Automated Fill / Finish System

Abstract

1. A closed system for mixing fluids for use in a bioprocessing system, comprising: automated means for manipulating a tube weld between a first tube fluidly connected to a first consumable and another tube fluidly connected to a mixing consumable, the tube weld forming a closed fluid connection between the first consumable and the mixing consumable; automated means for transferring a first fluid contained by the first consumable through the fluid connection to the mixing consumable; and automated means for determining an amount of fluid transferred to or from the mixing consumable, wherein the system is further configured to manipulate a tube weld between a second tube fluidly connected to a second consumable and the other tube fluidly connected to the mixing consumable, and transfer the second fluid between the second tube and the other tube to mix with the first fluid in the mixing consumable.

Description

[Technical Field]

[0001] The present disclosure relates to an automated fill / finish system for use in, for example, an automated bioprocessing system to perform fill / finish of final drug product and consumable bags prior to cryopreservation. [Background technology]

[0002] Bioprocessing plays a vital role in many industries, including pharmaceuticals, food, biofuels, and other major sectors. As the bioprocessing industry continues to grow, it is not surprising that there is an increasing reliance on bioprocessing technologies, including bioprocessing systems.

[0003] For example, bioprocessing is used in autologous cell therapy, a promising type of therapy with significant clinical and commercial potential, ranging from treating cancer to repairing genetic defects. These therapies involve removing cells from a patient, manipulating them over a period of days to weeks, and reintroducing the cells into the patient's body to produce a therapeutic effect. The steps taken during autologous cell therapy are often complex; for example, a typical CAR-T process may involve a sequence of steps beginning with thawing cryopreserved white blood cells, followed by washing to remove DMSO, T-cell enrichment, activation, transduction, expansion, concentration, formulation filling / finishing into IV bags, and cryopreservation, along with several other intermediate washing steps.

[0004] Because bioprocessing is complex, it is desirable to automate the process while maintaining a closed system that eliminates the need to perform each step in such sophisticated clean rooms. A closed system is one that does not expose the process to the ambient environment and therefore cannot introduce contaminants from the environment or cross-contaminate from other processes being performed simultaneously. Some systems attempt to provide a solution for this, involving complex consumables, such as connecting a sample to all other necessary processing stations via tubing fluidly connected to the consumable, and providing pumping and valving to enable each step to be performed in a specific sequence. The term "consumable" is sometimes used to refer to any container, such as an IV bag, that contains a sample, such as a fluid. The fluid may include one or more of a cell sample, a reagent, a cryoprotectant, or any other variety of fluids. However, these consumables are complex to manufacture and install, and therefore relatively expensive and, in some cases, unreliable. Each consumable must be individually tailored to the process being performed, making the system inflexible to modifications and costly to adapt to new processes. Indeed, the challenge with automating such a system is how to provide a system that is amenable to modification and that can form secure connections between consumables and other fluid containers while also maintaining a sterile, closed system.

[0005] Tube welding can be used to form fluid connections between tubes that connect to respective containers (i.e., "consumables"). Sterile tube welding machines allow two tubes with closed ends to be connected without exposing the contents of each tube to the environment, and they are the only widely accepted means of forming reusable connections within a single system. However, tube welding requires precise manipulation to properly insert the tubes into the welder and visual inspection by the operator after each weld to confirm a successful weld.

[0006] Tubing connected to consumables typically moves freely, creating problems for automated bioprocessing systems because it is difficult for automated bioprocessing systems to position the tubing and its end when inserting it into a welding machine. Furthermore, tube welding requires long lengths of tubing, which can tangle the tubing within the system and / or interfere with other components within the system. Therefore, due to the substantial complexity and stringent reliability requirements associated with applying tube welding to bioprocessing systems, little progress has been made in automating bioprocessing systems that utilize tube welding. Furthermore, in cases such as autologous cell therapy, the use of consumables is particularly challenging to incorporate into automated bioprocessing systems because the consumables are soft and flexible and change stiffness based on the volume of fluid held within the consumable. These characteristics make it difficult for automated systems to accurately hold and position the consumables during processing.

[0007] One challenge faced when automating bioprocessing methods is the final "fill / finish" step, in which the cellular drug is mixed with a cryoprotectant and dispensed into multiple "removal consumables" before being frozen for storage and transport. After the cellular drug is mixed with the cryoprotectant, the removal consumables must be frozen for only a short time (approximately one hour) before the cryoprotectant can damage the cells. Due, at least in part, to the aforementioned difficulties associated with handling and connecting tubing while maintaining a closed system, existing systems typically pre-connect the removal consumables to a mixing chamber. However, this can limit the number of removal consumables to approximately 10, resulting in low space efficiency and inflexibility for scaling and modifying the process. Furthermore, there is a risk of cross-contamination, and there is no easy way to verify that contamination has not occurred. Summary of the Invention [Problem to be solved by the invention]

[0008] For the above reasons, there is a need for an automated system that can efficiently handle and process consumables while maintaining a closed environment. [Means for solving the problem]

[0009] Described herein is a closed system for mixing fluids (e.g., reagents) used in a bioprocessing system, comprising: automated means for manipulating a tube weld between a first (e.g., flexible) tube fluidly connected to a first consumable and another (e.g., flexible) tube fluidly connected to a mixing consumable, wherein the tube weld forms a closed fluid connection between the first consumable and the mixing consumable; automated means for transferring a first fluid contained by the first consumable to the mixing consumable via the fluid connection; and automated means for determining the amount of fluid transferred to or from the mixing consumable, wherein the system is further configured to operate a tube weld between a second tube fluidly connected to a second consumable and another tube fluidly connected to the mixing consumable, and transfer the second fluid between the second tube and the another tube to mix with the first fluid in the mixing consumable.

[0010] Such a system reduces the loading and unloading time of consumables compared to prior art systems. This is advantageous when mixing the contents of the consumables, because the faster the process must be performed, the more likely the mixture may separate, or, for example, the cryoprotectant may be harmful to the cell sample. Manipulating the fluid connections between the consumables reduces internal contamination and the need for additional labor to perform this step. Advantageously, the system can be configured as an automated fill / finish system for a bioprocessing system. The fill / finish system can be configured to mix a cellular drug contained in a first consumable with a cryoprotectant contained in a second consumable.

[0011] Preferably, at least a portion (e.g., an end) of the first tube is flexible. Similarly, at least a portion (e.g., an end) of the "another" tube is preferably flexible. Indeed, each portion (e.g., an end) of the tube that is manipulated (as described herein) to form a fluid connection is preferably flexible. Thus, the tube may be referred to as "flexible tubing," and this term may also include portions of the tube, such as ends, that are flexible.

[0012] As used herein, the terms "automated" or "autonomous" preferably connote that a particular system or step may be automatically operated and / or controlled by automation, e.g., without the need for human intervention. For example, a closed system may follow an automated sequence of operations.

[0013] As used herein, the term "closed system" may connote a functionally closed system, or more preferably a completely closed system, in which a physical barrier is maintained between the contents of the consumable and its surroundings, such as other parts of a bioprocessing system. In this way, the risk of contamination of the consumable or its surroundings is reduced.

[0014] The means for determining the amount of fluid transferred to or from the mixed consumable may monitor a characteristic of the mixed consumable, such as the weight of the mixed consumable or the volume of fluid contained in the mixed consumable. Alternatively, or additionally, the means for determining may monitor a characteristic of a different consumable, such as the first and second consumables and / or the removal consumable that receives fluid from the mixed consumable. Alternatively, or additionally, the means for determining the amount of fluid may monitor the flow rate of fluid through one or more of the fluid-connected tubes. Advantageously, the means for determining may allow precise volumes of fluid to be pumped between the consumables. For example, it is advantageous for the removal consumable to contain a precise volume of the mixture.

[0015] The automated means for manipulating the tube weld may be configured to form a closed, sterilized, and / or sterile tube weld between each tube of the two consumables. In other words, the "means for manipulating" may comprise a "tube welder" or a "tube welding device."

[0016] The automated means for manipulating the tube weld may further comprise means for engaging and / or positioning the tube, at least a portion (eg, an end) of the tube preferably being flexible.

[0017] The automated means for transferring may be configured to transfer fluid between two fluidly connected consumables via tubing welded to form the fluid connection. The automated means for transferring fluid may comprise a pumping arrangement configured to apply a pumping action, preferably a peristaltic pumping action, to at least one of the tubing forming the fluid connection. In other words, the means for transferring fluid may be a "peristaltic pump."

[0018] The system (e.g., automated means) may be further configured to manipulate a tube weld between a tube fluidly connected to the mixing consumable and a tube fluidly connected to the removal consumable to transfer (at least a portion of) the mixture (e.g., of the first fluid and the second fluid) contained in the mixing consumable to the removal consumable. The system may further comprise automated means for severing the fluid connection between the two consumables.

[0019] The system may further include automated means for sealing each tube after fluid transfer to and from the mixing consumable is complete. The automated means for sealing may be an RF sealer or a heat sealer. The automated means for sealing may also provide means for severing the fluid connection between the two consumables. The automated means for sealing may be configured to seal the tubing connected between the mixing consumable and the first consumable and / or the second consumable. Alternatively, the first consumable and the second consumable may remain connected to the mixing consumable after fluid transfer to the mixing consumable is complete. The automated means for sealing may be configured to seal other consumables, such as a removal consumable containing the mixture transferred from the mixing consumable. In this manner, the filled removal consumable may be removed from the system.

[0020] The automated means for manipulating the tube weld may further comprise means for engaging and / or positioning the tube, wherein at least a portion (e.g., an end) of the tube is preferably flexible. Alternatively, or additionally, at least a portion of the first tube fluidly connected to the first consumable is held at least partially along a predetermined path.

[0021] By holding a portion of the tubing along a predetermined path, the tubing can be reliably engaged by a robotic device at any location along the predetermined path. As used herein, the term "predetermined path" preferably indicates that the position of the tubing is known at one location, and preferably at multiple locations, along its length, thereby defining a known path between the known locations. It will be appreciated that it is not required that the entire tubing have a predetermined path, provided that at least a portion of the tubing has a sufficiently known path to allow it to be reliably engaged by an automated system (e.g., a robotic device).

[0022] The known position may be defined relative to other components in the system, such as an element having a fixed position (e.g., a tube-holding element having a known position), and / or may be defined by one or more identifying marks on the tube. More preferably, the position of the tube is known along at least one continuous length of the tube. The predetermined path may include one or more linear path segments, which may be established by holding the tube between one or more pairs of tube-holding elements, whereby the tube is substantially aligned along a known axis.

[0023] The system may include an automated processing station, and more preferably, a standalone automated processing station. As used herein, the term "processing station" preferably connotes a station of a bioprocessing system configured to perform a particular portion of a bioprocessing method, such as a fill / finish operation. A processing station may be located at a fixed location within the bioprocessing system during the bioprocessing method. As used herein, the term "standalone" preferably connotes that the processing station is self-contained and can perform operations, such as a fill / finish operation, without external intervention. Alternatively, a processing station may interact with other robotic devices, and such robotic devices may move around the bioprocessing system. As used herein, the term "automated" preferably indicates that at least one process is performed autonomously by the processing station. An autonomous process may occur without operator intervention and may be defined according to a bioprocessing workflow.

[0024] At least one of the automated means for manipulating the tube weld, the automated means for transferring fluids, and the automated means for sealing may be provided on the processing station. Alternatively, at least one of the automated means for manipulating the tube weld, the automated means for transferring fluids, and the automated means for sealing are provided on a separate mobile unit (e.g., a "mobile manipulation unit") configured to automatically cooperate with the processing station. The system may include multiple mobile manipulation units, each of which may be capable of performing one or more of the manipulation, transfer, sealing, and / or cutting operations in the bioprocessing system. Preferably, at least one of the automated means for manipulating the tube weld, the automated means for transferring fluids, and the automated means for sealing comprises a robotic device, such as a robotic arm having an end effector configured to perform one or more of the operations (i.e., the manipulation, transfer, sealing, and / or cutting operations).

[0025] The automated means for transferring may comprise a pumping arrangement configured to apply a pumping action, preferably a peristaltic pumping action, to at least one of the tubes forming the fluid connection. The system may further comprise automated means for severing the fluid connection between the two consumables.

[0026] The system may further comprise an automated means for mixing the first and second fluids in the mixing consumable, for example, the system may further comprise a mixing system provided on the processing station.

[0027] The means for mixing may include an automated mixing system, which may include a mixing zone positioned so that the mixing consumable receives the first fluid and the second fluid from the first consumable and the second consumable, respectively. The mixing system may include means for agitating the mixture of the contents of the first consumable and the second consumable.

[0028] The means for agitation may include a roller configured to be rolled over the mixing consumable and / or a rocker plate configured to rock the mixing consumable, thereby promoting mixing of the first and second fluids. The means for agitation may include an ultrasonic source, a vibration source, and / or an orbital shaker. The mixing system may include means for controlling the temperature of the mixing consumable, such as a Peltier device or plate configured to cool the mixing consumable located within the mixing zone.

[0029] The processing station may include a plurality of slots configured to hold (e.g., releasably) the first consumable, the second consumable, and the removal consumable. Preferably, the slots are positioned adjacent to the mixing system to facilitate manipulation of the first consumable, the second consumable, and the tube welds between the removal consumable and the mixing consumable. The slots may be arranged in a linear array. The slots may be positioned above the mixing system. The first consumable, the second consumable, and the removal consumable may each be provided on a device described herein, thereby allowing any of the consumables to be added, held, and / or removed from any of the slots. The slots may be positioned on a front surface of the processing station, such as to allow manipulation of the consumables by a robotic device.

[0030] The robotic device may be part of a processing station or may be a separate robotic device that is movable relative to the processing station (e.g., a mobile unit or "mobile manipulation unit"). If the robotic device is a mobile manipulation unit, the mobile manipulation unit may be capable of autonomously moving around the floor of the bioprocessing system to access the processing stations, or the mobile manipulation unit may be mounted on a rail (or network or multiple rails) to facilitate movement around the bioprocessing system.

[0031] The mobile unit may be configured to feed at least one of the first consumable and the second consumable to the plurality of slots to facilitate supply of at least one of the first fluid or the second fluid to the mixing system. The mobile unit may be configured to perform a handling operation, a transfer operation, a sealing operation, and / or a cutting operation. The handling operation, the transfer operation, the sealing operation, and the cutting operation may be performed by the same robotic device (such as the same mobile operation unit). Alternatively, these functions may be performed by different robotic devices, which may be part of the processing station or may be a unit separate from the processing station (i.e., a second mobile operation unit). For example, the first mobile operation unit may feed (and / or remove) consumables to (or from) the plurality of slots, and the second mobile operation unit (or a robotic device that is part of the processing station) may operate tube welds, transfer fluids, and seal and / or cut tubes. Preferably, each mobile manipulation unit is capable of performing all of the feeding, handling, transferring, sealing and cutting operations, although it will be appreciated that in use these tasks may be divided between different robotic devices, such as between different mobile manipulation units.

[0032] The processing station may include a (first) automated transport system configured to deliver at least one of the first consumable and the second consumable to the mixing system to supply at least one of the first fluid or the second fluid to the mixing system. The first automated transport system may be referred to as an intake transport system.

[0033] The automated delivery system may be further configured to deliver both the first consumable and the second consumable to the mixing system to provide both the first fluid and the second fluid to the mixing system.

[0034] The intake transport system may deliver other consumables, such as empty intake consumables, to the mixing system.

[0035] The processing station may further include a (second) automated transport system configured to remove the unloading consumable from the mixing system after it has been filled with the resulting mixture of the first and second fluids. The second automated transport system may be referred to as the unloading transport system. The unloading transport system may remove other consumables, such as empty first and second consumables, from the mixing system.

[0036] The or each automated transport system may be configured to position the consumables to be engaged by a means for manipulating a tube weld between the respective consumables and the mixing system. The transport system may include a motorized rail configuration in which the consumables are suspended from rails and can be moved along the rails via motorized tracks. The or each automated transport system may be used with one or more robotic devices and / or one or more of the mobile manipulation units described above. The system may be configured to hold the consumables and their corresponding tubes in one or more predetermined positions, such that the means for manipulating the tube weld (such as a robotic device) can securely engage the tubes at the predetermined positions or along a predetermined path. For example, the system may be configured to engage a tube with a consumable held within a device described herein, the device being configured to hold the tube at least partially along a predetermined path.

[0037] The system may further comprise means for identifying an identification mark on at least one of the consumables.The system may further comprise one or more sensors configured to measure one or more parameters of the consumables.

[0038] Also provided herein is a closed system for mixing (e.g., reagent) fluids for use in a bioprocessing system, comprising automated means for mixing a first fluid contained by a first (e.g., "uptake") consumable and a second fluid contained by a second (e.g., "uptake") consumable in a third (e.g., "mixing") consumable, and then loading the resulting mixture of the first and second fluids into a fourth (e.g., "outtake") consumable, each consumable configured to form (at least a portion (e.g., end) of) a fluid conduit to one or more fluids contained by the consumable. and automated means for manipulating a closed fluid connection between the two consumables to transfer a fluid between the two consumables; automated means for transferring a fluid between the two fluidly connected consumables; automated means for determining a weight of a volume of the resulting mixture of the first and second fluids transferred to a fourth consumable; and automated means for sealing a portion of each tubing such that one or more fluids in the consumables can be sterilely sealed from the surrounding environment before severing the fluid connection operated between the two consumables.

[0039] Also disclosed herein is a method of mixing fluids for bioprocessing, comprising mixing two or more fluids using and / or within a closed system as described above and herein.

[0040] Also described herein is a method for mixing fluids (e.g., reagents) within a closed system for use in a bioprocessing system, the method comprising the steps of: mixing a first fluid contained by a first consumable and a second fluid contained by a second consumable within a mixing consumable, and then loading the resulting mixture of the first and second fluids into a take-out consumable, each consumable comprising tubing (at least a portion (e.g., an end) of which is preferably flexible) configured to form a fluid conduit to one or more fluids contained by the consumable; operating a fluid connection between two of the consumables to transfer fluids between the consumables; determining a weight of the volume of the resulting mixture of the first and second fluids transferred to the take-out consumable; and sealing a portion of each tubing to isolate one or more fluids within the consumable from the surrounding environment before severing the fluid connection operated between the two consumables.

[0041] Preferably, one or more of the above-mentioned "mixing" step, "operating the fluid connection" step, "determining the weight" step, and "sealing the portion" step are performed autonomously, and more preferably, all of these steps may be automated, and thus the method may be described as an "automated method."

[0042] Also described herein is a device for holding a consumable (e.g., a bag) for use in an automated bioprocessing system, the consumable having at least one flexible tube fluidly connected thereto, the device comprising a first portion for holding the consumable and a second portion configured to hold the flexible tube, the second portion configured to hold the flexible tube at least partially along a predetermined path.

[0043] By holding a portion of the tubing along a predetermined path, the tubing can be reliably engaged by a robotic device at any location along the predetermined path. As used herein, the term "predetermined path" preferably indicates that the position of the tubing is known at one location, and preferably at multiple locations, along its length, thereby defining a known path between the known locations. It will be appreciated that it is not required that the entire tubing have a predetermined path, provided that at least a portion of the tubing has a sufficiently known path to allow it to be reliably engaged by an automated system (e.g., a robotic device).

[0044] The known position may be defined relative to other components of the device, such as an element having a fixed position (e.g., a tube retaining element or means for engagement), or may be defined by one or more identifying marks on the tube. More preferably, the position of the tube is known along at least one continuous length of the tube. The predetermined path may include one or more linear path segments, which may be established by retaining the tube between one or more pairs of tube retaining elements, thereby aligning the tube substantially along a known axis.

[0045] Advantageously, the first portion provides a means for holding the consumable, which is typically a soft, flexible, fluid-filled bag, and the first portion supports the consumable. Furthermore, the second portion provides a means for holding at least one flexible tube, thereby reducing the free movement of the tube so that one or more positions of the flexible tube along a predetermined path are known. Thus, in effect, by following a predetermined path, a system (such as the systems described above and herein) that is programmed to know or recognize the predetermined path also knows the position of the held portion of the flexible tube. In this manner, the flexible tube is subject to manipulation by the system. This manipulation may include, for example, welding the flexible tube to another tube by an automated robotic arm, which requires the system to find, grasp, and manipulate the end of the tube. For example, the device may be located in a slot, storage section, or transport system of the systems described above and herein. In use, an automated means for manipulating a tube weld (such as a tube welder on a robotic arm) can engage tubes along a predetermined path, thereby creating a fluid connection and subsequent fluid transfer. In existing systems, engaging tubes can be particularly difficult because, due to the flexibility of the tubes, they generally may not be located at well-defined positions in space. Thus, connections made between flexible tubes can be unreliable.

[0046] The first portion may comprise a structure configured to hold the consumable. Advantageously, the structure supports the consumable, thereby reducing the flexibility of the consumable. The structure may be rigid.

[0047] The structure may be configured as a tray with multiple sides defining a recessed portion within which the consumable is held. The tray provides additional support for the consumable by securely holding the consumable. In this manner, the consumable maintains a relatively fixed shape. Because the consumable is held within the tray, varying stiffness based on the volume of fluid within the consumable no longer adversely affects the function of the system, since the tray is movable and can be easily moved between various positions.

[0048] At least one of the sides defining the recessed portion may have a groove, slot, or hole for the tube to pass through. This allows a portion of the tube to be guided outside the tray without being deformed by the sides of the tray. This allows for consistent and reliable fluid communication between the tube and the consumable.

[0049] The second portion may include a frame. The second portion (e.g., the frame) may have at least one tube retention element configured to hold the tube in at least one position along the predetermined path. In this manner, the tube is securely held in position by the at least one tube retention element, thereby reducing undesired free movement of the flexible tube.

[0050] The tube retaining element may be any suitable means for retaining the portion of the tube, including a clip, hook, or clasp. The portion of the tube may be permanently retained by at least one tube retaining element or may be removably secured thereto.

[0051] The second portion (e.g., the frame) may have a plurality of tube retaining elements configured to retain the tube at a plurality of positions along the predetermined path. This further reduces undesirable free movement of the flexible tube by securely retaining the flexible tube at a plurality of positions. At least one of the plurality of positions may be identifiable by an identification mark, such as a unique barcode, QR code, RF tag, and / or NFC tag. The identification marks may each be located at the same position as one of the plurality of retaining elements, and thus the positions along the predetermined path may be identified by a system, such as the closure system described above and herein, using a means for identifying the identification mark. In this way, the system knows the position of the retained flexible tube.

[0052] The frame may be configured as a lattice or grid. The lattice or grid may include a first set of parallel bars intersecting a second set of parallel bars at repeating intervals. The bars may have a rigid structure. The first and second sets of parallel bars may be perpendicular to each other. Advantageously, this configuration allows for easy mobility of an automated system; for example, an automated robotic arm may be programmed to move in translation (i.e., up and down), allowing it to easily move along the lattice or grid. Additionally, the grid forms a predetermined, winding path for at least one tube, thereby holding long tubes in a compact configuration and thereby providing a suitable base for saving space.

[0053] At least one tube retaining element can be configured to retain a tube at an intermediate position on the lattice or grid. The term "intermediate position" refers to a position substantially midway between two intersecting bars. In this manner, a robotic arm of an automation system can move between multiple positions along a predetermined path using only translational movement.

[0054] The second portion can be configured to provide a lid for the first portion, thereby holding the consumable between the first and second portions. The lid covering the consumable is useful for stacking multiple consumable holders on top of each other, thereby saving space. The consumables can be stacked in a closed system, such as in a storage section of a processing station. Additionally, the lid covering the consumable protects the consumable, thereby reducing the chance of damage to the consumable and reducing the risk of contamination.

[0055] The second portion may be slidable relative to the first portion, preferably parallel to the longitudinal axis of the first portion.

[0056] Alternatively, the second portion may be attached to the first portion using a hinge and configured to be movable between an open configuration and a closed configuration using the hinge. Preferably, an axis parallel to the plane of the first portion and an axis parallel to the plane of the lid are parallel to each other when in the open configuration, thereby improving accessibility of the flexible tubing and / or consumables by a robotic device. The robotic device may be programmed to move the consumable holder between the two configurations.

[0057] The second portion may be securable to the first portion in the closed configuration, which provides improved stability when multiple consumable holders are stacked and improved protection for the consumables within the holder when in the closed configuration.

[0058] The device may further comprise means for cooling the consumables held within the first portion. The means for cooling may comprise at least one airport in the first portion and / or the second portion. The airport may be configured to receive a supply of cool air from an external air source.

[0059] Preferably, the plurality of tube retaining elements comprises a first tube clip and a second tube clip, the tube clips being spaced apart to define a predetermined path therebetween.

[0060] Alternatively, the first portion may comprise a tray having a cavity shaped to receive the consumable and a removable cover configured to seal the consumable within the cavity.

[0061] The device may further comprise means for engagement to facilitate manipulation of the device, which means is preferably provided on the first portion of the device.

[0062] The device may further include identification markings to facilitate identification of consumables held within the device.

[0063] Those skilled in the art will understand that any apparatus feature described herein may be provided as a method feature, and vice versa. It will be understood that specific combinations of the various features described and defined in any embodiment described herein may be implemented and / or provided and / or used independently.

[0064] Furthermore, it will be understood that embodiments are described herein purely by way of example and that modifications of detail can be made within the scope of the present disclosure. Furthermore, herein, "means-plus-function" features may alternatively be expressed in terms of their corresponding structures.

[0065] One or more embodiments will now be described, by way of example, with reference to the accompanying figures. [Brief explanation of the drawings]

[0066] [Figure 1] FIG. 1 shows a first embodiment of a closure system. [Figure 2] FIG. 1 shows a second embodiment of a closure system. [Figure 3] FIG. 1 shows a second embodiment of a closure system. [Figure 4] FIG. 1 shows a second embodiment of a closure system. [Figure 5]FIG. 10 shows a third embodiment of the closure system. [Figure 6a] FIG. 10 shows some examples of consumable items that can be removed. [Figure 6b] 1A-1C illustrate examples of cassette frames for holding multiple consumables. [Figure 7] FIG. 1 is a schematic diagram of multiple consumables fluidly connected to a tubing network. [Figure 8] FIG. 1 is a schematic diagram of a first configuration of tools and consumables that can operate according to a first workflow. [Figure 9] FIG. 10 is a schematic diagram of a second configuration of tools and consumables that can operate according to a second workflow. [Figure 10] 10 is a schematic diagram of an alternative implementation of a means for transferring reagents between two fluidly connected consumables. FIG. [Figure 11a] 1A and 1B show a first embodiment of a device for holding a consumable product having at least one flexible tube connected thereto in an open configuration. [Figure 11b] 1A-1C show a first embodiment of a device for holding a consumable product having at least one flexible tube connected thereto in a closed configuration. [Figure 12a] 10A and 10B show a second embodiment of a device for holding a consumable product having at least one flexible tube connected thereto. [Figure 12b] 10A and 10B show a second embodiment of a device for holding a consumable product having at least one flexible tube connected thereto. DETAILED DESCRIPTION OF THE INVENTION

[0067] In the following description and accompanying drawings, corresponding features may preferably be identified using corresponding reference numerals in order to avoid having to describe these common features in detail for every embodiment.

[0068] Generally speaking, this specification describes an automated system (e.g., an automated system including a processing station) configured to aseptically connect consumables (e.g., bags), pump fluids between the consumables, and aseptically seal the consumables together. More specifically, the system is configured to aseptically connect a first "uptake" consumable (e.g., an uptake consumable containing cells) to a larger mixing consumable, preferably using a robotic tube welder, and then transfer contents from the first consumable to the mixing consumable, preferably using a robotic pumping means (e.g., a pumping mechanism). The system then aseptically connects a second "uptake" consumable (e.g., an "uptake" consumable containing cryoprotectant) to the larger mixing consumable, preferably using a robotic tube welder, and may transfer some or all of the contents from the second consumable into the mixing consumable using a robotic pumping means. The first and second consumables can then be severed from the mixing consumable (while maintaining sterility), preferably using a robotic tube sealer. The robotic tube sealer may be part of a robotic tube welder. For example, a Peltier may be used to cool the fluid while a mixing chamber is gently rocked to mix the fluid.

[0069] The system may then sequentially aseptically connect the mixed consumables to one or more dispensed ("product") consumables, preferably using a robotic tube welder, followed by controlled transfer of fluid between the mixed consumables and each dispensed consumable container, preferably using a robotic pumping means. The dispensed consumables may then be severed, preferably using a robotic tube sealer. This final "controlled transfer" step may be repeated until all of the fluid contained in the mixed consumable has been dispensed.

[0070] As will be appreciated, in a preferred embodiment, the system can be described as a robotic welding / sealing / pumping and transport system for performing fill / finish operations.

[0071] In summary, as will be described in more detail with reference to various embodiments, the system includes automated means for sterilely connecting the consumables, pumping fluid between the consumables, and then sterilely sealing the consumables. Ideally, the system also includes automated means for mixing the fluids within the mixed consumable and for accurately measuring the weight of the fluid dispensed into or from the mixed consumable. Means for cooling the mixed consumable to maintain a desired temperature of the mixed fluid are also preferred, as are means for maintaining traceability of the input and output fluids.

[0072] As mentioned above, the consumables referred to in this specification are preferably bags configured to contain fluids, each bag having flexible tubing that forms a fluid connection for its contents, the tubing being sealed (e.g., clamped) before being connected to the tubing of another such consumable.

[0073] The automated "sterile" connection and disconnection technology that forms part of the system described herein allows for the rapid filling of large numbers of consumables (e.g., bags), which is not possible with existing systems that typically can only fill 10 pre-connected bags at a time. In fact, the system described herein achieves much shorter loading and unloading times than existing systems, which require manual connection of the intake consumables at the start of the process and then manual disconnection / heat sealing of all of the withdrawal consumables after fluid transfer is complete.

[0074] FIG. 1 illustrates a first embodiment of a closed system 100 that may form part of a bioprocessing system. Following a step in a cell therapy process, such as enrichment, activation, transduction, expansion, and / or concentration, the system 100 may be configured to perform a fill / finish operation in which a cellular therapeutic agent is mixed with a cryoprotectant and the mixture is dispensed into multiple smaller "removal" consumables 10 for subsequent cryopreservation. Accordingly, the system 100 may be referred to as a fill / finish system 100. However, it will be appreciated that the system 100 may be operated for other purposes. Because the cryoprotectant may be harmful to cells, the fill / finish operation must be performed quickly. In particular, all removal consumables 10 must be filled, sealed, and cryopreserved within one hour. As described in more detail below, the system 100 has several features that allow for precise and uniform mixing of cells and cryoprotectant, may allow for temperature control of the consumables 10, and allows for the mixture to be filled into multiple removal consumables 10 within a short period of time while being gentle on the cells.

[0075] 1, system 100 may be configured as a processing station 110, such as fill / finish station 110. By implementing system 100 in processing station 110, all steps required for a fill / finish operation may be performed in one location, thereby simplifying control of processing station 110 and transfer of consumables 10 to and from processing station 110.

[0076] The system 100 includes an automated means 120 for mixing a first reagent contained by a first consumable 10-1 and a second reagent contained by a second consumable 10-2 in a third consumable 10-3, and then loading the resulting mixture of the first and second reagents into a fourth consumable 10-4. The first consumable 10-1 and the second consumable 10-2 may be referred to as "take-in consumables." The third consumable 10-3 may be referred to as a "mixing consumable." The fourth consumable 10-4 may be referred to as a "take-out consumable," such as a "vial" or "container."

[0077] When the system 100 is configured as a fill / finish system 100, the first consumable 10-1 may contain a cellular drug product, and the second consumable 10-2 may contain a cryoprotectant and, optionally, any formulation for infusion. It will be appreciated that the first consumable 10-1 and the second consumable 10-2 are interchangeable within the scope of this disclosure. Furthermore, the first consumable 10-1 and the second consumable 10-2 may contain different reagents and / or additional reagents or mixtures of reagents. As used herein, the term "fluid" may refer to any liquid or gas, including reagents, cell samples, infusion formulations, cryoprotectants, and / or any mixtures thereof. Additional uptake consumables 10-1, 10-2 may be provided to transfer their contents into the mixing consumable 10-3.

[0078] The mixing consumable 10-3 preferably has a larger volume than the intake consumables 10-1 and 10-2 so that the first and second reagents can be completely contained within the mixing consumable 10-3. For a fill / finish operation, the mixture of the first and second reagents is dispensed into multiple intake consumables 10-4, e.g., 4 to 100 intake consumables 10-4. Thus, the intake consumable 10-4 may have a smaller volume than the intake consumables 10-1 and 10-2 and / or the mixing consumable 10-3. Where appropriate, the term "consumable" may refer to any of the first, second, third, and / or fourth consumables 10. The operation of the fluid connections and the transfer of reagents between each consumable 10 are described in more detail below.

[0079] Each consumable 10 includes flexible tubing 11 configured to form a fluid conduit for one or more reagents contained by the consumable 10. The flexible tubing 11 has an "upstream end" that fluidly connects to the corresponding consumable 10 and a "downstream end" that defines a sealed or closed end of the tubing 11. Optionally, two or more tubes 11 may be connected to a consumable 10 to facilitate multiple connections and / or transfers of reagents simultaneously. As discussed in more detail below, a tube welder 160 may be used to form closed fluid connections between consumables 10 via their respective tubes 11.

[0080] Multiple fluid connections may be made between the mixing consumable 10-3 and multiple removal consumables 10-4. Therefore, the mixing consumable 10-3 should have a length of tubing 11 sufficient to allow multiple connections and disconnections by the tube welder 160. To prevent entanglement of this length of tubing 11 with other parts of the system 100 and to facilitate engagement by the tube welder 160, the mixing consumable 10-3 may be held in a device 1 that holds the tubing 11 along a predetermined path. An example of such a device 1 is discussed further with respect to FIG. 11 . Other (intake and / or removal) consumables 10 may also be held in a device (such as a rigid tray) that has tube alignment features to aid in robotic movement and tube location. An example of another device 50 for holding consumables 10 is described with respect to FIG. 12 .

[0081] The automated means for mixing 120 may comprise a mixing system 120 provided on a processing station 110, which may be a "standalone" station 110 (or "apparatus") for a bioprocessing system. The mixing system 120 may comprise a mixing zone 122 in which a third consumable 10-3 is positioned to receive the first and second reagents from the first and second consumables 10-1 and 10-2, respectively.

[0082] The mixing system 120 may comprise means for agitating the mixture of the contents of the first (uptake) consumable 10-1 and the second (uptake) consumable 10-2. For example, the means for agitation may comprise a roller (not shown) configured to roll over the mixing consumable 10-3, thereby promoting mixing of the first and second reagents. Alternatively, or additionally, the means for agitation may comprise a rocker plate (not shown) on the mixing zone 122 configured to rock the mixing consumable 10-3, thereby promoting mixing of the first and second reagents. Other examples of means for agitation may be an ultrasonic source, a vibration source, or an orbital shaker. Any of these means for agitation may be provided in any suitable combination depending on the requirements.

[0083] The mixing system 120 may include means for controlling the temperature of the mixed consumable 10-3. For example, the mixing zone 122 may include a Peltier device or cold plate (not shown) configured to cool the mixed consumable 10-3 when located within the mixing zone 122. The means for controlling the temperature may be configured to maintain the mixed consumable 10-3 at a temperature of approximately 4 degrees.

[0084] The system 100 (preferably the processing station 110) may include a first automated ("uptake") transport system 130 configured to transport at least one of the first consumable 10-1 and the second consumable 10-2 to the mixing system 120 to supply at least one of the first reagent and the second reagent to the mixing system 120.

[0085] Preferably, the (first) automated transport system 130 is further configured to feed both the first consumable 10-1 and the second consumable 10-2 to the mixing system 120 to supply both the first reagent and the second reagent to the mixing system 120. The transport system 130 may also feed an empty fourth consumable 10-4 to be filled with the mixture of the first and second reagents from the mixing system 120. The transport system 130 may include a rail system 132 including one or more rails, and the consumables 10 (e.g., the first consumable 10-1 and / or the second consumable 10-2) may be configured to move along these rails. The transport system 130 may include means (not shown) for moving the consumables 10 along the rails 132, thereby sequentially positioning them adjacent to the mixing system 120. For example, the rail system 132 may include a motorized track (not shown) whereby the consumables 10 may be suspended from the rails 132 and moved along the rails 132 via the motorized track.

[0086] The processing station 110 may further include a second automated (“take-out”) transport system 140 configured to remove the fourth consumable 10-4 from the mixing system 120 after it has been filled with the resulting mixture of the first and second reagents. The (second) transport system 140 may remove other consumables 10, such as the empty first and second consumables 10-1 and 10-2, from the mixing system 120. Similar to the (first) “take-out” transport system 130, the (second) “take-out” transport system 140 may include a rail system 142 including one or more rails, along which the consumables 10 (e.g., the fourth consumable 10-4) are configured to move. The transport system 140 may include means (not shown) for moving the consumables 10 along the rails 142, thereby sequentially positioning them adjacent to the mixing system 120. Similar to the (first) transport system 130, the rail 142 may be equipped with a motorized track (not shown), thereby allowing the consumable 10 to be suspended from the rail 142 and moved along the rail 142 via the motorized track.

[0087] The rails 142 of the transport system 140 may be housed within a refrigerated tunnel / section to maintain the temperature of the removed consumables 10-4 at approximately 4 degrees.

[0088] The processing station 110 may further include a storage section 190 configured to accommodate a plurality of mixed consumables 10-3. The storage section 190 may have a first portion 192 configured to store unused mixed consumables 10-3 and a second portion 194 configured to store used mixed consumables 10-3. Examples of the storage section 290 are described in more detail below in connection with Figures 2-4.

[0089] By providing the intake transport system 130 and the extraction transport system 140, each consumable 10 can be positioned adjacent to the mixing section 120, where fluid connections between the consumables 10 can be operated and reagents can be transferred. In other words, the transport systems 130, 140 (alternatively referred to as a "carousel") enable rapid management of the inflow and outflow of the consumables 10. This rapid management allows multiple sequential fluid connections to be made between the consumables 10 and the mixing system 120 via their corresponding tubing 11 without collision or congestion in the system 100.

[0090] The system 100 comprises an automated means 160 for manipulating a closed fluid connection between two consumables 10 for transferring reagents between the two consumables 10. The automated means for manipulating 160 may form the closed fluid connection by forming a (sterile) tube weld between the flexible tubing 11 of each of the two consumables 10. In other words, the automated means for manipulating 160 may comprise an automated tube welding device or automated "tube welder" 160.

[0091] As used herein, the term "tube welder" 160 refers to any device configured to join (i.e., weld) a first tube to a second such tube (preferably at their free ends), thereby forming a sterile (and preferably closed) fluid connection between the tubes. The weld formed between the two tubes is preferably a sterile weld.

[0092] Briefly, the automated tube welding machine 160 may include a first fastening unit and a second fastening unit. Each fastening unit may include a pair of jaws movable between an open position for receiving a flexible tube between the jaws and a closed position for clamping the received tube. The fastening units may be located on a robotic arm. When the tube is clamped, the flexible tube is pinched, preferably preventing fluid flow through the tube. The fastening units may be operated to grip the tube without clamping it closed, thereby allowing the tube to be engaged and positioned without preventing fluid flow. Once the first tube is clamped by the first fastening unit and the second tube is clamped by the second fastening unit, a cutting blade may be heated and moved to intersect the clamped portions of both tubes. This separates each tube into an upstream portion leading to the respective consumable and a downstream portion already formed as a closed end of the tube. Heat from the cutting blade is transferred to the tube, thereby at least partially melting each flexible tube at the newly formed cut end. The fastening unit is then moved to position the upstream tubes adjacent to one another. The downstream section may be discarded. After the cutting blades are removed, the upstream sections are forced together, welding the tubes to form a single tube. This joint may be referred to as a butt weld. At this stage, the joint between the tubes may remain pinched, and a pinch-release mechanism may be operated to remove the pinched portion, thereby establishing a fluid path through the joined tubes. Additionally, a quality control (QC) mechanism may be provided to verify the integrity of each weld. The tube welder 160 allows for the rapid formation of a closed connection between the tubes 11. The system 100 may include additional tube welders 160, which may be particularly advantageous when tube welding is a rate-limiting step.

[0093] The automated means for manipulation 160 may further comprise means for engaging and / or positioning the flexible tubing 11. For example, the system 100 may comprise at least one robotic arm 162 having an end effector for gripping the tubing 11. For example, the means for manipulation 160 may comprise an end effector on the robotic arm 162 configured as a tube welder, where a fastening unit of the tube welder 160 is configured to grip the tubing 11 without clamping it, thereby enabling the tubing 11 to be positioned. In this manner, the robotic arm 162 may move to engage a first tube 11 connected to a first consumable 10 and a second tube 11 connected to a second consumable 10, and then form a tube weld between the first tube 11 and the second tube 11. Alternatively, the means for manipulation 160 may comprise a fixed tube welder located on the processing station 110, whereby a robotic arm with a gripping unit may engage and position the tubing 11 within the fixed tube welder 160.

[0094] The system 100 comprises an automated means 170 for transferring reagents between two fluidly connected consumables 10. The automated means 170 for transfer may be configured to transfer reagents between the two fluidly connected consumables 10 via their respective flexible tubings 11 after the flexible tubings 11 have been welded together to form a fluid connection. The automated means 170 for transfer may comprise a pumping arrangement 170 configured to apply a pumping action, preferably a peristaltic pumping action, to the flexible tubing via a peristaltic pumping mechanism. For example, the system 100 may comprise a peristaltic pump 170.

[0095] As used herein, the term "peristaltic pump" may refer to a rotary peristaltic pump or a linear peristaltic pump. A peristaltic pump may be configured to compress a portion of flexible tubing 11 and then translate the compressed portion along the length of tubing 11 in a pumping direction, thereby forcing fluid through tubing 11.

[0096] Advantageously, peristaltic pump 170 can allow fluid to be rapidly pumped through tubing 11 while minimizing wear and potential contamination of tubing 11. Furthermore, the pumping action of peristaltic pump 170 is gentle on cells. Peristaltic pump 170 can be configured as an end effector of robotic arm 172. The end effector and / or robotic arm 172 can be the same end effector and robotic arm 162 that provide means 160 for manipulating closed fluid connections. Preferably, system 100 includes a first robotic arm 162 having an end effector that constitutes tubing welder 160 and a second robotic arm 172 having an end effector that constitutes peristaltic pump 170. System 100 can include additional peristaltic pumps 170, which can be particularly advantageous when fluid transfer is a rate-limiting step.

[0097] The system 100 also includes an automated means 180 (not shown) for sealing a portion of each flexible tubing 11, thereby aseptically sealing one or more reagents within the consumables 10 from the surrounding environment before severing the fluid connection operated between the two consumables 10. The means for sealing 180 is sometimes referred to as a "tube sealer." The means for sealing 180 may be provided on the same end effector as either or both of the tubing welder 160 and / or the peristaltic pump 170. The means for sealing 180 is preferably an RF sealer, although it may be any type of heat sealer that melts the flexible tubing 11 to prevent fluid flow therethrough. Advantageously, providing the means for sealing 180 can help prevent leakage from the consumables 10. This is particularly important for removable consumables 10-4, which may be stored for significant periods of time and subsequently transported to other locations after being frozen.

[0098] The system 100 may also include automated means for severing the fluid connection between the two consumables 10. The automated means for severing may be provided by the automated means for sealing 180, preferably an RF sealer. Alternatively, the tube welder 160 may provide the means for severing the fluid connection, for example, by using a heated cutting blade. In this manner, after fluid is transferred between the two consumables 10, the means for severing may sever the consumables 10, thereby allowing the consumables 10 to be transported to a different location for storage or disposal.

[0099] The system 100 includes (automated) means for determining the amount of fluid transferred to or from the mixing consumable 10-3, such as fluid transferred from the intake consumables 10-1, 10-2 or fluid transferred to the removal consumable 10-4. For example, the determining means may determine the weight of a volume of the resulting mixture of the first and second reagents transferred to the fourth consumable 10-4. The means for determining the amount of fluid may be a weight sensor and / or may include any combination of a gravimetric sensor, an ultrasonic sensor, a flow sensor, and / or a liquid level sensor. For example, the weight sensor may include a gravimetric sensor configured to monitor the weight of the removal consumable 10-4 and thereby determine the weight of the mixture transferred from the mixing consumable 10-3 into the removal consumable 10-4.

[0100] Alternatively, or in addition, the weight sensor may include a weight measurement sensor configured to monitor the weight of the mixed consumable 10-3, and the weight sensor may calculate the weight of the fluid transferred into the extraction consumable 10-4 based on the change in weight of the mixed consumable 10-3 during transfer.

[0101] Alternatively, or additionally, the weight of the mixture in the removal consumable 10-4 may be calculated based on the volume of fluid pumped by the automated means for transferring reagents 170, which may be determined by a flow sensor, such as flow sensor 175 described in connection with FIG. 10 . The flow sensor may determine the flow rate by monitoring the velocity of air bubbles moving through the tube 11. A weight measurement sensor may be located on the platform of the system 100, which weight sensor determines the weight of the consumable 10 placed on the platform. In particular, the weight measurement sensor may be located on the mixing zone 122 of the mixing system 120, thereby measuring the weight of the mixing consumable 10-3 when placed on the platform.

[0102] Alternatively, or in addition, a weight measurement sensor may be located on the rail 142 of the take-out transport system 140 to measure the weight of the consumable 10 held on the rail 142. Optionally, the rail 132 of the take-out transport system 130 may also have a weight measurement sensor.

[0103] Each consumable 10 may include an identification mark, such as a QR code or barcode. Alternatively, or additionally, an RF tag or an NFC tag may be used. The identification mark may enable each consumable 10 to be uniquely identified and tracked during fill / finish operations and also during subsequent stages, such as storage and dispensing. The system 100 may have means for identifying the identification mark on each consumable 10. The means for identification may include at least one image capture device, which may be located on one or more of the robotic arms 162, 172. The means for identification may be a machine vision system.

[0104] The system 100 may include one or more sensors configured to measure one or more parameters of the consumable 10. For example, the one or more sensors may include the gravimetric, ultrasonic, flow, and / or liquid level sensors described above, and may include a sensor for measuring the temperature of the mixed consumable 10-3. The one or more sensors may include a camera (not shown) for measuring the progress of mixing within the mixed consumable 10-3. This camera may be the same camera as the camera that provides the means for identifying the identifying mark on each consumable 10, or may be a different camera.

[0105] An exemplary fill / finish operation performed in the system 100 will now be described. First, multiple consumables 10 are loaded into the system 100. For example, at least one first consumable 10-1 and at least one second consumable 10-2 may be loaded onto the intake transport system 130, each consumable including a respective first and second reagent. Multiple empty fourth consumables 10-4 may also be loaded onto the intake transport system 130. At least one third consumable 10-3 may be loaded into the storage section 190, such as within the first portion 192. The loading of the consumables 10 may be performed by a human operator or by a separate robotic device in the bioprocessing system. When the consumables 10 are loaded into the system 100, the means for identification may scan each of the corresponding identification marks on the consumables 10, thereby identifying and tracking each of the consumables 10 throughout the fill / finish operation.

[0106] The third consumable 10-3 can be moved from the storage section 190 to the mixing zone 122 of the mixing section 120, for example, by an end effector of one of the robotic arms 162, 172. The tube welder 160 automatically welds the tubing 11 connected to the first consumable 10-1 to the tubing 11 connected to the third consumable 10-3. The peristaltic pump 170 automatically pumps fluid (e.g., cellular material) from the first consumable 10-1 to the third consumable 10-3. The fluid connection between the first consumable 10-1 and the third consumable 10-3 is cut, and the corresponding tubing 11 is sealed, thereby maintaining a closed system. Similarly, the tube welder 160 welds the tubing 11 connected to the second consumable 10-2 to the tubing 11 connected to the third consumable 10-3. A peristaltic pump 170 pumps fluid (e.g., cryoprotectant) from the second consumable 10-2 to the third consumable 10-3. The fluid connection between the second consumable 10-2 and the third consumable 10-3 is cut and the corresponding tubing 11 is sealed, thereby maintaining a closed system.

[0107] It will be appreciated that the steps described above may be performed in a different order, and some steps may be performed simultaneously. For example, it is not necessary to disconnect the first consumable 10-1 from the third consumable 10-3 before the tube welder 160 connects the second consumable 10-2 to the third consumable 10-3. During pumping, a valve may be present on the tubing 11 to prevent backflow of fluid when both intake consumables 10-1, 10-2 remain connected to the mixing consumable 10-3. Additionally, fluid transfer from the second consumable 10-2 may be used to flush out residual fluid left in the first consumable 10-1 (or vice versa). Pumping of reagents by the peristaltic pump 170 may occur whenever the corresponding consumables 10 are connected. Additionally, disconnection of the intake consumables 10-1, 10-2 from the mixing consumable 10-3 may occur much later in the fill / finish operation, or may not occur at all. For example, intake consumables 10-1, 10-2 and mixing consumable 10-3 may be removed from system 100 so that they remain connected and are disposed of.

[0108] The third consumable 10-3 may be agitated to mix the reagents. This may occur while one or both of the reagents are being pumped into the third consumable 10-3 and / or after both reagents have been pumped into the third consumable 10-3. Agitation may be achieved using any of the means for agitation previously described, such as rocker plates and / or rollers. Similarly, the third consumable 10-3 may be cooled using a Peltier device or cold plate in the mixing zone 122. After the first and second reagents are sufficiently mixed (as determined by one or more sensors in the system 100), the tube welder 160 and peristaltic pump 170 perform multiple sequential connections and transfers to multiple fourth consumables 10-4.

[0109] More specifically, the tube welder 160 welds the tubing 11 connected to the third consumable 10-3 to the tubing 11 connected to the fourth consumable 10-4. The peristaltic pump 170 then pumps a predetermined weight of the mixture from the third consumable 10-3 into the fourth consumable 10-4 based on measurements by the weight sensor and / or flow sensor. The fluid connection between the fourth consumable 10-4 and the third consumable 10-3 is then severed and the corresponding tubing 11 is sealed, thereby maintaining a closed system.

[0110] The above steps are repeated with multiple additional fourth consumables 10-4 until the mixture in the third consumable 10-3 is dispensed. The third consumable 10-3 may be moved into the second portion 194 of the storage section 190, for example, by the end effector of one of the robotic arms 162, 172. After each fourth consumable 10-4 is filled with the mixture, it is removed from the mixing section 120 using the pick-up and transport system 140. Similarly, the empty first consumable 10-1 and second consumable 10-2 may be removed from the mixing section 120 using the pick-up and transport system 140. In this manner, it may be possible to fill 4 to 100 fourth consumables 10-4 with the mixture contained in the third consumable 10-3 without crowding the consumables 10 near the mixing section 120 or tangling the tubes 11.

[0111] The consumables 10 may then be removed from the system 100. The consumables 10 may be removed by a human operator or using a robotic device in the bioprocessing system. The empty first consumables 10-1 and second consumables 10-2 may be removed from the retrieval transport system 140 for disposal. The empty third consumable 10-3 may be removed from the second portion 194 of the storage section 190 for disposal. A plurality of filled fourth consumables 10-4 may be transported from the retrieval transport system 140 to a cryopreservation unit. If the consumables 10 are removed by a robotic device, an identification mark on each consumable 10 may allow the consumables 10 to be distinguished from one another by a machine vision system.

[0112] It will be appreciated that the loading and unloading steps may occur between other steps of the fill / finish operation. For example, while dispensing a mixture from a third consumable 10-3 into a plurality of fourth consumables 10-4, an empty fourth consumable 10-4 may be added to the input transport system 130 and removed from the output transport system 140. Advantageously, this means that the transport systems 130, 140 do not need to have the capacity to hold all of the consumables 10 simultaneously.

[0113] At least one of an automated means 160 for manipulating the fluid connection, an automated means 170 for transferring reagents, and an automated means 180 for sealing may be provided on the processing station 110. In the embodiment shown in FIG. 1 , the means 160 for manipulating, the means 170 for transferring, and the means 180 for sealing are all provided on the processing station 110. In particular, the processing station has a base unit 111 divided into a first portion 111a and a second portion 111b. Robot arms 162, 172 may be attached to an upper surface of the first portion 111a. An upper surface of the second portion 111b may support the mixing system 120 and / or the storage system 190. A housing 115 may be attached to and extend vertically from the second portion 111b of the base unit 111. The housing 115 may have a portion configured to form a mixing zone 122 for supporting the mixing consumable 10-3. The transport systems 130, 140 may be mounted laterally to the housing 115. Specifically, the intake transport system 130 may include an intake conveyor housing 134 having rails 132 extending from the sides thereof. The intake conveyor housing 134 may have a front portion configured to hold the first intake consumable 10-1 and the second intake consumable 10-2 when the first intake consumable 10-1 and the second intake consumable 10-2 are fluidly connected to the mixed consumable 10-3 supported in the mixing zone 122. In other words, the intake transport system 130 is configured to position the consumables 10 to be engaged by a means 160 for operating the fluid connection between each consumable 10 and the mixing system 120.

[0114] Similarly, the pick-up transport system 140 may include a pick-up conveyor housing 144 having rails 142 extending from its sides. The pick-up conveyor housing 144 may have a front configured to hold at least one of the pick-up consumables 10-4 when the pick-up consumables 10-4 are fluidly connected to the mixed consumable 10-3. In other words, the pick-up transport system 140 is configured to position the consumables 10 to be engaged by a means 160 for operating the fluid connection between each consumable 10 and the mixing system 120. As shown in FIG. 1 , three pick-up consumables 10-4 (two full pick-up consumables 10-4 and one empty pick-up consumable 10-4) are held at the front of the pick-up conveyor housing 144. In this manner, the robotic arms 162, 172 are positioned adjacent to both the mixed consumable 10-3 and the transport systems 130, 140, thereby enabling closed fluid connections and fluid transfers to be operated between the consumables 10 without the need for long tubing 11.

[0115] Alternatively, in a second embodiment of a closed system 200 shown in FIGS. 2-4 , at least one of the automated means for manipulating fluid connections 260, the automated means for transferring reagents 270, and the automated means for sealing 280 may be provided on a separate mobile unit 250 configured to automatically cooperate with processing station 210. System 200 shares some functionality with closed system 100 described in connection with FIG. 1 , which will not be described in detail again for the sake of brevity. However, in this system 200, autonomous mobile unit 250 provides all of the means for manipulating 260, the means for transferring 270, and the means for sealing 280. In this manner, mobile unit 250 may also perform other operations within the bioprocessing system as a whole, such as facilitating loading and / or unloading of consumables 10 into and / or from system 200, such as loading / unloading from an external storage area, other processing stations, and / or a cryopreservation unit.

[0116] The system 200 also includes a storage section 290. While not described in detail in connection with FIG. 1 , it will be appreciated that the system 100 of the first embodiment may also include a storage section 190 similar to the storage section 290 of this second embodiment. The storage section 290 is configured to store a plurality of third “mixed” consumables 10-3. The mixed consumables 10-3 may be held within a device 1, such as the device 1 described in connection with FIGS. 11 a and 11 b. As shown in particular in FIG. 4 , the storage section 290 may have a first portion 292 configured to store a plurality of devices 1 holding unused mixed consumables 10-3, and a second portion 294 configured to store a plurality of devices 1′ holding used mixed consumables 10-3. It will be appreciated that these portions 292, 294 may be interchangeable without affecting the present invention.

[0117] The first portion 292 may have a first hatch 293 for allowing the mixed consumables 10-3 to be inserted into and / or removed from the first portion 292. For example, a user may load one or more unused mixed consumables 10-3 into the first hatch 293 before performing one or more fill / finish operations. The second portion 294 may have a second hatch 295 for allowing the mixed consumables 10-3 to be inserted into and / or removed from the second portion 294. For example, a user may remove one or more used mixed consumables 10-3 from the second hatch 295 after completing one or more fill / finish operations. Alternatively, or additionally, the mixed consumables 10-3 may be inserted into or removed from the storage section 290 between fill / finish operations. As described later in connection with FIG. 11, the device 1 may allow consumables to be stacked and stored compactly within the storage section 290, and the device 1 may be moved from a closed configuration to an open configuration during fill / finish operations.

[0118] 5 shows a third embodiment of a closed system 300, which includes a processing station 310 and a mobile unit 350. The mobile unit 350 provides a means for manipulation 360, a means for transfer 370, and a means for sealing 380 via a first robotic arm 362 and a second robotic arm 372. The robotic arms 362, 372 are attached to a base unit 352, which can move autonomously relative to the processing station 310. Alternatively, the robotic arms 362, 372 can be attached to the processing station 310 similar to the first embodiment shown in FIG.

[0119] In this third embodiment, a plurality of slots 312 are disposed within the processing station 310, each slot configured to receive and store a consumable 10. As shown, the processing station 310 includes ten slots 312. However, it will be appreciated that there may be any (reasonable) number of slots 312 to hold any number of consumables 10. Here, a first consumable 10-1 for holding a first reagent is seen to be held within the first slot 312, and a second consumable 10-2 for holding a second reagent is shown to be held within the second slot 312. The processing station 310 also includes a mixing system 320 having a mixing zone 322 for supporting a third "mixed" consumable 10-3. As previously mentioned, the mixing system 320 may include means for agitation and means for cooling. A fourth "take-out" consumable 10-4 for receiving a mixture of the first and second reagents from the mixing system 320 is seen to be held in the tenth slot 312. However, it will be appreciated that there may be additional take-out consumables 10-4 in other slots 312. Each of the slots 312 may have a weight sensor, thereby allowing the amount of fluid in each of the take-out consumables 10-4 to be determined. Consumables 10, such as take-out consumables 10-1, 10-2 and take-out consumable 10-4, may be held in a device such as device 50 described in connection with FIG. 12.

[0120] Thus, according to the above-described method, consumables 10 may be added to and / or removed from slots 312 as needed. For example, input consumables 10-1, 10-2 and multiple empty output consumables 10-4 may be placed in slots 312, for example, by a human operator or a robotic device (e.g., mobile unit 350). Conceptually, mobile unit 350 can be viewed as providing an alternative to an automated transport system, as it delivers consumables 10 to slots 312 of processing station 310. Mixed consumable 10-3 may be placed in mixing zone 322 of mixing system 320 from either storage section 390 (not shown) on processing station 310 or an external storage area. Mobile unit 350 may then operate the fluid connections and fluid transfers as described above, and consumables 10 may be added to / removed from slots 312 whenever needed. For example, after reagents are transferred from the import consumables 10-1, 10-2 to the mixing consumable 10-3, the import consumables 10-1, 10-2 may be removed from the slot 312. The filled extraction consumable 10-4 may be removed from the slot 312 and moved to an external cryogenic storage unit. An empty extraction consumable 10-4 may be added to an available slot 312, such as to replace the removed import consumables 10-1, 10-2 and / or the filled extraction consumable 10-4.

[0121] 6a shows an example of a plurality (e.g., ten) of dispensing consumables 10-4 (only some of the dispensing consumables 10-4 are labeled), which are held within a housing 2. These dispensing consumables 10-4 may be referred to as vials 10-4. Each of the vials 10-4 has a tube 11 (only some of the tubes are labeled) for facilitating welding to other tubes in the closed system 100, 200, 300, such as the tube 11 connected to the mixing consumable 10-3.

[0122] 6b shows an example of a "cassette" (or "cartridge") frame 3 that can be used to hold multiple removal consumables 10-4 within corresponding openings 3-1 (only some of the openings are labeled). In this way, once all of the removal consumables 10-4 have been filled with the mixture from the mixing consumable 10-3, the frame 3 can be moved to a cryopreservation unit rather than transporting all of the removal consumables 10-4 individually. Furthermore, by storing the removal consumables 10-4 within a single frame 3, only one identification mark is required to identify all of the stored removal consumables 10-4.

[0123] FIG. 7 shows a tubing network 11-1 connecting multiple (e.g., five) dispensing consumables 10-4 to a single filling section 11-2. In this way, the tubing welder 160 only needs to form a single connection between the tubing 11 connected to the mixing consumable 10-3 and the filling section 11-2, which may speed up the fill / finish process. A peristaltic pump 170 may then transfer the mixture to all of the pre-connected dispensing consumables 10-4. The tubing network 11-1 may be sealed when each dispensing consumable 10-4 receives the required weight of the mixture. The dispensing consumables 10-4 may then be disconnected, so that each dispensing consumable 10-4 connects to only a single tubing 11.

[0124] A first workflow for transferring a mixture from a mixing consumable 10-3 to a plurality of removal consumables 10-4 will be described with reference to Figure 8. In this example, the closed system 100, 200, 300 has a first tool 101 comprising a peristaltic pump 170 and a second tool comprising a tube welder 160 and a tube sealer 180, although it will be appreciated that these may be provided as separate tools. In this example, the first tool 101 may be a fixed tool and the second tool 102 may be mobile, for example on a robotic arm. A single tube 11 is connected to the mixing consumable 10-3.

[0125] As shown, a tube welder 160 connects the mixing consumable 10-3 and the first delivery consumable 10-4 via their respective tubes 11. A peristaltic pump 170 then performs controlled transfer of fluid from the mixing consumable 10-3 to the first delivery consumable 10-4a. The second tool 102 then seals the first delivery consumable 10-4a using a tube sealer 180 and welds the second delivery consumable 10-4b and the mixing consumable 10-3 via their respective tubes 11. This process can then be repeated to transfer fluid to multiple additional delivery consumables 10-4. More specifically, the peristaltic pump 170 then transfers the mixture to the second delivery consumable 10-4b. While this is occurring, the second tool 102 may move into position ready to seal the second ejection consumable 10-4b and weld the third ejection consumable 10-4c to the mixed consumable 10-3. One cycle of this process takes approximately 30 seconds to pump, 30 seconds to seal, and 1 minute to weld. Thus, in this case, it may be possible to fill 30 ejection consumables 10-4 within an hour.

[0126] Next, a second workflow for transferring a mixture from a mixing consumable 10-3 to multiple output consumables 10-4 will be described with reference to FIG. 9 . In this workflow, the tube welder 160 and pump 170 operate in parallel, allowing more output consumables 10-4 to be filled within an hour. However, this workflow is more complex because the output consumables 10-4 operate on two different lines (or similar lines) to avoid tangling the tubes 11. In this example, each system 100, 200, 300 has a first tool 101 comprising a peristaltic pump 170 and a tube sealer 180, and a second tool 102 comprising a tube welder 160. However, it will be appreciated that the peristaltic pump 170 and the tube sealer 180 may be provided on separate tools. A first flexible tube 11a and a second flexible tube 11b are connected to the mixing consumable 10-3. The first tube 11a and the second tube 11b may have pinch valves to prevent fluid flow therethrough.

[0127] In the first step, the first tool 101 pumps fluid through the first tube 11a into the first removal consumable 10-4a, sealing the first removal consumable 10-4a. Simultaneously, the tube welder 160 welds the second tube 11b to the second removal consumable 10-4b. The third removal consumable 10-4c and the fourth removal consumable 10-4d can then be sent into position for subsequent steps.

[0128] In a second step, the second tool 102 having the tube welder 160 moves to the third discharge consumable 10-4c and welds the first tube 11a to the third discharge consumable 10-4c, and the first tool 101 moves to pump fluid through the second tube 11b into the second discharge consumable 10-4b, and then seals the second discharge consumable 10-4b.

[0129] In a third step, the second tool 102 having the tube welder 160 moves to the fourth removal consumable 10-4d and welds the second tube 11b to the fourth removal consumable 10-4d. The first tool 101 moves to pump fluid through the first tube 11a into the third removal consumable 10-4c, then seals the third removal consumable 10-4c. The fifth and sixth removal consumables (not shown) can be sent into position for subsequent steps.

[0130] In a fourth step, the second tool 102 having the tube welder 160 moves to the fifth discharge consumable and welds the first tube 11a to the fifth discharge consumable, and the first tool 101 moves to pump fluid through the second tube 11b into the fourth discharge consumable 10-4d, and then seals the fourth discharge consumable 10-4d.

[0131] The above steps can be repeated to transfer fluid to multiple additional dispensing consumables 10-4. The time it takes to fill one dispensing consumable 10-4 can be about 30 seconds for the longer of the transfer and pumping and sealing time, and about 1 minute for the welding time. This means that about 40 dispensing consumables 10-4 can be filled in one hour.

[0132] 10 illustrates an alternative means 170 for transferring reagents between two fluidly connected consumables 10. This means for transfer 170 may be implemented in any of the systems 100, 200, 300 described herein. The means for transfer 170 may include a valved air source 173 connected to the mixing consumable 10-3 via a sterile air filter 174. The flexible tubing 11 connecting between the mixing consumable 10-3 and each of the plurality of dispensing consumables 10-4 includes a flow sensor 175. The flow sensor 175 is preferably a disposable medical-grade flow sensor 175. Preferably, welding, sealing, and / or cutting occurs on the flexible tubing 11 between the flow sensor 175 and the dispensing consumable 10-4 (rather than between the mixing consumable 10-3 and the flow sensor 175).

[0133] Advantageously, flow sensor 175 allows for the transfer of precise volumes of fluid into each of dispensed consumables 10-4. Air may thus be pumped into mixing consumable 10-3 by valved air source 173, whereby, due to increased pressure, the mixture within mixing consumable 10-3 is forced through flexible tubing 11 and into dispensed consumable 10-4. It will be appreciated that pumping air through sterile air filter 174 satisfies the requirement for a functionally closed system, which is deemed sufficient to prevent contamination between the contents of consumable 10 and the environment.

[0134] A device 1 for holding a consumable 10 will now be described with reference to Figures 11a and 11b. The device 50 is configured to hold a consumable 10 to which at least one flexible tube 11 is fluidly connected. The device 1 comprises a structure 20 ("first portion") for holding the consumable 10. The structure 20 may have a longitudinal axis with a first end 20a and a second end 20b.

[0135] The structure 20 may be configured as a tray 20. As such, the tray 20 may define a recess 21 shaped to receive the consumable item 10. The tray includes a pair of opposing side walls 23 a, 23 c and at least one end wall 23 b, with the side walls 23 a, 23 c and end wall 23 b together generally defining the recess 21, which here is generally rectangular.

[0136] Recess 21 ideally has dimensions comparable to those of consumable 10 so that consumable 10 fits snugly into recess 21, thereby holding consumable 10 in place, thereby reducing the flexibility of consumable 10 by holding consumable 10 in a given shape.

[0137] The tray 20 may be rigid and made of any suitable material, such as plastic or metal. In other examples, the tray 20 may include a material that has a degree of flexibility, such as a resilient material. In this manner, the consumable 10 may be pressed into the recess 21 by slightly stretching one or more sides of the tray 20 upon insertion. After release, the sides of the tray 20 flex and return to the original shape in which the consumable 10 was inserted, thereby securing the consumable 10.

[0138] In an alternative embodiment, tray 20 may comprise a rectangular plate with a hole in the center, thereby forming an "open" structure. Structure 20 may further comprise at least one clamp configured to secure consumable 10 to the plate. The at least one clamp may be located on the structure to hold consumable 10 against gravity. When more than one clamp is present, the clamps may be located on more than one side of structure 20. This may allow device 1 to be positioned in different orientations while holding consumable 10 in place and minimizing changes to its shape.

[0139] The device 1 includes a lid 30 ("second portion") configured to cover the consumable and secure it within the tray recess 21, and further configured to hold flexible tubing 11 connected to the consumable 10. The lid 30 may include a frame 40 having a plurality of tube retention elements 41 configured to hold the flexible tubing 11 at a plurality of positions along a predetermined path. The frame 40 may be configured as a grid including a first set of parallel bars that cross (or intersect) at repeated intervals with a second set of parallel bars.

[0140] Due to the location of each tube retaining element 41 at an intermediate position on the grid 40, e.g., midway between two intersections, the predetermined path followed by the tubes 11 may be a winding (e.g., serpentine) path as shown. This advantageously allows long tubes to be held in a compact configuration by the device 1, avoiding tangling of the tubes 11 with each other, with other components in the bioprocessing system or processing station 110, or with other tubes 11. This also allows for longer tubes 11, which is desirable for tube welding because it allows for multiple connections and cuts to be made at different locations along the length of the tube.

[0141] The tube 11 may be secured to each of the plurality of tube retaining elements 41 by applying a force to the tube 11 to force it into the tube retaining element 41, thereby causing the tube retaining element 41 to secure the tube 11 in a given position. The tube retaining element 41 may alternatively comprise any suitable means for coupling this portion of the tube 11 to the frame 40, such as a hook or clasp. The portion of the tube 11 held by the tube retaining element 41 may be permanently retained or removably secured.

[0142] The lid 30 may be secured to the first end 20a of the tray 20. The lid 30 may have a width dimension smaller than that of the tray 20, thereby allowing the tray 20 to receive a portion of the lid 30 through a third recess on its upper surface. This allows the opposing side walls 23a, 23c of the tray and the opposing side walls 31a, 31c of the frame 40 to overlap. In this manner, each side wall 23a, 23c of the tray 20 may be attached to the respective side wall 31a, 31c of the frame 40.

[0143] A second recess 24 (e.g., a gap or slot) through which the tube 11 can pass is provided in the side of the lid 30 that is attached to the first end 20a of the tray 20. The second recess 24 is preferably aligned with the portion of the consumable 10 that connects to the flexible tube 11. There can be more than one such second recess 24 on the side of the lid 30 in case the consumable 10 includes more than one tube 11.

[0144] Preferably, the lid 30 is attached to the tray 20 using a hinge such that the lid 30 moves between an open configuration and a closed configuration via the hinge. Figure 11a shows the open configuration in which the longitudinal axis of the tray 20 is aligned with the longitudinal axis of the lid 30, such that the lid 30 resides in a plane parallel to the tray 20. In other words, in the open configuration, the device 1 may form a generally flat plate. Figure 11b shows the device 1 after the lid 30 has been moved to the closed configuration using the hinge, with the lid 30 rotated about the first end 20a of the tray 20 and folded inward across the top surface of the tray 20.

[0145] The lid 30 may be attached using a pair of screws 22 on opposite sides of the first end 20a of the tray 20. Each of the screws 22 may be inserted perpendicular to the longitudinal axis of the tray 20 through one of the side walls 23a, 23c of the tray 20 and through one of the corresponding side walls 31a, 31c of the frame 40 so as to hinge the tray 20 and lid 30 together. The tray 20 and lid 30 pivot about the screws 22, thereby allowing them to move between open and closed configurations using the hinge. The lid 30 may be securable to the tray 20 to hold the device 1 in the closed configuration.

[0146] In other examples, the lid 30 may be attached to the tray 20 by another means using a hinge, which may include at least one of a butt hinge, a ball-bearing hinge, a piano hinge, and a strap hinge. In these examples, the attachment means may be positioned substantially in the center of the first end 20a of the tray 20, or alternatively, may be positioned on an opposing side of the first end 20a of the tray 20. Alternatively, the lid 30 may slide relative to the tray 20, such as parallel to the longitudinal axis of the tray 20.

[0147] Next, an alternative device 50 for holding consumables 10 will be described with reference to Figures 12a and 12b. The device 50 is configured to hold consumables 10 fluidly connected to at least one flexible tube 11. In the example shown in Figure 12a, the consumables 10 are connected to two flexible tubes 11. The device 50 includes a housing 70 configured to hold the consumables 10. In other words, the housing 70 constitutes a first part of the device 50 for holding the consumables 10. The device 50 may also provide insulation and / or thermal conduction for the consumables 10, thereby allowing the temperature of each consumable 10 to be individually adjusted.

[0148] The upper and lower surfaces may be provided on the housing 70 and separated by a pair of opposing side walls 73 a, 73 c (i.e., a first side wall 73 a and a second side wall 73 c) and at least one end wall 73 b, thereby forming a cubical shape. The housing 70 may have a longitudinal axis with a first end 70 a and a second end 70 b.

[0149] The housing 70 may include a tray 70 having a cavity 71 shaped to receive the consumable 10. The top surface of the housing 70 may be a removable cover 72 that substantially encloses the consumable 10 within the cavity 71. In this manner, the consumable 10 may be conveniently added to and / or removed from the device 50. Furthermore, this means that the device 50 has a rigid outer surface that may protect the consumable 10 and allow the device 50 to be securely inserted into a slot 312 in a processing station 310 of the closed system 300.

[0150] Preferably, the cavity 71 has dimensions comparable to those of the consumable 10 so that the consumable 10 fits snugly within the cavity 71, thereby holding the consumable 10 in place. This reduces the flexibility of the consumable 10 by holding the consumable 10 in a given shape. The housing 70 can be rigid and made of any suitable material, such as plastic or metal. Alternatively, the housing 70 can include a material with some flexibility, such as any elastic material. In this manner, the consumable 10 can be pressed into the cavity 71 by slightly stretching the cavity 71 during insertion. The housing 70 then flexes and returns to its original shape after the consumable 10 is inserted, thereby securing the consumable 10. Advantageously, using the device 50 to house the consumable 10 with a bag prevents the bag from bulging outward when full. The housing 70 also includes external insulation and internal cool air flow path designations so that the consumable 10 contained within the housing 70 can be maintained at a designated temperature. A thermistor (not shown) may also be incorporated into the housing 70 to monitor temperature.

[0151] The housing 70 may include at least one clamp 75 for holding the consumable 10 within the cavity 71. In this example, the housing 70 has the clamp 75 within the cavity 71, near the first end 70a of the housing 70. The clamp 75 may be a tab or a hook. The consumable 10 may be attached via a hanging aperture provided in the bag of the consumable 10.

[0152] The housing 70 may include a means for engagement 76 provided on an exterior surface of the housing 70. In this example, the means for engagement 76 is a handle 76 attached to the first side wall 73 a. The handle 76 may allow the device 50 to be manipulated and moved by a human operator and / or a robotic device, such as a robotic arm 162, 172. For example, the handle 76 may allow the device 50 to be transported, placed, and / or removed from a slot 312 in a processing station 310 of the closed system 300 described herein.

[0153] One or more ribs 78 may be provided around the periphery of the housing 70 and extend between the top and bottom surfaces of the housing 70. Identification marks, such as a barcode, a QR code, or an NFC code, may be provided on the device 50 to enable the device 50 to be identified by a machine vision system. For example, the device 50 may be automatically identified when inserted into the slot 312 of the processing station 300.

[0154] The housing 70 may include at least one recess 74 and an end (e.g., second end 70b) of the housing through which the tube 11 may pass. The recess 74 is preferably aligned with the portion of the consumable 10 that connects to the flexible tube 11. Multiple recesses 74 may be present on the housing 70 for when the consumable 10 is fluidly connected to two or more tubes 11.

[0155] The device 50 includes a second portion 80 configured to hold the flexible tubing 11 connected to the consumable 10. The second portion 80 may extend from the second end 70b of the housing 70 and is preferably located adjacent to the recess 74. The second portion 80 may include a plurality of tube retaining elements 81 (e.g., tube clips) for holding the flexible tubing 11 at multiple positions along a predetermined path. In this example, the second portion 80 includes pairs of tube retaining elements 81 that are spaced apart such that a portion of the tubing 11 can be held substantially taut between the tube retaining elements 81 to facilitate engagement by a robotic device. In this manner, a robotic device can engage the tubing 11 at a position between the pair of tube retaining elements 81.

[0156] The tube 11 may be secured to each of the tube retaining elements 81 by applying a force to the tube 11 to force it into the tube retaining element 81, thereby causing the tube retaining element 81 to secure the tube 11 in a given position. The tube retaining element 81 may alternatively comprise any suitable means for coupling this portion of the tube 11 to the second portion 80, such as a hook or clasp. The portion of the tube 11 retained by the tube retaining element 81 may be permanently retained or removably secured.

[0157] The device 50 may include means 77 for cooling the consumable item 10 held within the housing 70. In this example, the means for cooling 77 is at least one air port 77 (or "air duct") in the first portion 70 and / or the second portion 80 of the device 50, such that cool air can be supplied to the at least one air port 77 for cooling the consumable item 10. Specifically, the device 50 includes a first external air port 77a in communication with an internal air port 77b to facilitate the introduction / exhaust of air into / from the cavity 71. A second external air port 77c is provided in the housing 70 to allow air to flow out / into the housing 70.

[0158] 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 can 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 details shown in the accompanying drawings that are not described in detail herein or defined in the claims. Indeed, such excessive features may be omitted from the drawings without detriment to the invention. Moreover, other and further embodiments of the present invention will be apparent to those skilled in the art from a study of the specification, and such embodiments may be devised without departing from the basic scope of the present invention, as determined by the scope of the following claims. [Explanation of symbols]

[0159] 1 device 1' device 2. Housing 3 frames 10 Consumables 10-1 First Consumable 10-2 Secondary Consumables 10-3 Third Consumable 10-4 Fourth Consumable 10-4a First Consumables Extracted 10-4b Secondary Consumables 10-4c Third Removal Consumables 10-4d Fourth Extraction Consumable 11 Flexible tube 11a First flexible tube 11b Second flexible tube 11-1 Tube Network 11-2 Filling part 20 Structure, tray 20a First end 20b Second end 21 Recess 22 screws 23a, 23c side wall 23b End wall 24 Second recess 30 Lid 31a, 31c side wall 40 frames 41 Tube Retaining Element 50 different devices 70 Housing 70a first end 70b second end 71 Cavity 72 Removable Cover 73a, 73c side wall 73b End wall 74 recess 75 Clamp 76 Handle, means for engagement 77 Cooling Means 77a External Airport 77b Internal Airport 77c Second External Airport 78 Ribs 80 Second Part 81 Tube Retaining Element 100 Closure System 101 First Tool 102 Second Tool 110 Filling / Finishing Station, Processing Station 111 base unit, 111a First Part 111b Second part 115 Housing 120 Automated means for mixing, mixing systems 122 Mixed Zone 130 First Automated Transport System 132 Rail 134 intake conveyor housing 140 Second Automated Transport System 142 Rail 144 take-out conveyor housing 160 Tube Welding Machine 162 Robot Arm 170 Automated means for transport, peristaltic pumps 172 Robot Arm 173 Valved Air Source 174 Sterile Air Filter 175 Flow Sensor 180 Automated means for sealing, tube sealer 190 Storage Section 192 First Part 194 Second Part 200 Closure System 250 Mobile Units 260 Automated means for operating fluid connections 270 Automated means for transferring reagents 280 Automated means for sealing 290 Storage Section 292 First Part 293 First Hatch 294 Second Part 295 Second Hatch 300 Closure System 310 Processing Station 312 Slots 320 Mixed System 322 Mixed Zone 350 Mobile Unit 352 base unit 360 Automated means for operation 362 Robot Arm 370 Automated means of transport 372 Robot Arm 380 Automated means for sealing 390 Storage Section

Claims

1. A closed system for mixing fluids used in a bioprocessing system, An automated means for operating a tube weld between a first tube fluidly connected to a first consumable and another tube fluidly connected to a mixed consumable, wherein the tube weld forms a closed fluid connection between the first consumable and the mixed consumable, An automated means for transferring the first fluid contained in the first consumable to the mixed consumable via the closed fluid connection, Automation means for determining the amount of fluid transferred to or from the mixed consumables, Equipped with, The closure system is further configured to operate a tube weld between a second tube fluidly connected to a second consumable and another tube fluidly connected to the mixed consumable, thereby transferring the second fluid between the second tube and the other tube to mix with the first fluid in the mixed consumable.

2. The system according to claim 1, further configured to operate a tube weld between the other tube fluidly connected to the mixed consumable and a further tube fluidly connected to the extraction consumable, thereby transferring at least a portion of the mixture of the first fluid and the second fluid contained in the mixed consumable to the extraction consumable.

3. The system according to claim 1, further comprising automated means for sealing and / or cutting each tube after the transfer of the fluid to or from the mixed consumable is complete.

4. The system according to claim 1, comprising an automated processing station, and more preferably a standalone automated processing station.

5. The system according to claim 4, wherein at least one of the automated means for operating the tube welding section, the automated means for transferring fluid, and the automated means for sealing is provided on a separate mobile unit configured to automatically cooperate with the automated processing station.

6. The system according to any one of claims 1 to 5, wherein at least one of the automated means for operating a tube weld, the automated means for transferring fluid, and the automated means for sealing comprises a robotic device such as a robotic arm having an end effector configured to perform one or more of the operations.

7. The system according to claim 1, wherein the automated means for transfer comprises a pumping configuration configured to apply a pumping action, preferably a peristaltic pumping action, to a flexible tube.

8. The automated processing station comprises a plurality of slots configured to hold the first consumable, the second consumable, and the dispensed consumable, preferably the slots are arranged adjacent to the mixing system to facilitate the operation of the tube welding portion between the first consumable, the second consumable, and the dispensed consumable and the mixed consumable, according to claim 4.

9. The system according to claim 4, wherein the automated processing station comprises an automated conveying system configured to supply at least one of the first and second consumables to the mixing system in order to supply at least one of the first fluid or the second fluid to the mixing system.

10. The system according to claim 9, wherein the automated transport system is further configured to supply both the first and second consumables to the mixing system in order to supply both the first fluid and the second fluid to the mixing system, and the system further comprises an automated transport system configured to remove the removed consumables from the mixing system after the resulting mixture of the first and second fluids has been filled.

11. The system according to claim 1, further comprising means for identifying at least one identification mark among the consumables.

12. The system according to claim 1, further comprising one or more sensors configured to measure one or more parameters of the consumables.

13. An automated method for mixing fluids in a closed system used in a bioprocessing system, wherein the method is: A step of mixing a first fluid contained by a first consumable and a second fluid contained by a second consumable in a mixing consumable, and then taking out the resulting mixture of the first and second fluids and filling a consumable, wherein each consumable comprises a flexible tube configured to form a fluid conduit to the one or more fluids contained by the consumable, A step of operating the tube welding portion between two of the consumables in order to transfer fluid between the consumables, The steps include determining the weight of a certain volume of the mixture of the first fluid and the second fluid obtained, which is transferred to the consumable item being removed, A method comprising the step of sealing a portion of each flexible tube so that the one or more fluids within the consumables can be isolated from the surrounding environment before disconnecting a fluid connection between two consumables.

14. A device for holding consumables used in an automated bioprocessing system, wherein at least one flexible tube is fluidly connected to the consumables, and the device is A first part for holding the aforementioned consumables, A second portion configured to hold the aforementioned flexible tube, Equipped with, The second portion of the device is configured to hold the flexible tube at least partially along a predetermined path.

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