing 255-1 of the cell consumable 250 and to position it so that it can be connected to the flexible tubing 155-1, 155-2 corresponding to the cartridge consumables 150 stored in the first subsection 31a of the consumables storage section 31. The second portion 300b is configured to hold the second flexible tubing 255-2 of the cell consumable 250 and to position it so that it can be connected to the flexible tubing 155-3, 155-4 corresponding to the cartridge consumables 150 stored in the second subsection 31b of the consumables storage section 31.

[0116] Advantageously, having first and second portions 300a, 300b of the tubing connection section 300, each positioned to connect tubing in one of the subsections 31a, 31b of the consumable storage section to one of the tubings 255-1, 255-2 of the cellular consumable, allows connections to be made between the consumables 150, 250 without crossing the tubing 155, 255. This reduces the likelihood of the tubing 155, 255 becoming tangled and maintains the tubing 155, 255 in a substantially two-dimensional plane, thereby simplifying manipulation of the tubing 155, 255 by the robotic device 5. Although not shown in FIG. 4A , the consumable storage section 31 may have a slot 32 at an intermediate position, the slot 32 being in both the first and second subsections 31a, 31b. The consumable storage section 31 may have a third subsection 31c, which is preferably formed by a single slot 32. In this manner, when it is necessary to connect tubing 155-1, 155-2 from one of the cartridge consumables 150-1, 150-2 in the first subsection 31a to a second cell consumable tubing 255-2 (or when it is necessary to connect tubing 155-3, 155-4 from one of the cartridge consumables 150-3, 150-4 in the second subsection 31b to a first cell consumable tubing 255-1), the slot 32 in the third subsection 31c can be used to exchange two of the cartridge consumables 150 between the first subsection 31a and the second subsection 31b. In other words, the third subsection 31c forms a buffer position for one of the cartridge consumables 150 so that only one cartridge consumable 150 needs to be engaged at a time to effect a swap. By allowing swapping of cartridge consumables 150 between the first subsection 31a and the second subsection 31b, any cartridge consumable 150 can be connected to either of the cell consumable tubing 255-1, 255-2 without crossing the tubing.

[0117] The fluid connection system 30 also includes a sampling device 400, which allows for a sample to be taken from the cytological consumable 250. A specific example of the sampling device 400 is described below in connection with Figures 7A-7C. Briefly, the sampling device 400 includes an air input 420 that allows for a sample to be taken from the cytological consumable 250 and allows any fluid remaining in the tubes 255-1, 255-2 to be returned to the cytological consumable 250 after the sampling process.

[0118] 4B shows the tube connection section 300 in more detail. In this example, the tube connection section 300 is a tube connection panel 300 located between the consumables storage section 31 (which holds the cartridge consumables 150) and the cell storage section 34 (which holds the cell consumables 250) in the fluid connection system 30. During use, a plurality of tubes 155-1, 155-2, 155-3, 155-4, and 155-5 may extend to an upper edge 300a of the tube connection panel 300, with each tube corresponding to a cartridge consumable 150 in one of the slots in the consumables storage section 31. Similarly, a plurality of tubes 255-1, 255-2, and 255-3 may extend to a lower edge 300b of the tube connection panel 300, with each tube 255 connected to a cell consumable 250 in the cell storage section 34.

[0119] The tube connection section 300 includes a plurality of tube clips 500 (only some of the tube clips are labeled). Specific examples of the tube clips 500 are described in relation to FIGS. 8A and 8B . The tube clips 500 include a first plurality of tube clips 500a, which are located adjacent to the upper edge 300a of the tube connection panel 300 and may be referred to as “cartridge consumable tube clips 500a.” In this manner, each tube 155 corresponding to one of the cartridge consumables 150 can be held in place within the tube connection section 300 by at least one of the cartridge consumable tube clips 500a. More specifically, the first cartridge consumable tube 155-1 is held by at least the first cartridge consumable tube clip 500a-1. Preferably, the first cartridge consumable tube 155-1 is held by a first pair of cartridge consumable tube clips 500a-1, 500a-1′ (e.g., an “upper” cartridge consumable tube clip 500a-1 and a “lower” cartridge consumable tube clip 500a-1′). Similarly, each of the second through fifth cartridge consumable tubes 155 is held by at least one cartridge consumable tube clip, and preferably, a pair of cartridge consumable tube clips. For clarity, not all tube clips are labeled. By using the pair of tube clips 500a-1, 500a-1′, the tube 155-1 is held between the pair of tube clips along a predetermined axis. This allows the robotic device 5 to engage the tube 155-1 with greater consistency because the position of the tube 155-1 is known not only at a single point, but also along the continuous length of the tube 155-1.

[0120] The tube clip 500 includes a second plurality of tube clips 500b, which are located adjacent to the lower edge 300b of the tube connection panel 300; the second plurality of tube clips may be referred to as "cell consumable tube clips 500b." In this manner, each tube 255 connected to the cell consumable 250 may be held in place within the tube connection section 300 by at least one of the cell consumable tube clips 500b. More specifically, the first cell consumable tube 255-1 is held by at least the first cell consumable tube clip 500b-1. Preferably, the first cell consumable tube 255-1 is held by a first pair of tube clips 500b-1, 500b-1' (e.g., an "upper" cell consumable tube clip 500b-1 and a "lower" cell consumable tube clip 500b-1'). Similarly, each of the second (and third) cell consumable tubing 255 is held by at least one cell consumable tubing clip, and preferably, a pair of cell consumable tubing clips. For clarity, not all tubing clips are labeled. The distance between pairs of tubing clips in the second plurality of cell consumable tubing clips 500b may be greater than the distance between pairs of cell consumable tubing clips. This may allow additional space for a linear peristaltic pump along the axis of the tubing between the pairs of cell consumable tubing clips.

[0121] 4B, the sampling device 400 may be mounted in a central location on the tubing connection section 300 that allows for connection of either of the cell consumable tubings 255-1, 255-2. For example, the sampling device may be provided within an external frame held by one of the tubing clips 500. As described below, the sampling device 400 allows for both sampling and purging through either of the cell consumable tubings 255-1, 255-2.

[0122] A method for connecting two tubes using the tube connection section 300 will now be described. In this example, a first cell consumable tube 255-1 is connected to a first cartridge consumable tube 155-1. However, it will be appreciated that this method may be used to connect other tubes 155, 255.

[0123] In FIG. 5A, the robotic device 5 engages the first cartridge consumable tube 155-1 with one of a pair of jaws of the end effector, releases the first cartridge consumable tube 155-1 from the passive clip on the respective cartridge 100-1, pulls the tube 155-1 onto the upper edge 300a of the tube connection section 300, and clips the tube 155-1 into the first pair of cartridge consumable tube clips 500a-1, 500a-1'.

[0124] In FIG. 5B, the robotic device 5 engages the first cell consumable tube 255-1 with one of the rear pair of jaws of the end effector, releases the first cell consumable tube 255-1 from the passive clip adjacent to the cell consumable 250, pulls the tube 255-1 to the lower edge 300b of the tube connection section 300, and clips the tube 255-1 into a first pair of cell consumable tube clips 500b-1, 500b-1' in the second plurality of tube clips 500b.

[0125] As will be described below in connection with Figures 8A and 8B, the tube clip 500 is an active tube clip 500 that engages and holds the tube 155-1.

[0126] In FIG. 5C , in step (1), the robotic device 5 engages the first cartridge consumable tube 155-1 (e.g., with a first pair of end effector jaws) and pulls the first cartridge consumable tube 155-1 through a first pair of cartridge consumable tube clips 500a-1, 500a-1′. In step (2), the robotic device 5 continues to pull the tube 155-1 past the lower cell consumable tube clip 500b-1′ of the first pair of cell consumable tube clips 500b-1, 500b-1′. In step (3), the robotic device 5 engages the first cell consumable tube 255-2 below the lower cell consumable tube clip 500b-1′ (e.g., engages a second pair of end effector jaws while still holding the first cartridge consumable tube 155-1 against the first pair of end effector jaws). With both tubes 155-1, 255-1 held in their respective pairs of jaws of the end effector, one or more of the tube clips, such as lower cell consumable tube clip 500b-1′, can be released and the tubes 155-1, 255-1 can be pulled away from the surface of the tube connection section 300 by the robotic device 5.

[0127] The robotic device 5 may then perform a tube weld between the first cartridge consumable tube 155-1 and the first cell consumable tube 255-1, thereby forming a single joined tube 355-1 between the first cartridge consumable 150-1 and the cell consumable 250. After the weld is completed, in step (4), the robotic device 5 may return the joined tube 355-1 toward the tube connection section 300 so that the joined tube 355-1 is reengaged by one or more of the tube clips (i.e., so that it is reengaged by the tube clips that were already released before the weld). Next, the first and second pairs of jaws of the end effector may be opened to release the joined tube 355-1. Preferably, the end effector may pull the joined tube 355-1 upward to remove slack existing between the first pair of cell consumable tube clips 500b-1, 500b-1′. In this manner, the joined tubing 355-1 can be engaged between a first pair of cell consumable tubing clips 500b-1, 500b-1' by a peristaltic pump (on the end effector), thereby allowing fluid to be pumped between the first cartridge consumable 150-1 and the cell consumable 250.

[0128] The subsequent formation of the connection will now be described with reference to Figure 5D. In step (1), the tube sealer of the robotic device 5 seals the joined tube 355-1 between a first pair of cartridge consumable tube clips 500a-1, 500a-1', preferably at the top of the gap therebetween. As a result, the joined tube 355-1 is divided into a first cartridge consumable tube 155-1 and a first cell consumable tube 255-1. In step (2), the robotic device 5 engages the second cartridge consumable tube 155-2 (e.g., with a first pair of jaws of an end effector) and pulls the second cartridge consumable tube 155-2 through the second pair of cartridge consumable tube clips 500a-1, 500a-2'. In step (3), the robotic device 5 continues to pull the tubing 155-2 through the lower cartridge consumable tube clip 500a-2' so that there is enough tubing below the tube clip 500a-2' so that the second cartridge consumable tube 155-2 reaches the first cell consumable tube 255-1 held in the first pair of cartridge consumable tube clips 500a-1, 500a-1'. In step (4), the robotic device 5 engages the first cell consumable tube 255-1 (e.g., engages the second pair of jaws of the end effector while nevertheless holding the second cartridge consumable tube 155-2 against the first pair of jaws of the end effector). With both tubes 155-2, 255-1 held in their respective pairs of jaws of the end effector, one or more of the tube clips, such as the lower first cartridge consumable tube clip 500a-1', can be released and the tubes 155-2, 255-1 can be pulled away from the surface of the tube connection section 300 by the robotic device 5.

[0129] In step (5), the robotic device 5 may pull down the tubes 155-2, 255-1 so that both tubes 155-2, 255-1 are held below the lower, first cartridge consumable tube clip 500a-1′. The robotic device 5 may then perform a tube weld between the second cartridge consumable tube 155-2 and the first cell consumable tube 255-1, thereby forming a single joined tube 355-2 between the second cartridge consumable 150-2 and the cell consumable 250. The robotic device 5 may then return the joined tube 255-2 toward the tube connection section 300 so that the joined tube 355-2 is reengaged by one or more of the tube clips (i.e., reengaged by the tube clips that were already released before the weld). The first and second pairs of jaws of the end effector may then be opened to release the joined tube 355-2. As previously mentioned, the robotic device 5 may perform further manipulation of the tubing to remove excess slack.

[0130] While the above steps have been described in relation to first connecting a first cartridge consumable tube 155-1 to a first cell consumable tube 255-1 and then connecting a second cartridge consumable tube 155-2 to the first cell consumable tube 255-1, it will be appreciated that the same steps apply to making connections between any of the other tubes 155, 255 connected to any of the consumables 150, 250.

[0131] Alternative Fluid Connection Systems While the fluid connection system 30 shown in Figures 4A and 4B is preferred, several alternative fluid connection systems will now be described in conjunction with Figures 6A-6D. Except where expressly noted, these alternative systems may share some components with the preferred system already described. Accordingly, to avoid the need to describe in detail the common features discussed above for every alternative, corresponding features will preferably be identified using corresponding reference numerals.

[0132] FIG. 6A illustrates a first alternative fluid connection system 30-1 (sometimes referred to as an “above-standard, field-welded” configuration). This system 30-1 is the same as the preferred fluid connection system 30, except that the sampling device 400 is absent and, instead, an air supply 80 (e.g., a filter) is provided in the same location. The air supply 80 may also be used to purge the tubing as previously described, but is not configured to collect fluid samples from the cytological consumables 250. To collect samples, the fluid connection system 30-1 also includes a sampling unit 90 corresponding to the sampling unit 90 described in connection with FIG. 3. The sampling unit 90 has multiple sampling vessels 95. Thus, while the first alternative fluid connection system 30-1 includes a device 400 that performs both sampling and purging, it is clear that this is not an absolute requirement. This system 30-1 is relatively simple to implement. However, purging the area upstream of the welds can be difficult, multiple welds may be required to perform both sampling and purging, and additional consumables must be installed by the user.

[0133] 6B illustrates a second alternative fluid connection system 30-2 (sometimes referred to as an "integrated into the consumable" configuration). This system 30-2 is the same as the first alternative fluid connection system 30-1, except that instead of having an air supply 80 (in the same location as device 400 in the preferred system), each of cartridge consumables 150-1, 150-2, 150-3, and 150-4 has a corresponding air supply 80-1, 80-2, 80-3, and 80-4. For example, an air filter or air-containing bag may be pre-welded onto cartridge consumables 150 (e.g., each of cartridge consumables 150) that provides valve control. Valve control may include a three-way valve or stopcock to switch between air supply 80 and cell consumable 250. Alternatively, valve control may include two pinch valves or a pinch valve and an in-line check valve. The valve control may be fully integrated into each of the cartridge consumables 150 and actuated externally (e.g., by a robotic device and / or an external solenoid). Alternatively, the valve control function may be split between the cartridge consumables 150 and the bioprocessing system (i.e., the cartridge consumables 150 contain tubing between the air source 80 (e.g., a filter) and the cartridge consumables 150, which may be installed on a valve seat within the bioprocessing system, e.g., on the bioprocessing apparatus 1). In this manner, purging may be accomplished by actuating the valve control and pumping air from one of the air sources 80 through the connected tubing to return fluid to the cell consumables 250. Advantageously, fluid can be purged from any position in the connected tubing (not just downstream of the weld), and no connections or welds are required to form the weld. This allows for a simple "plug and play" process for the operator. Further advantageously, this fluid connection system 30-2 and corresponding method allows for the lines to be thoroughly purged with air before performing a subsequent weld. This may reduce the risk of a failed weld as a "dry" weld may be performed rather than a wet weld (where fluid remains in the tube when the weld is performed).However, cartridge consumables 150 are more complex and must be modified to include individual air sources 80 (increasing the cost of each consumable 150). Additionally, multiple sterile filters can fail, and therefore multiple filters must be inspected before use.

[0134] FIG. 6C shows a third fluid connection system 30-3 (sometimes referred to as a "switch and manifold" configuration). This system 30-3 has only a single tubing connection. To allow connections to be made from any of the cartridge consumables 150 to the cell consumable 250, a valved manifold 81 is provided to allow switching between the cell consumable tubing 255-1, 255-2. The valved manifold 81 may be pre-attached to the cell consumable 250 and may include an air source 80, such as an air filter. This allows for many-to-many connections between the cartridge consumable 150, the cell consumable tubing 255, and the sampling unit 90. Furthermore, the required tubing can be kept relatively short. Furthermore, the system 30-3 can be operated using only a single pump. However, the manifold 81 is a separate consumable that must be provided and modified, thereby increasing the expense and complexity of the system 30-3.

[0135] FIG. 6D shows a fourth alternative fluid connection system 30-4 (sometimes referred to as a "double switch partition" configuration). In this system 30-4, the cell consumable tubing 255-1, 255-2 can be welded to a common intermediate tubing 85, which is then welded to one of the cartridge consumable tubings 155. This again allows for many-to-many connections and, in some cases, can be operated using only a single pump. However, the system requires the intermediate tubing 85 to be present, and more welds may be required to make each connection. To perform purging, an air supply 80 can be attached to the intermediate tubing 85. The air supply 80 can remain in place on the intermediate tubing 85 even when other connections are made with the ends of the intermediate tubing. The air supply 80 can have valves to allow air to be pumped upward toward the cartridge consumable 150 or downward toward the cell consumable 250. In this way, purging can be performed in multiple directions before sealing. Advantageously, this system 30-4 is relatively simple to implement and allows for purging in multiple directions, however, the switches on the air supply 80 can be complicated and the air supply is an additional consumable item that must be installed by the user.

[0136] Sampling Device One process frequently performed in bioprocessing systems is sampling, in which a small volume of fluid is extracted from the cell consumable 250 for testing, for example, to monitor cell growth. The sample can be from about 100 μl to about 5 ml in volume. For testing, the sample may need to be transported to a separate cell counter, such as an “at-line” device. One way this can be accomplished is by welding a sampling consumable to the first tube 255-1 or the second tube 255-2 of the cell consumable 250. Fluid is then pumped from the cell consumable 250 to the sampling consumable, and the sampling consumable is disconnected to facilitate testing (e.g., testing elsewhere in the bioprocessing system). However, because the tubing 255-1, 255-2 connecting the cell consumable 250 and the sampling consumable can be long, a large amount of fluid may remain in the tubing 255-1, 255-2. A similar problem occurs when the length of the internal flow path in a rigid manifold is long. It will be appreciated that any of the features described herein with respect to flexible tubing may also be applied to flow paths within a rigid fluid manifold. In particular, if small samples (e.g., about 100 μl) need to be periodically withdrawn from the sampling consumable 250, a large amount of fluid may be wasted in the "dead volume." Furthermore, if fluid remains in the tubing 255-1, 255-2 for an extended period of time, the fluid may become expired. If such expired fluid is subsequently mixed with other fluids in the bioprocessing system, it may contaminate the remaining fluids.

[0137] 7A shows a schematic diagram of a sampling device 400 that addresses the above-mentioned problem. The sampling device 400 has a fluid connection 410 configured to connect to flexible tubing 255 of a fluid-containing consumable (e.g., cell consumable 250). In this example, the cell consumable 250 is a bioreactor 250, but it will be appreciated that the sampling device 400 can be used to sample from any cell-containing consumable within a bioprocessing system. The fluid connection system 410 can include a fluid connection tube 412, which can be tube-welded to other tubes within the bioprocessing system, such as tubes 255-1, 255-2 connected to the cell consumable 250. The sampling device 400 also includes an air input 420 configured to allow sterile air to be supplied to the device 400. The air input 420 can be an air filter that filters air entering the device 400 from the surroundings. Alternatively, the air input 420 can be a syringe or bag containing sterile air.

[0138] The fluid connection tube 412 leads to a first junction 413, which connects the fluid connection tube 412 to both the sampling section 430 and the bypass section 440. The first junction 413 splits one input into two outputs (or mixes two inputs into one output), and therefore may be constituted by a Y-connector, a T-connector, or the like.

[0139] The sampling portion 430 may include a sampling tube 432. The sampling tube 432 may have a first end 432a and a second end 432b, with the first end 432a of the sampling tube 432 connected to the fluid connection 410 (e.g., via a junction 413). Preferably, the sampling portion 430 is connected to a sample container 434. In this manner, fluid fills the sample container 434 when pumped into the fluid connection 410. The sample container 434 may have a tapered shape, with the fluid first filling the narrow end of the taper and then filling toward the wider end of the taper. In this manner, a small volume of fluid may be accurately measured when first filling the narrow end of the taper, yet the sample container 434 is capable of accepting a larger volume of fluid. That is, the sample container 434 provides proportional accuracy for both small and larger samples of fluid. Alternatively, the sampling tube 432 itself may be long enough to hold the fluid sample. The sampling device 400 may include a level sensor to determine the volume of fluid collected in the sampling portion 430 .

[0140] In this example, the second end 423b of the sampling tube 432 is connected to the air supply 420. Thus, as the fluid sample fills the sampling portion 430, air displaced from the sampling portion 430 flows out of the device 400 via the air input 420. Alternatively, the sample container 434 may comprise a bag or syringe that can expand or contract to accommodate the pumped fluid, thereby obviating the need to connect the sampling portion 430 to the air input 420 (via the second end 432b of the sampling tube 432).

[0141] The bypass section 440 includes a bypass tube 442. The bypass section 440 may have a first end 442a and a second end 442b. The first end 442a of the bypass tube 442 is connected to the fluid connection section 410 (e.g., via a junction 413), and the second end 442b of the bypass tube 442 is connected to the air input section 420. If both the sampling tube 432 and the bypass tube 442 are connected to the same air input section 420, a second junction 423 may be present. For example, the air input section 420 may include an air input tube 422, which is connected to both the second end 432b of the sampling tube 432 and the second end 442b of the bypass tube 442 by a second junction 432. The second junction 423 splits one input into two outputs (or mixes two inputs into one output) and may therefore be constituted by a Y-connector or a T-connector. Alternatively, the sampling unit 430 may not be connected to either the air input unit 420 or the sampling unit 430, and the bypass unit 440 may be connected to a separate air input unit 420 (e.g., a separate air filter or a separate bag of sterile air).

[0142] The sampling device 400 also includes means for restricting fluid flow through the device 400, such that fluid pumped into the fluid connection 410 flows only into the sampling section 430, and air pumped from the fluid connection 410 passes only through the bypass section 440.

[0143] The method for collecting a sample may generally proceed as follows. First, a fluid connection 410 is connected to flexible tubing 255-1, 255-2, which is connected to a fluid-containing consumable (e.g., a cytology consumable 250). This connection is preferably made by a tubing welder using a robotic device. Fluid is then pumped from the consumable 250 through the fluid connection 410 into the sampling portion 430 of the device 400. Pumping may be achieved using a peristaltic pump (e.g., downstream of the sampling device 400) that engages the flexible tubing 255-1, 255-2. A means for restricting fluid flow ensures that fluid entering the device 400 is bypassed to the sampling portion 430 rather than entering the bypass tubing 442. Once sufficient fluid has been received within the sampling portion 430 (e.g., within the sample container 434), the pumping direction is reversed. The fluid restriction means ensures that air from air input 420 is pumped out of device 400 through bypass 440, instead of removing the fluid sample from sample container 434. In other words, when the fluid remaining in flexible tubes 255-1, 255-2 is pumped back into cytological consumables 250, air is drawn from air input 420 into flexible tubes 255-1, 255-2 via bypass tubing 442. This means that all of the fluid retained in flexible tubes 255-1, 255-2 can be returned to cytological consumables 250, while still retaining the fluid sample within device 400.

[0144] The means for restricting fluid flow through the device 400 may be constituted by a first check valve 435 that allows fluid to flow only from the fluid connection 410 into the sampling portion 430. More specifically, the first check valve 435 is disposed along the sampling tube 432 and restricts fluid flow to moving only from the first end 432a of the sampling tube 432 to the second end of the sampling tube 432. The first check valve 435 allows fluid to flow only in one direction, which means that air from the air supply 420 will not purge the fluid sample from the sampling portion 430. The first check valve 435 is preferably located on the sampling tube 432 between the sample container 434 and the air input 420. In this manner, the fluid sample does not need to pass through the first check valve 435.

[0145] The means for restricting fluid flow through device 400 may be constituted by a second check valve to allow fluid to flow only from air supply input 420 to fluid connection 410 through bypass tube 442. More specifically, second check valve 445 is disposed along bypass tube 442 and restricts the flow of fluid (e.g., air) to travel only from second end 442b of bypass tube 442 to first end 442a of bypass tube 442. Second check valve 445 allows fluid to flow in only one direction, meaning that fluid from fluid connection 410 does not enter bypass tube 442.

[0146] As an alternative to using either or both of the check valves 435, 445, the means for restricting fluid flow may comprise a portion of pinchable tubing. For example, the sampling tube 432 and / or the bypass tube 442 may be formed from flexible tubing that may be pinched by an external pinch valve during use. While pumping fluid into the device 400, the bypass tube 442 may be pinched so that fluid is diverted into the sampling tube 432. While pumping fluid out of the device 400, the sampling tube 432 may be pinched so that air is diverted from the air input 420 to the fluid connection 410 via the bypass tube 442.

[0147] Sampling portion 430 may include an extraction port (not shown in FIG. 7A) for removing a fluid sample from sampling portion 430. For example, a syringe may be attached to the extraction port and the fluid sample may be removed from the extraction port after fluid has been collected in sample vessel 434. The extraction port may include a needleless connector or a luer lock capped port or a septum for use with a syringe needle.

[0148] The device 400 may include an external housing (not shown). The external housing may comprise a frame for holding the components of the device 400 in place relative to one another. Retaining components of the device 400, such as the fluid connection 410, air input 420, and extraction port, in place facilitate consistent engagement by a robotic device. The external housing may have one or more engagement features to facilitate mounting the device within a bioprocessing system (e.g., as held in a tubing clip) or to facilitate manipulation of the device 400 by a robotic device. Alternatively, or additionally, multiple sampling devices may be held within a single cartridge (e.g., a sampling cartridge), allowing the sampling devices to be easily loaded into a bioprocessing system by a user and then moved around the bioprocessing system by the robotic device 5. For example, the sampling cartridge may comprise a housing configured to hold one or more of the devices 400 (e.g., 10 devices 400), which may be used one at a time as needed within the bioprocessing system.

[0149] It will be appreciated that any of the components described above (e.g., sampling tube 432) may be comprised of several components joined together. Figure 7B shows an exploded view of device 400, with the individual parts provided by the components shown in Table 1.

[0150] [Table 1]

[0151] The soft PVC welded pillow 465 may be attached to the Y-connectors 474, 476 using, for example, cyanoacrylate adhesive bonds.

[0152] The arrangement of components shown in Figure 7B is purely exemplary, and the shape of device 400 may be modified. For example, Figure 7C shows an alternative configuration of device 400 in which fluid connection 410 and air input 420 are positioned adjacent to each other.

[0153] Tube Clip An example of a tube clip 500 will now be described with reference to Figures 8A and 8B. Figure 8A shows the tube clip 500 when assembled, and Figure 8B shows an exploded view of the tube clip 500, revealing the internal components. As shown, the components are generally assembled using a number of screws 590. However, for clarity of illustration, not all of these screws 590 are labeled.

[0154] The tube clip 500 comprises a body 510 that may facilitate attachment of the tube clip 500 to other portions of a bioprocessing system, such as the tube connection section 300 described above.

[0155] Tube clip 500 has a tube sheet 520 with a contour shaped to receive a tube in place on tube sheet 520. In this example, the contour is substantially "C" shaped. Alternatively, the contour may be generally "V" shaped, rectangular, semicircular, or any other suitable shape for holding and receiving a tube in place. Tube sheet 520 is attached to upper surface 510a of body 510, for example, by one or more screws.

[0156] Tube clip 500 also has a retaining element 530 including a retaining arm 531. Retaining element 530 can be moved to move retaining arm 531 relative to tubesheet 520 between an open position to allow a tube to be received by tubesheet 520 and a closed position to hold the tube in place on tubesheet 520. Retaining arm 531 can have a step (or stepped portion) so that tubes of different diameters can be used with the same tube clip 500. Retaining arm 531 can be hooked.

[0157] Preferably, the tubesheet 520 comprises a first (upper) portion 522 and a second (lower) portion 524, the upper and lower portions 522, 524 of the tubesheet 520 being spaced apart parallel to the axis of the tubes with a gap within which the retaining arms 531 are positioned to contact the tubes. In this manner, the retaining arms 531 apply symmetrical forces to the tubes to prevent bending while the tubes are engaged.

[0158] The tube clip 500 also includes an actuator 540 configured to move the retaining arm 531 between an open position and a closed position. The actuator 540 is controllable to move the retaining arm 531 between a plurality of intermediate positions, allowing tubes of different diameters, such as 4 mm or 6 mm tubes, to be properly engaged (and / or clamped) by the tube clip 500. Furthermore, in each of the intermediate positions, the retaining arm 531 may apply a different force to the tube contacted against the tube sheet 520, thereby controlling fluid flow through the tube. For example, the closed position may apply a force that completely clamps the tube (i.e., occludes the tube) and prevents any fluid flow through the tube. An intermediate position may firmly hold the tube, restricting (but not blocking) fluid flow through the tube. Another intermediate position may lightly hold the tube without substantially restricting fluid flow through the tube. Preferably, the actuator 540 may move the retaining arm 531 through a continuous range of positions to apply a continuous range of forces to the held tube.

[0159] Actuator 540 is housed within body 510. Actuator 540 connects to retaining element 530 by shaft 542, which extends from top surface 510a of body 510. Actuator 540 is preferably a motor, which imparts rotational motion to shaft 542, thereby rotating retaining arm 531 to move between the open and closed positions. Retaining element 530 may be biased by spring 534 to counter the force applied by actuator 540. In this manner, retaining arm 531 is automatically moved to the closed position when actuator 540 is disengaged. More specifically, spring 534 pulls retaining arm 531 to the closed position to engage (but not pinch) the tube. This provides a fail-safe against dropping the tube, and actuator 540 only needs to be controllable to rotate in one direction.

[0160] In addition to the rotational movement of the retaining element 530, a force from the actuator 540 is transmitted to the retaining element 530 by a cam element 528 (referred to herein as a "pinch cam"), causing the retaining arm 531 to also move laterally as it moves between the open and closed positions. The pinch cam 528 is mounted within an opening 525 in the tubesheet 520. A first bearing 526 is provided within this opening 525 to facilitate smooth movement of the pinch cam 528 relative to the tubesheet 520. The pinch cam 528 has a lobe-shaped portion such that, as the retaining element 530 continues to rotate (e.g., to bring the retaining arm 531 in front of the tubesheet 520), the retaining arm 531 subsequently moves laterally toward the tubesheet 520, compressing the tube between the retaining cam 531 and the tubesheet 520. A spring 534 also limits this lateral movement.

[0161] A cap 544 may be provided for mounting the retaining element 530 and the tube sheet 520 to the body 510 via the shaft 542. To facilitate smooth movement of the retaining element 530 relative to the cap 544, an opening 535 may be provided in the retaining element 530, and a second bearing 536 may be provided within the opening 535.

[0162] Cam 528 is mounted directly to actuator 540 and supported by first bearing 526. The top of cam 528 fits into second bearing 536 and is offset from the center of rotation of actuator 540. As a result of this offset, retaining element 530 is moved laterally as cam 528 rotates. The opposite face of the lobe of cam 528 has an arm drive with a vertically protruding tab that engages retaining element 530. Thus, as cam 528 rotates, retaining element 530 and retaining arm 531 also rotate.

[0163] The tube clip 500 may also include a tube guide 550. The tube guide 550 may include a second tube sheet 551 longitudinally offset (i.e., offset along the axis of the received tube) from the first tube sheet 520. The tube guide 550 may also include a front fin 552 positioned to extend adjacent to the tube along the longitudinal axis. In this manner, the tube guide 550 helps hold the tube along a predetermined axis, thereby improving consistent engagement of the held tube by an external robotic device. The front fin 552 may continue to support the tube during the engagement process because it is thinner than the spacing between the jaws of the robotic device when they grip the tube. The tube guide 550 may be attached to the front surface 510b of the body 510 of the tube clip 500 by one or more screws 590 (only some of the screws are labeled).

[0164] The tube clip 500 may include at least one sensor for detecting one or more of the presence of a portion of tubing within the tube clip 500 and / or whether the portion of tubing held within the tube clip 500 contains fluid. For example, the at least one sensor may be an air bubble sensor 560 disposed on the front surface 510b of the body 510 of the tube clip such that the longitudinal axis of the held tubing passes through the air bubble sensor 560. The air bubble sensor 560 is configured to detect whether the tubing is wet or dry.

[0165] The at least one sensor may include a force sensor (not shown) that senses the force (e.g., torque) applied to the tube by the retention arm, thereby indicating whether a tube is present within the tube clip 500. The combination of the air bubble sensor 560 and the force sensor allows the tube clip 500 to determine whether a tube is present and whether the tube is wet or dry. The force sensor may be connected in a control loop to the actuator 540, thereby allowing a precise force to be applied to the tube. This is particularly advantageous when different sizes of tube may be used within the tube clip 500, because the actuator 540 can clamp with a predetermined, consistent force (regardless of tube size), allowing for consistent engagement.

[0166] Tube clip 500 may include processor 580, which is housed within body 510. Processor 580 may receive external commands, such as commands to operate actuator 540 to move retention arm 531 between an open position, a closed position, and a plurality of intermediate positions. Processor 580 may receive measurements from at least one tube sensor. These measurements may be recorded by the processor and / or transmitted externally. As described above, a force sensor may be connected to actuator 540 in a control (feedback) loop, thereby allowing a precise force to be applied to the tube.

[0167] Alternative Sampling and Purging Devices Next, some alternative sampling / purging devices and methods are briefly described.

[0168] Figure 9A shows a first method for extracting a sample from a cytological consumable, referred to as the "upstream" option. Here, an air source can be incorporated into the line and used to generate a "slug" of fluid within the tubing. The tubing can then be sealed, and the sample removed. The steps can proceed as follows: (1) Install and mechanically weld the cytological consumable; (2) Install and weld a sampling device onto the tubing (or an additional length of tubing); (3) Pump fluid until a volume of fluid to be sampled exceeds the valve, then activate the valve and continue pumping to force air into the line and pump a "slug" into the sampling device; (4) Seal the sample; and (5) Repeat steps (2)-(4) to generate subsequent samples. This process is deterministic, maintains relatively short tubing lengths, allows for variable volume samples to be collected (slug length depends on the amount of pumping), and provides flexible output vessel selection.

[0169] Figure 9B shows a second method for extracting samples from cell consumables, called the "post-hoc" option. Here, an air source is repeatedly welded onto a new sample line after a sample is taken. The steps proceed as follows: (1) Weld the sample along with the filter; (2) Pump the sample; (3) Weld the sample section and replace it with a new section; and (4) Return the air and purge the line. This process is generally simple. However, because the weld line keeps changing, sampling can be difficult when many samples are taken. Furthermore, it is difficult to maintain short tubing lengths and accurately control the sample volume. Similarly, to achieve flexibility in the output sample container, the welds must be predefined (welds on two sides).

[0170] Figure 9C shows a third method for extracting a sample from a cytological consumable, called the "consumable-integrated" option. The steps proceed as follows: (1) Weld sample; (2) Optionally, purge tubing; (3) Pump into sample container; and (4) Seal. This is relatively simple, with the only constraint being that the sample container be pre-welded. While this option is deterministic, it can be difficult to extract samples. This option keeps the tubing relatively short, allowing for variable volumes to be extracted (although this can be difficult for smaller samples). Flexibility of the output sample container can also be difficult due to the presence of air forming an air spring that resists fluid movement.

[0171] Figure 9D shows a fourth method for extracting samples from cytological consumables, referred to as the "top air line with expandable volume" option. Here, continuous tubing is provided to an air source (air filter or expandable volume), which includes an offchute (e.g., a bag or syringe) that provides a sealable, expandable volume. The steps proceed as follows: (1) Install and weld the sampling device; (2) Unblock the offchute containing the sample; (3) Pump into the selected offchute (preferably with the tubing to the air source blocked); (4) Seal and remove the selected offchute. While this option is not particularly simple, it keeps tubing lengths reasonably short, allows for variable fluid sample volumes, and provides versatility in the output container.

[0172] Figure 9E shows a fifth method for extracting samples from cell consumables, called the "pinch valve manifold" option. The "pinch valve manifold" option is a variation of the "top air line with expandable volume" option. Here, a pinch valve is provided on the off-chute.

[0173] Figure 9F shows a sixth method for extracting samples from the cell consumable, called the "sampling line drawdown" option. Here, a fixed length of tubing is pre-loaded onto a spool with a filter. Because the tubing length can be increased, the spool can be used to collect multiple samples. The steps proceed as follows: (1) Connect the end of the tubing to the cell consumable. (2) Pump a fixed volume of fluid from the cell consumable into the tubing. (3) Seal the tubing on each side of the fixed volume of fluid and remove the sealed portion of the tubing. (4) Pump the remaining fluid out the (new) end of the tubing.

[0174] Figure 9G is a further variation of the "sampling line drawdown" option. Here, a chain of consumables may be provided with a wider inner diameter (e.g., 5 mm to provide 5 cm of sample per ml). The chain may have pre-installed ports at regular intervals or may have built-in check valves and connectors. This option offers more structure than the option in Figure 9F, but increases manufacturing complexity.

[0175] While the foregoing is directed 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 may be made within the scope of the present invention. Moreover, those skilled in the art will understand that the present invention may not be limited by the embodiments disclosed herein or to the details shown in the accompanying drawings, which are not described in detail herein and are not defined in the claims. Indeed, such superfluous features may be omitted from the drawings without prejudice to the invention.

[0176] Moreover, other and further embodiments of the invention will become apparent to those skilled in the art upon consideration of this specification and can be conceived without departing from the basic scope of the invention as determined by the appended claims. [Explanation of symbols]

[0177] 1. Bioprocess Equipment 1a Front 5. Robotic Devices 20 Storage System 22 storage slots 22a, 22b storage slots 23 Refrigerator 26 Media Storage Section 30, 30', 30-1, 30-2, 30-3, 30-4 Fluid Connection System 31 Consumables Storage Section 31a First Subsection 31b Second subsection 31c Third subsection 32 transport slots 34 Cell Consumables Storage Section 35 Bioreactor Platform 40 Incubator System 43 Incubation Chamber 45 Incubation Platforms 80, 80-1, 80-2, 80-3, 80-4 Air supply source 81 Manifold 85 Intermediate tube 90 sampling units 95 Sample Container 100 cartridges 100-1, 100-2, 100-3, 100-4 Cartridges 120 First Part 130 Second Part 131 tube clips 150-1, 150-2, 150-3, 150-4 Consumables 155 tubes 155-1, 155-2, 155-3, 155-4, 155-5 Tubes 155a free end 254 Removable Cap 250 cell consumables 255 tubes 255-1 First Tube 255-2 Second Tube 255-3 Third Tube 255a tube 300 Tube Connection Section 300a First portion, upper edge 300b Second portion, lower edge 355-1, 355-2 Jointed tubes 400 Sampling Devices 410 Fluid Connection 412 Fluid Connection Tube 413 First Junction 420 Insertion section 423 Second Junction 430 Sampling section 432 Sampling tube 432a first end 432b second end 434 Sample Container 435 First check valve 440 Bypass section 442 Bypass Tube 442a first end 442b second end 445 Second check valve 465 Soft PVC Welded Pillow 474, 476 Y connector 500, 500a, 500a-1, 500a-1', 500b, 500b-1, 500b-1' Tube Clips 510 main unit 510a top side 510b front 520 tube sheet 522 First (Upper) Part 524 Second (lower) part 525 Opening 528 Cam element, pinch cam 530 Holding Element 531 Holding Arm 534 Spring 536 Opening 540 Actuator 542 Shaft 544 Cap 550 Tube Guide 551 Second Tube Sheet 552 Front Fin 560 Air Bubble Sensor 580 processor 590 Screw

Claims

1. A device for collecting a fluid sample from a consumable containing a fluid in a bioprocess system, wherein a tube is fluid-coupled to the consumable, and the device is A fluid connection part connected to the tube of a consumable containing fluid, and configured to enable the pumping of fluid or air through the device, An air inlet unit configured to enable the supply of sterile air to the device, A sampling unit connected to the fluid connection unit, wherein the sampling unit is configured to receive a fluid sample from the consumable via the fluid connection unit while pumping into the device, A bypass tube having a first end connected to the fluid connection section and a second end connected to the air injection section, wherein the bypass tube is configured to receive air supplied from the air injection section, send the air from the device through the fluid connection section so as not to pass through the sampling section, and thereby purge fluid from the tube connected to the consumables, A device comprising means for restricting the fluid flow through the sampling section and the bypass tube, respectively, such that the fluid pumped into the fluid connection section flows only into the sampling section, and the air pumped from the fluid connection section passes only through the bypass tube.

2. The device according to claim 1, further comprising a sampling tube having a first end connected to the fluid connection portion and a second end connected to the air injection portion, wherein the sampling portion is provided between the first end and the second end of the sampling tube.

3. The device according to claim 2, wherein the sampling unit is comprised of a sample container disposed between the first end and the second end of the sampling tube.

4. The device according to claim 3, wherein the sample container has a tapered shape.

5. The device according to claim 1, wherein the sampling unit is provided with an extraction port for removing the fluid sample from the sampling unit.

6. The device according to claim 1, wherein the means for restricting the fluid flow through the device comprises a check valve for allowing fluid to flow from the fluid connection portion into the sampling portion.

7. The device according to claim 6, further comprising a sampling tube having a first end connected to the fluid connection portion and a second end connected to the air injection portion, wherein the sampling portion is provided between the first end and the second end of the sampling tube, and the check valve is located on the sampling tube between the sampling portion and the air injection portion.

8. The device according to claim 1, wherein the means for restricting the fluid flow through the device comprises a check valve for allowing air to flow through the bypass tube from the air inlet to the fluid connection.

9. The device according to claim 1, wherein the fluid connection portion comprises a flexible tube of a certain length, thereby enabling the connection of the consumable to the tube by tube welding.

10. The device according to claim 1, wherein the air intake section is an air filter configured to supply sterilized air from the surroundings.

11. The device according to claim 1, wherein the air supply unit comprises a container for sterile air.

12. The device according to claim 1, wherein the air injection unit is a single air injection unit connected to both the sampling unit and the bypass tube.

13. The device according to claim 1, further comprising an external housing.

14. A sampling cartridge comprising a housing, wherein the housing is configured to hold one or more of the devices described in claim 1.

15. A method for collecting a fluid sample using the device described in Claim 1, The steps include connecting the fluid connection part to the tube connected to the consumable, The steps include: pumping fluid from the consumables into the sampling section of the device via the fluid connection section; A method comprising the step of pressurizing the fluid remaining in the tube and returning it to the consumable, thereby drawing air into the tube from the air inlet via the bypass tube.

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