GB2614464A - Bioprocessing system - Google Patents

Abstract

A bioprocessing system, comprising: a series of processing stations for performing operations for bioprocessing; an automated system, comprising: means for manipulating a fluid connection between a first container and a separable second container whereby to create an aseptic connection that enables a controlled transfer of fluid or cell material between the first container and the second container, wherein the means for manipulating a fluid connection is configured to create an aseptic connection that can be disconnected after the transfer of fluid or cell material is complete to enable a further such fluid connection to be manipulated between the first container and a separable third container, and one or more sensors configured to detect fluid leakage from the aseptic connection; and means for controlling an automated sequence of operation of the processing stations.

Description

BIOPROCESSING SYSTEM

FIELD OF THE INVENTION

The present invention relates to a bioprocessing system for manipulating biologic samples, and more specifically to an automated bioprocessing system, which may be used to perform automated cell therapy for example.

BACKGROUND TO THE INVENTION

Therapeutics are increasingly using cells rather than small molecules as the starting point. The approaches to manufacturing these products are rapidly evolving to keep up with constantly emerging new therapies. In recent years, there has been an increased use of a number of new classes of cell therapies.

One class is autologous cell therapies.

Autologous cell therapies are a promising class of therapy, which have significant clinical and commercial potential ranging from treating cancer to fixing genetic defects. These therapies involve taking cells from a patient, manipulating the cells over the course of days to weeks, and re-introducing the cells back into that patient's body to produce a therapeutic effect. The steps taken during autologous cell therapies are often complex: for example a typical CAR-T process may involve a sequence of steps starting with a cryopreserved leukopak, thawing, washing to remove DMSO, enrichment of T cells, activation, transduction, expansion, concentration, formulation fill finish into an IV bag, and cryopreservation, with several other intermediate washing steps. To date, these processes have typically been performed with labour intensive manual processes in expensive class five cleanrooms or isolators.

Due to the complexity of bioprocessing, there is a desire to automate the process while maintaining a closed system that removes the need to perform the steps in such a high grade cleanroom. A closed system is one where there is no exposure of the process to the surrounding environment such that there can be no ingress of contaminants from the environment or cross contamination from other processes that are being performed simultaneously. There are systems that have tried to provide a solution to this, but involve a complex consumable element, which connects the sample to all the other necessary processing stations, for example via a tube that is fluidly connected to the consumable element, and provides pumping and valving to allow the steps to be performed in a particular sequence. However, these consumable elements are very complex to manufacture and install and are consequently relatively expensive, and potentially unreliable. Each consumable element needs to be individually tailored to the process being performed, making the system inflexible to modifications and expensive to adapt to new processes. Furthermore, typically only one consumable element can be operated / manipulated at once by these systems, which makes the bioprocessing expensive and space inefficient to scale up for use with multiple patients. Often, the system is still not capable of performing all the steps required for a complete bioprocessing method, and instead multiple isolated units may be operated in sequence, which means that additional labour and expertise is required to transfer the cells (e.g. patient samples) between the isolated units. This also introduces a further risk of cross contamination, and there is no simple way to validate that contamination has not occurred.

One way of forming sterile connections between tubes is tube welding, a process that is typically performed manually. Sterile tube welders allow connections to be made between two tubes with closed ends without exposing the contents of either tube to the environment, and are the only widely accepted means of reusably creating connections within a single system. However, existing tube welding systems are generally heavy, require precise manual manipulation to insert the tubes into the welder correctly, and need visual inspection by an operator after each weld to confirm successful welding. As a result of the manual operation, large portions of the tubes are often discarded by the user during each tube welding operation. Furthermore, conventional tube welding systems are not additionally configured to cut through a tube, and reseal securely the ends of the separated tubes afterward, which means that they cannot maintain closure of the contents when disconnecting tubes.

There has been little progress in attempts to automate bioprocessing systems that utilise tube welding, due to the substantial complexity and size of existing tube welding systems, and the strict requirements for reliability when applied to a bioprocessing system.

There is a need for a bioprocessing system that can optionally handle multiple patient samples at the same time, and for improved ways of manipulating aseptic fluid connections for the closed transfer of fluids and cell material, ideally which can maintain sterility / prevent contamination of the consumables and patient samples irrespective of whether the manipulation is performed within a sterile or non-sterile atmosphere in such a system.

SUMMARY OF THE INVENTION

Described herein is a bioprocessing system, comprising: a series (e.g. a plurality) of processing stations for performing operations for bioprocessing; an automated system, comprising: means for manipulating a fluid connection between a first container and a separable second container whereby to create an aseptic connection that enables a controlled transfer of fluid or cell material between the first container and the second container, wherein the means for manipulating a fluid connection is configured to create an aseptic connection that can be disconnected after the transfer of fluid or cell material is complete to enable a further such fluid connection to be manipulated between the first container and a separable third container; and means for controlling an automated sequence of operation of the processing stations.

Advantageously, such a system may be used to process multiple patient samples at the same time, while maintaining separation between the different samples, e.g. held in one or more of the containers. As referred to herein, a "container" may be considered to be a form of "consumable" (element) in the context of the present invention.

The means for manipulating a fluid connection may be further configured to seal a disconnected fluid connection, such that the transfer of fluid or cells to or from the first and second containers is inhibited (and preferably prevented).

The processing system may further comprise means for installing the one or more containers into each of the series of processing stations and moving the containers between stations.

The processing system may further comprise means for enabling the transfer of fluid or cells between aseptically connected containers.

The processing system may be located within a non-sterile atmosphere.

The processing system may further comprise means for inspecting the fluid connection, preferably wherein the fluid connection is inspected automatically.

The processing system may further comprise a camera with a microscope lens to inspect the aseptic connection between the tubes and/or to identify each of the containers. The processing system may further comprise one or more sensors configured to detect fluid leakage from the aseptic connection, for example when fluid is pumped through the tubes once joined. The one or more sensors may comprise at least one of: a fluid sensor and a pressure sensor.

The means for manipulating a fluid connection may be further configured to apply to the joined tubes a force (e.g. a tensile force) on either side of the aseptic connection such that a mechanical property can be determined.

The automated sequence of operation(s) may be controlled according to one or more predetermined workflow(s), preferably one or more reconfigurable bioprocessing workflow(s).

Preferably, the series of processing stations includes means to perform concentrations, washing and incubation.

The system may be configured to process multiple containers at the same time, preferably wherein two or more of the containers contain patient samples. A first container containing a first patient sample may be processed using a different predetermined workflow to a second container containing a second patient sample.

Also described herein is an automated system for fluidly connecting two containers (e.g. for use with the above-described bioprocessing system), wherein at least the first container has a tube fluidly connected at a first end thereto, with a second end of the tube configured to form an aseptic connection with another such tube, the automated system comprising: a robotic device configured to engage the second end of the tube that is fluidly connected to the first container, and to position the tube into one or more positions to be manipulated; and means for manipulating a portion of the tube towards the second end of the tube whereby to configure the second end of the tube for creating an aseptic connection with another such tube.

The means for manipulating a portion of the tube may further comprise: means for clamping a portion of the tube towards the second end of the tube whereby to form a pinched portion in the tube such that the tube is fluidly sealed upstream of the pinched portion; and means for removing a section of the tube downstream of the pinched portion whereby to remove the second end of the tube such that a new second end of the tube is thereby formed that has not previously contacted another such tube.

The automated system may further comprise means for enabling a controlled transfer of fluid and cell material between the first container and the second container The means for enabling a controlled transfer of fluid and cell material may be further configured to draw fluid away from the pinched portion in the tube before the aseptic connection is made with another such tube.

The means for clamping a portion of the tube may be a station of the processing system separate to the robotic device. The means for removing a section of the tube may be a station of the processing system separate to the robotic device. At least one of: (i) the means for clamping a portion of the tube; and (ii) the means for removing a section of the tube, may be configured as an end effector for a robotic arm.

The means for removing a section of the tube may comprise at least one of: a cutting blade and a heating device, for example a laser, an RF heater, and ultrasound heater, or an inductance heater. The means for removing a section of the tube may be configured to remove a section of tube without directly contacting the tube.

The automated system may further comprise means for manipulating the tube such that the pinched portion formed in the tube remains fluidly sealed when the tube is removed from the means for clamping.

The automated system may further comprise means for manipulating the tube, once joined with another such tube, to release the pinched portion whereby to establish a fluidic path through the joined tubes. The means for manipulating a portion of the tube may further comprise means for sterilising the second end of the tube. The tube may further comprise an internal valve configured such that the flow of fluid or cell material into or out of the first container through the tube can be inhibited (preferably prevented) when not connected to another such tube.

The automated system may further comprise means for joining the second end of the tube with another such tube. The means for joining the tubes may comprise means for welding the tubes together to form a tube weld. The means for joining the tubes may comprise a connection piece configured to connect between the second end of the tube and the other such tube, preferably wherein the connection piece is configured to receive a sterilizing fluid, for example steam, once the tubes are fluidly connected whereby to create the aseptic connection.

The end effector may comprise at least one gripping unit configured to engage and move the tube. The tube may comprise a holding device located around the tube, whereby the gripping unit grips the holder in order to engage and move the tube. The holding device may be movable along a length of the tube, such that the tube can be translated (e.g. rotated or linearly) through the holding device when the gripping unit grips the holding device. The tube may have one or more protrusions on its external surface for the gripping unit to engage.

Also disclosed herein is a method of performing bioprocessing in a system having a series of processing stations for performing operations for bioprocessing using one or more containers (e.g. such as the bioprocessing system described above), the method comprising: configuring an automated system to: manipulate a fluid connection between a first container and a separable second container whereby to create an aseptic connection that enables a controlled transfer of fluid or cell material between the first container and the second container, wherein manipulating the fluid connection creates an aseptic connection that can be disconnected after the transfer of fluid or cell material is complete to enable a further such fluid connection to be manipulated between the first container and a separable third container; and controlling an automated sequence of operation of the processing stations.

The method may further comprise controlling the automated sequence of operation according to a predetermined workflow, preferably a reconfigurable bioprocessing workflow.

Also described herein is a robotic end effector for joining a first tube to another such tube (preferably via a tube weld) whereby to form a fluidic path therethrough, comprising (e.g. one of more of the following): means for engaging the tube and moving it into one or more positions to be manipulated; and/or means for clamping a portion of the tube whereby to form a pinched portion of the tube towards an end of the tube such that the tube is fluidly sealed upstream of the pinched portion; and/or means for removing a section of the tube downstream of the pinched portion whereby to remove said end of the tube such that a new end of the tube is thereby formed within the pinched portion that has not previously contacted another such tube; and/or means for joining the pinched portion at the new end of the tube with a corresponding pinched portion of another such tube; and/or means for manipulating the tube, once joined with the another such tube, to release the pinched portion whereby to establish a fluidic path between the joined tubes. In one aspect, the robotic end effector may comprise all of these recited features.

As used herein, the term "bioprocessing" preferably includes cell therapy, such as autologous and allogenic cell therapies, as well as vaccines and (small batch) bioprocess, for example.

As used herein, the term "automated system" preferably connotes a system operated and/or controlled by automation, and which term preferably includes one more of the following: robotic devices, conveyers, one or more actuators configured to engage and/or move containers or indeed any combination of these features that are capable of moving and/or manipulating the containers and/or tubes within the system.

As used herein, the term "robotic device" preferably connotes an automated machine or device programmed to perform specific mechanical functions, and which term preferably includes robots, cobots, x-y-robots, robotic arms, and one or more actuators, possibly also comprising one or more robot end effectors, and will typically also include one or more sensors, microprocessors and power supply.

As used herein, the term "aseptic connection" preferably connotes a connection where contents of the respective containers being connected are not exposed to the surrounding air or atmosphere. The term "aseptic connection" may equivalently be referred to as a "closed connection" or a "sterile connection", for example As used herein, the term "fluid" preferably connotes liquid and/or gas, and may further include material such as cell material contained therein It will be understood by a skilled person that any apparatus feature described herein may be provided as a method feature, and vice versa. It will also be understood that particular combinations of the various features described and defined in any aspects described herein can be implemented and/or supplied and/or used independently.

Moreover, it will be understood that the present invention is described herein purely by way of example, and modifications of detail can be made within the scope of the invention. Furthermore, as used herein, any "means plus function" features may be expressed alternatively in terms of their corresponding structure

BRIEF DESCRIPTION OF THE DRAWINGS

Example embodiments of the present invention will now be described with reference to the accompanying figures, in which: Figure 1 shows a schematic diagram of an embodiment of an automated bioprocessing system; Figure 2 shows an example of a peristaltic pumping unit for pumping fluid along a tube; Figure 3 shows an example of a tube suitable for use within the automated bioprocessing system; Figure 4 shows a cross section through another example of a tube suitable for use in the automated bioprocessing system; Figure 5 shows a gripping unit and a tube adapted to be held thereby; Figure 6a to 6c show various different consumables suitable for holding media or reagents for use in the automated bioprocessing system, suitable for use within a centrifuge in the automated bioprocessing system, and suitable for use as a cell expansion vessel in the automated bioprocessing system, respectively; Figures 7a to 71 show a first embodiment of an apparatus for forming aseptic connections between tubes in the automated bioprocessing system, at various steps along the connection process; Figures 8a to 8d show the first embodiment of the apparatus for forming aseptic connections between tubes in the automated bioprocessing system, at various steps along a disconnection process; Figures 9a to 9d show a second embodiment of an apparatus for forming aseptic connections between tubes in the automated bioprocessing system, at various steps along the connection process; Figures 10a to 10d show the second embodiment of the apparatus for forming aseptic connections between tubes in the automated bioprocessing system, at various steps along the disconnection process; Figure 11a shows two tubes each with a flange at an end, and Figure 11b shows the tubes of Figure 11a after the tubes have been connected using the flanges; Figures 12a to 12d show an apparatus for forming the flanges of Figures 11a and 11b; Figure 13 shows a third embodiment of an apparatus for forming aseptic connections between tubes in the automated bioprocessing system; Figures 14a and 14b show a fourth embodiment of an apparatus for forming aseptic connections between tubes in the automated bioprocessing system, at two steps along the connection process; Figures 15a and 15b show a fifth embodiment of an apparatus for forming aseptic connections between tubes with flanges in the automated bioprocessing system, at two steps along the connection process; Figures 16a to 16d show a sixth embodiment of an apparatus for forming aseptic connections between tubes in the automated bioprocessing system, at various steps along the connection process, and Figures 16e and 16f show the seventh embodiment of the apparatus for forming aseptic connections between tubes in the automated bioprocessing system, at two steps along the disconnection process; Figure 17a shows an eighth embodiment of an apparatus for forming aseptic connections between tubes in the automated bioprocessing system, and Figure 17b shows the connector used to form the connection of Figure 17a; Figure 18 shows a ninth embodiment of an apparatus for forming aseptic connections between tubes in the automated bioprocessing system; Figure 19 shows a tenth embodiment of an apparatus for forming aseptic connections between tubes in the automated bioprocessing system; and Figure 20 shows an eleventh embodiment of an apparatus for forming aseptic connections between tubes in the automated bioprocessing system.

DETAILED DESCRIPTION

An exemplary embodiment of a bioprocessing system 1 according to the present invention is shown in Figure 1. The system 1 has a series (e.g. a "plurality") of processing stations 20 configured to perform processing steps for bioprocessing, and an (automated) system for automating (at least part of) the process.

In this exemplary embodiment, the system 1 has processing stations 20 in the form of a thawing station 4, a centrifuge 6, a magnetic cell separator 8, a controller rate freezer 10, and a refrigerator 11, though additional and alternative stations 20 (not shown) for processing can be installed depending on the specific process being performed by the system 1.

The processing stations 20 may include any combination of a concentration station, a cryopreservation unit, a washing station, a cell enrichment station, a cell expansion station, a cell selection station, stations for determining cell count, cell viability or cell type, or stations for any other suitable processing or analysis step. The system 1 also has an incubator 12 that is large enough to contain and incubate multiple consumables 13 at a time, including under perfusion.

For example, the incubator 12 may be capable of storing twenty consumables 13 and operate at around 37°C, though the number of consumables 13 can be chosen to meet the needs of the particular bioprocessing to be performed. Each consumable 13 may contain cellular samples, reagents or fluids, and each consumable 13 connects to a first end of a tube (150 not shown) which leads to a second end of the tube 150, which is fluidly sealed when unconnected (or "free"). Thus, as referred to herein, a "consumable" may be in the form of a "container", which may for example hold cell material to be processed in a cell therapy process.

All of the consumables 13 and reagents may be pre-loaded in the system 1 before a particular bioprocessing begins, though additional reagents can be added throughout the process if required (for example at day 7 of a 10-day therapy process). The additional reagents may be required for reactivation of cells, or to add additional media to the consumables 13 for example.

A particular bioprocessing may be defined by a bioprocessing workflow, and preferably the system 1 can be configured to carry out several bioprocessing workflows. For example, the system 1 can carry out the same bioprocessing workflow in parallel for multiple patient samples, or it can carry out different bioprocessing workflows in parallel for multiple patient samples. Each bioprocessing workflow may use a different subset of the processing stations 20 in the system 1. In a preferred embodiment, the system 1 comprises stations 20 to perform concentrations, washing and incubation processes.

The system 1 comprises an automated system configured to install one or more consumables 13 into each of the series of processing stations 20 and to move the consumables 13 between stations 20. In this embodiment, the automated system includes a robotic device 2 that can move the consumables 13 between the various stations 20, and can manipulate the tubes 150 connecting to each of the consumables 13. Alternatively, or additionally, the robotic device 2 may be configured to move the processing stations 20 in order to connect the consumables 13 to the processing stations 20.

The robotic device 2 may be mounted on rails 18, which allows the robotic device 2 to have access to all areas of the system 1 such as the stations 20. The robotic device 2 may be configured as a co-operative robot ("cobot"). The robotic device 2 may have a robotic arm 3 for manipulating the consumables 13 and tubes 150, as shown here, or may include a conveyer belt, one or more actuators, or any combination of the above aspects.

The automated system is configured to manipulate a fluid connection between a first consumable 13 and a separable second consumable whereby to create an aseptic connection that enables a controlled transfer of fluid or cell material between the first consumable 13 and the second consumable 13. Here, the robotic device 2 is used to form (or manipulate) fluid connections between the tubes 150 so that separate consumables 13 can be connected together.

The connection between tubes 150 may be performed by an end effector 100 located on the robotic arm 3, or the robotic arm 3 may move and place the tubes within a separate connection unit (not shown) at one of the stations 20 where the tubes 150 are subsequently connected. In either case, the connections between tubes 150 are made aseptically such that the contents of the consumables 13 and tubes 150 are never open or exposed to the surrounding air or atmosphere at any stage.

The fluid connections are also reversible, such that the tubes 150 can be disconnected and reconnected to different consumables 13 as many times as necessary in order to perform the required bioprocessing method. In other words, the automated system is configured to create an aseptic connection that can be disconnected after the transfer of fluid or cell material is complete to enable a further such fluid connection to be manipulated between the first consumable and a separable third consumable. As mentioned above, during both the connection and disconnection, the consumables 13 and tubes 150 never have their contents exposed to the surrounding air or atmosphere such that a controlled transfer of fluid and/or cell material occurs only between the consumables 13 that are connected together As a result, it is not strictly required to have a sterile atmosphere around stations 20, consumables 13, or robotic device 2, but an enclosure 14 may be provided to prevent access by operators and/or to provide a sterile atmosphere or otherwise control the environment for example by controlling the temperature, light levels or other conditions. Several ways to form aseptic connections between the consumables 13 will be discussed later in more detail.

The system 1 also has a pumping unit 30 (not shown) which pumps fluid along the tubes 150 once the robotic device 2 has successfully connected two consumables 13 via their respective tubes 150. The pumping unit 30 may also be located on the robotic arm 3 or may be a static component placed at one of the stations 20 into which the tubes 150 are placed by the robotic arm 3 for pumping to occur. The pumping unit 30 may be a peristaltic pumping unit 30 like the pumping unit 30 shown in figure 2. This pumping unit 30 has a rotating wheel 31 driven by a motor on a shaft (not shown). The pumping unit 30 also has a clamp 32, and prior to a pumping operation, the tube 150 is positioned by the robotic device 2 between the rotating wheel 31 and the clamp 32. The pumping unit 30 subsequently compresses the tube 150 between the rotating wheel 31 and the clamp 32, and when the rotating wheel 31 rotates, it pumps fluid along the tube 150. Furthermore, the pumping unit 30 can be used to prevent any flow of fluid through the tube 150 by compressing the tube 150 between the rotating wheel 31 and the clamp 32 without rotating the wheel 31. While a pumping unit 30 is preferred, transfer of fluids and cell material could for example be effected by way of gravity, or by addition of gas via a sterilising filter.

The robotic arm 3 may have at least one gripping unit (50 not shown) to allow the consumables 13 and the tubes 150 to be held and moved by the robotic device 2. The tubes 150 preferably have a standardised shape and diameter so that connections between tubes 150 can be consistently performed by the robotic device 2. Each tube 150 may have a section that is enclosed by a rigid external casework that can be more easily manipulated by the robotic arm 3. Alternatively, the tube 150 may have a series of protrusions spaced along its external length that are more easily manipulated. For example, figure 3 shows a tube 150 with a series of protrusions in the form of radially (outwardly) extending flange regions 40 that have been pre-moulded at various positions along its length.

Figure 4 shows a cross section through a tube 150 that has a non-circular profile, which may allow the tube 150 to be easily manufactured by attaching two flat strips of material together Furthermore, the tube 150 can more easily be flattened by the gripping units 50 or by the pumping unit 30 in order to pump fluid through the tube 150 or to pinch the tube 150 shut to prevent any movement of fluid. The tubes 150 are preferably formed from a thermoplastic, but could be formed with other materials such as a silicone (elastomeric) material. Figure 5 shows a tube 150 with rigid external casework in the form of handling sections 41. A gripping unit 50 has two grippers 55 which can be used to grip onto the handling sections 41. In this way the grippers 55 can apply tension to the tube 150 to straighten it to be placed into the pumping unit 30 or into another piece of apparatus such a pinch valve (not shown) for preventing flow of fluid.

The robotic arm 3 may also comprise various sensors and cameras to be used during operation of the system 1 or for inspection and quality control. For example, each consumable 13 may be identified by the camera on the robotic arm 3 such as by using a unique bar code or OR code on each consumable 13. The tubes 150 and/or rigid external casework on the tubes 150 may also be identified in this way. This allows every consumable 13 and sample to be uniquely and automatically tracked through a cell therapy process, facilitating integration with Electronic Batch Records (EBRs). Other identification methods may be used, such as by using unique radio-frequency identification (RFID) tags.

For quality control, the cameras and sensors inspect the connections between tubes 150 to verify that a successful connection has been created. The camera may have a microscope lens to allow for a detailed inspection of the connections between tubes 150. During inspection by the cameras and sensors, the connection may be tested in a number of ways. Ultrasound waves may also be used to confirm whether there are cavities in the connection, and/or the gripping unit 50 may be used to apply pressure to the tubes 150 at or near the connection. The gripping unit 50 may be used to apply tension to the connection between the tubes 150 and measure a stress-strain profile of the joined tubes 150. A fluid sensor may be used to detect fluid leakage from the connection. If the measured stress-strain profile, visual inspection by the camera, or parameters measured by the sensors indicate that the connection between tubes 150 is defective, then the tubes 150 may be disconnected and a new fluid connection manipulated until a successful aseptic connection is formed. The quality control may be performed automatically each time a connection is made without input from an operator. The connections between tubes 150 may be isolated from the respective consumables 13 until the quality control has been performed. This may be achieved by pinching the tubes 150 and/or by allowing outflow of fluid only. In this way, even if a defective connection is found, the contents of the consumables 13 still remain isolated from the surrounding air or atmosphere. In the event of a defective connection, the process can be repeated until a satisfactory connection is made before any process materials enter the connection region.

The system 1 has a user interface 15 for a user to control its operation, including the automated system and the processing stations 20. The user interface 15 may also be located remotely to allow for remote monitoring and/or control of the system 1, for example with data stored in the "cloud". The system 1 has a loading hatch 16, where new consumables 13 can be loaded into the system 1, or equivalently where used consumables 13 can be removed from the system 1 after use. The operator can also use the user interface 15 to program the system 1 to perform a particular automated sequence of operations in a particular bioprocessing workflow, thereby providing a means for controlling an automated sequence of operation of the processing stations of the system 1.

An operator can also use the user interface 15 to automatically take regular samples from the process, which can be removed from the system via the loading hatch 16 without exposing any of the contents of the consumables 13 to the environment. The samples may be run on other third party equipment, such as to test for cell count, viability or any other parameter to monitor progress of the cell therapy process. By analysing the samples throughout a cell therapy process, the resulting data allows for adaptive control such as adjustment of gas, media and other parameters for each consumable 13 in the process.

By enabling reversible fluid connections between the consumables 13, each consumable 13 may have a simpler construction than previous consumables, allowing them to be manufactured at a low cost. Since the robotic system can perform all the steps required to execute a complete cell therapy process without human intervention, human error can be eliminated, and the robotic system can perform the steps very reliably. Furthermore, since all the consumables 13 can be disconnected and reconnected at any time, multiple cell therapy processes can be performed in parallel. Similarly, an operator can instruct the system 1 to begin a new therapy process at any time as long as the system 1 is not full.

Additionally, since any two consumables 13 can be connected by the robotic device 2, the process can easily be adapted to introduce additional steps or to perform an entirely different cell therapy method. To do so, the system 1 could be programmed to included different or additional steps and make use of additional consumables 13 or stations 20. For example, the system 1 could perform cell therapy methods such as CAR-T, NK cells, Treg therapies, HSCs or any other suitable process.

An example of a cell therapy process that can be performed by the bioprocessing system 1 will now be described.

First, an operator loads a set of consumables 13 via the loading hatch 16. These consumables 13 comprise a processed blood sample contained in a patient leukapheresis pack (leukopack), bags for media and reagents, and a bag to receive waste products.

After loading the consumables 13, the operator programs the desired cell therapy process via the user interface 15. Initially, the robotic device 2 places the leukopack into the thawing station 4 to thaw the contents of the leukopack.

Subsequently the end effector 100 of the robotic device 2 manipulates an aseptic connection between the leukopack and a consumable 13, and the pumping unit 30 transfers the contents of the leukopack into a consumable 13 via the aseptic connection. The robotic device 2 moves this consumable 13 into the centrifuge 6, which is may be a drum based centrifuge 6. The robotic device 2 sequentially makes a number of connections between the consumable 13, the media bag, and the waste bag to wash the sample multiple times with a buffer solution. For example the consumable 13 may be washed three times in this way. Then the blood sample is moved from the consumable 13 to a temporary holding bag, such that density gradient media are added from one of the reagent bags to the consumable 13, before the blood sample is returned to the consumable 13 where density gradient separation is performed.

Now the blood sample is transferred to a fresh consumable 13, where further aseptic connections are made by the robotic device 2 in order to add activation reagents. The robotic device 2 gently rocks and/or rotates the consumable 13 to mix the activation reagents with the blood sample, before transferring the consumable 13 to the incubator 12 for 24 hours. Then the consumable 13 is removed from the incubator 12, and the blood sample is transferred to a retronectin-containing consumable 13 where a viral vector is subsequently added. This consumable 13 is returned to the incubator 12 for 24 hours. After the robotic device 2 removes the consumable 13 from the incubator 12, the robotic device 2 transfers the blood sample into a consumable 13 suitable for use in the centrifuge 6. After the consumable 13 is removed from the centrifuge 6, the blood sample may be washed again several times by adding buffer solution from the media bag and removing waste to the waste bag.

The blood sample is then moved to an expansion vessel consumable 13 connected to a perfusion system and placed in the incubator 12 for seven days for cell expansion. Finally, the blood sample is removed from this consumable 13, transferred to another consumable 13 so that the blood sample can be concentrated in the centrifuge 6, before being transferred to an infusion bag where cryoprotectant and other formulation additives are added. This infusion bag is then placed in the controlled rate freezer 10 and cryopreserved, before being returned to the operator through the loading hatch 16.

While the above exemplary automated process follows a number of steps and requires the use of multiple consumables 13, each of the consumables 13 can be very simple in its form. For example, the bags for media and reagents may be like the consumable 300 shown in figure 6a, which has an inlet/outlet 301 where a tube 150 is connected. Figure 6b shows a consumable 310 suitable for use in the centrifuge 6, which as well as having an inlet/outlet 311, it also has a sterile air filter 312, and a vacuum actuated bung 313 to pull fluid in a chamber during use of the centrifuge 6. Examples of suitable consumables, centrifuge vessels and centrifuges can be found in EP1144026 and US10562041, and as they are well-known there is no need to described them further herein. Figure 6c shows a consumable 320 appropriate for use as an expansion vessel for the cell expansion step. It has an inlet 321 for media 326, an outlet 322 for waste, and an inlet/outlet 323 for cell inoculation, sampling, and/or cell harvest. The expansion vessel 320 contains cells 325 and a gas permeable membrane 324. As already discussed, these consumables 13 can be manufactured much more reliably and at a much reduced cost compared to prior art consumables. The system 1 can therefore provide an automated cell therapy process without (substantial) human intervention.

With reference to figures 7a to 71, a preferred embodiment of a method of manipulating fluidic aseptic connections between tubes 150 is described in detail. Here, the robotic system of the processing system 1 comprises a robotic arm 3 having an end effector 100. The end effector 100 is attached to the robotic arm 3 and has two gripping units 110a, 110b. The gripping units 110a, 110b may be the grippers 55 of gripping unit 50 described earlier, or could be a separate gripping units. The end effector 100 is configured to connect a first tube 150a and a second tube 150b together while maintaining a seal between the inside of the tubes 150a, 150b and the surroundings (i.e. the contents of the tubes and consumables are not exposed to the atmosphere). Each tube 150a, 150b connects to a respective consumable 13 (not shown). As used herein, the term "upstream" refers to a direction along the tubes 150a, 150b towards the first end of the tubes 150a, 150b that attaches to a respective consumable 13. Similarly, the term "downstream" refers to a direction along the tubes 150a, 150b towards the second "free" end of the tubes 150a, 150b. On each tube 150a, 150b, there is mounted a tube holder 130a, 130b, which can easily be gripped by the gripping units 110a, 110b. The tube holders 130a, 130b may equivalently be referred to as "holding devices" or "holders". The tube holders 130a, 130b can be moved along the tubes 150a, 150b via rotation of precession wheels 135a, 135b (i.e. to translate the tube 150 relative to its respective tube holder 130). The end effector 100 comprises a clamping unit 105 with a first jaw 120 and a second jaw 125 each divided into a first part 120a, 125a, and a second part 120b, 125b. The end effector 100 also comprises a blade 140 that can be moved between the parts of each jaw 120, 125 along a cutting plane.

In figure 7b, the gripping units 110a, 110b are shown to grip the respective tube holders 130a, 130b on the respective tubes 150a, 150b, and the tubes 150a, 150b have been positioned adjacent the clamping unit 105, with the jaws 120, 125 of the clamping unit 105 in an open position.

In figure 7c, the precession wheels 135a, 135b rotate to advance the tubes 150a, 150b through the jaws 120, 125. A camera 160 is used to confirm that each tube 150a, 150b is correctly positioned in the clamping unit 105, and that both tubes 150a, 150b cross the cutting plane. The tube holders 130a, 130b, may contain magnets to facilitate alignment of the tubes 150a, 150b in the clamping unit 105. The jaws 120, 125 of the clamping unit 105 may be coated with a low friction material, such that the tubes 150a, 150b slide within the clamping unit 105 and Poisson's ratio effects are minimised.

In figure 7d, the jaws 120, 125 of the clamping unit 105 are clamped together to pinch the tubes 150a, 150b flat at the cutting plane, thereby preventing any flow of fluid through the tubes 150a, 150b. Since the dimensions of all the tubes 150 in the system 1 are identical, the jaws 120, 125 of the clamping unit 105 are constructed to be stiff so that they fully encase the tubes 150a, 150b when clamped, with controlled tolerances to fully define tube form factor and alignment, irrespective of the tube tolerances. The tubes 150 may have pre-moulded flange regions, such as large flat flange regions to facilitate alignment with the clamping unit 105.

In figure 7e, the pumping unit 30 is used to pump fluid away from the clamping unit 105 in the direction of the arrows. This ensures that both the tubes 150a, 150b are fully dry at the cutting plane, and helps to further collapse the tubes 150a, 150b and keep them pinched shut.

In figure 7f, the blade 140 is heated by a heat source (not shown) to between 300°C and 400°C to sterilise and depyrogenate the blade 140. The heat source may use resistive heating to heat the blade 140 or a mounting block (not shown) in contact with the blade 140, or the blade 140 may be heated without direct contact such as through a laser heater. The blade 140 is allowed to cool partially before moving the blade 140 along the cutting plane between the first parts 120a, 125a and second parts 120b, 125b of the jaws 120, 125, thereby cutting through the tubes 150a, 150b.

Figure 7g depicts a cutaway through the clamping unit 105 viewed from above after the blade 140 is moved along the cutting plane to cut the tubes 150a, 150b. As a result, the first tube 150a is cut into a first part 150a connecting to its respective consumable 13, and a second part 150a' which previously led to the sealed end of the tube 150a. Similarly, the second tube 150b is cut into a first part 150b connecting to its respective consumable 13, and a second part 150b' which previously led to the sealed end of the tube 150b.

In figure 7h, the first parts 120a, 125a of the clamping unit 105 are moved relative to the second parts 120b, 125b of the clamping unit 105 to align the parts of the first tube 150a and second tube 150b that connect to their respective consumables 13. The blade 140 remains between the first tube 150a and the second tube 150b, and transfers the heat from the heat source to melt the ends of the tubes 150a, 150b. The blade 140 may be held between the tubes 150a, 150b for a predetermined time period and may have a predetermined heat profile. In this example, the first parts 120a, 125a translate relative to the second parts 120b, 125b of the clamping unit 105 in order to align the tubes 150a, 150b, but is should be appreciated that the alignment could also be performed in other ways, such as by rotating one of the parts of the clamping unit 105 relative to the other part. An infra-red camera or infra-red laser could be used in a closed loop to confirm that the ends of the tubes 150a, 150b have reached the correct temperature for welding and that a uniform temperature is reached. Alternatively, a thermistor, a thermocouple, or a resistance temperature detector (RTD) may be mounted on a component such as the blade 140, the mounting block or the heat source in order to monitor the temperature.

In figure 7i, the blade 140 is removed from between the first parts 120a, 125a and second parts 120b, 125b of the jaws 120, 125, and the clamping unit 105 brings the two tubes 150a, 150b into contact by translating the first parts 120a, 125a and second parts 120b, 125b towards each other The heat that was previously transferred to the tubes 150a, 150b by the blade 140 welds the tubes 150a, 150b together In figure 7j, the first jaw 120 and second jaw 125 of the clamping unit 105 are moved apart to unclamp the tubes 150a, 150b, which are now connected together to form a single tube 150.

In figure 7k, the camera 160 is used to inspect the connection between the two tubes 150a, 150b. The camera 160 has a microscope lens and is connected to a processing unit (not shown) which identifies if a weld is successful, and the camera 160 may be able to detect infra-red (IR) radiation. The precession wheels 135a, 135b may be rotated to apply a tensile force to the tube 150 in the direction of the arrows, and can simultaneously measure a stress-strain profile of the tube 150. The stress-strain profile may also be analysed by the processing unit to confirm whether the weld is successful.

Other mechanical tests may be used, such as a torsion test or a vibration test, for example. An ultrasound source or X-ray source may also be used to test for the presence of cavities in the connection. Fluid may also be pumped through the tube 150, and the camera 160 may be used to detect the presence of a leak.

Alternatively, the connection may be located in a sealed container with a pressure sensor that indicates a leak by detecting a pressure change inside the container Alternatively, external air pressure may be supplied to the sealed container and the camera 160 may observe whether air leaks into the connection. Alternatively, air may be pumped into the tubes 150a, 150b prior to welding, and then a vacuum could be applied in the sealed container to see whether air leaks out. A biocompatible die may be added to the outside of the weld. If the processing unit determines that the weld is not successful, the tube 150 may be re-clamped and re-welded. The inspection of the connection may be performed before the tubes 150a, 150b are released by the clamping unit 105. By keeping the tubes 150a, 150b pinched during inspection, even if a leak is present at the connection, the contents of the consumables 13 still remain isolated from the surrounding air and atmosphere.

In figure 71, the tube 150 is still pinched at the connection point leading to a kink that prevents flow of fluid through the tube 150. In order to open out the kink, the tube 150 is manipulated perpendicular to the direction in which the tube 150 was pinched by the clamping unit 105 in order to open the tube 150 to allow fluid flow past the connection point. The manipulation may be performed by one of the gripping units 110a, 110b, or by a separate gripping unit attached to the robotic arm 3. Alternatively, the gripping units 110a, 110b may rotate the tube by 90° inside the clamping unit 105 and partially re-clamp the tube 150 to remove the kink. There are other methods to open the tube 150, such as by applying a vacuum outside the tube 150, or by embedding magnets into the tube 150, welding a spring into the tube 150 to open the tube 150 when the clamping unit 105 releases the tube 150, or by embedding a shape memory allow into the tube 150, which can be actuated to change the shape of the tube 150. The inspection step described previously may also be performed after the tubes 150a, 150b are opened, which may provide a better functional test for the tubes 150a, 150b. Preferably the inspection step is performed both before the tubes 150a, 150b are released by the clamping unit 105, and after the tubes 150a, 150b are opened to allow fluid flow.

Now that the connection between the original tubes 150a, 150b is complete, the pumping unit 30 can be operated to pump fluid through the tube 150 between the consumables 13 in order to perform a step in the cell therapy process.

The disconnection process of the two consumables 13 will now be described with reference to Figures 8a to 8d.

In figure 8a, the jaws 120, 125 of the clamping unit 105 are closed to pinch the tube 150 that connects between the two consumables 13 (not shown). The clamping unit 105 for disconnecting the consumables 13 may be located on a different end effector 100 to the clamping unit 105 used to connect the consumables 13. In figure 8b, the blade 140 is heated by the heat source (not shown) to between 300°C and 400°C to sterilise and/or depyrogenate the blade 140. The heating profile used during disconnection may be different to the heating profile used during connection, in order to better seal the tube. The blade 140 is allowed to cool partially. In figure 8c, the blade 140 is moved along the cutting plane between the first parts 120a, 125a and second parts 120b, 125b of the jaws 120, 125, thereby cutting the tube 150 into a first tube 150a and a second tube 150b, each connecting to a respective consumable 13. The blade 140 remains between the tubes 150a, 150b for a predetermined time period to melt the ends of the tubes 150a, 150b. The predetermined time period used to melt the ends of the tubes 150a, 150b during disconnection may be different to the predetermined time period used to melt the ends of the tubes 150a, 150b during connection. In figure 8d, the blade 140 is removed from between the first parts 120a, 125a, and the second parts 120b, 125b of the jaws 120, 125 of the clamping unit 105. The jaws 120, 125 of the clamping unit 105 are opened to release the tubes 150a, 150b from the clamping unit 105. The gripping units 110a, 110b can now release the tube holders 130a, 130b, or manipulate the tube holders 130a, 130b to attach one or both of the tubes 150a, 150b to a different tube 150 connecting to a separate consumable 13 for a subsequent step in the cell therapy process. If the end effector 100 for disconnecting the consumables 13 is a different end effector 100 to the one for connecting the consumables 13, different heat sources and/or cutting methods may be used. For example, an RE source may be used to seal the tubes 150a, 150b during the disconnection process.

Various alternative "non-contact" methods for aseptically connecting and disconnecting two tubes 150a, 150b will now be described with reference to Figures 9 to 13.

Figure 9a shows two tubes 150a, 150b to be connected together, each tube 150a, 150b terminating in a closed end. In figure 9b, the heat source directly applies heat to the closed ends of the tubes 150a, 150b as indicated by the arrows. The heat source may be a source of electromagnetic radiation such as a laser that delivers light at infra-red or radio frequencies. The material that forms the tube 150 may contain additives to improve absorption of laser energy, or painted in a material that absorbs laser light. Preferably the additives enable two-photon polymerisation, which requires a high laser intensity for any activation, and would enable laser light to be non-linearly concentrated on the welding end of each tube 150, even when shown from the outside. Alternatively, the heat source may be a source of ultrasound waves, or the tubes 150 may contain additives that cause them to heat up during use of an induction heater. Any of the above heating methods, including the use of a wire or blade 140 can be used in combination.

In figure 9c, the heated ends of the tubes 150a, 150b are pressed together so that the tubes 150a, 150b weld together to form a single tube 150. This may be performed by using the precession wheels 135a, 135b described previously, or by directly manipulating the tubes 150a, 150b with the gripping units 110a, 110b.

In figure 9d, the kink at the connection of the tube 150 is removed using a similar method to those described previously. Inspection and quality control steps like the ones already discussed may also be applied using this process.

Figure 10a shows a tube 150 to be disconnected into two parts. In figure 10b, the tube is pinched inside a clamping unit 105 like the one previously described, where a first jaw 120 of the clamping unit 105 is divided into a first part 120a and a second part 120b, and a second jaw 125 of the clamping unit 105 is divided into a first part 125a, and a second part 125b. A space remains between the first parts 120a, 125a and the second parts 120b, 125b of the jaws 120, 125 when the tube 150 is clamped between the first jaw 120 and the second jaw 125. In figure 10c, the heat source directly applies heat to the tube 150 between the first parts 120a, 125a and the second parts 120b, 125b of the clamping unit 105, as shown by the arrow. As a result, the heat source cuts through the tube 150 into a first part 150a and a second part 150b. In figure 10d, the heat source continues to apply heat to the tubes to ensure that the cut ends of the tubes 150a, 150b are closed to the surrounding air Figure 11a shows two tubes 150a, 150b to be connected together via flanges 151a, 151b formed at their respective ends. In the depicted configuration, the two tubes 150a, 150b have been brought together using methods previously discussed. In figure 11b, the tubes are joined, welded or clamped together at the positions marked 170 such that a seal is present at the positions marked 175. The tubes 150a, 150b may be heated using any of the methods described previously in order to weld them together A method for forming the flanges will now be described.

Figure 12a shows a tube 150. In figure 12b, the tube 150 is mechanically pinched using a clamp 180 in order to prevent fluid flow through the tube 150. The pumping unit 30 may pump fluid away from the clamp. In figure 12c, the tube 150 is pushed into a heated die 190 to reform the tube 150 into a desired flange 151. In figure 12d, the die 190 is allowed to cool, and separated into a plurality of parts 190a, 190b, 190c, in order to free the flange 151 of the tube 150 from the die 190. The die 190 may be sterilised between each flange-forming operation by an autoclave or by heating the die to a high temperature such as a temperature above 400°C.

Figure 13 shows another apparatus for forming aseptic welds using steam sterilisation and heat welding. As well as a number of components already described in detail, the apparatus comprises a steam chamber 200 with a steam inlet 205. The tubes 150a, 150b to be welded together extend into the steam chamber 200 and may be open ended, but are pinched shut upstream such as using clamps or pumps like those already described. Steam is injected into the steam inlet 205 which sterilises the tubes 150a, 150b and the inside of the steam chamber. The heat from the steam also melts the ends of the tubes 150a, 150b that extend into the steam chamber 200. Then, the precession wheels 135a, 135b rotate to press and weld the ends of the tubes 150a, 150b together. Once welded, the tubes 150a, 150b can be unpinched upstream and the pumping unit 30 can pump fluid through the connected tubes 150a, 150b.

Figure 14a shows two tubes 150a, 150b to be connected together with an alternative method for forming aseptic welds, in which material is added to the tubes 150a, 150b. The tubes 150a, 150b may be cut using any above method, and may be pinched upstream to prevent fluid flow. In figure 14b, material 210 at a high temperature is injected around the ends of the two tubes 150a, 150b, once the tubes 150a, 150b are brought together. The material 210 is applied using an injection mould (overmould) around the outside of the joint between the two tubes 150a, 150b. This may be performed using UV cured glue, or a heat shrink adhesive.

Figure 15a shows two tubes 150a, 150b with flanges 151a, 151b like those described in relation to figures 11a, 11b and 12a to 12d. Here the tubes 150a, 150b, can be aseptically clamped together using the clamping unit 105 without the need for heat sources or welding. Heat may be used to sterilise the flanges 151a, 151b, or to provide additional welding. In figure 15a, the first parts 120a, 125a of the clamping unit 105 clamp the first tube 150a to pinch the tube 150a adjacent to the flange 151a. Similarly, the second parts 120b, 125b of the clamping unit 105 clamp the second tube 150b to pinch the tube 150b adjacent to the flange 151b. In figure 15b, the first parts 120a, 125a of the clamping unit are moved towards the second parts 120b, 125b of the clamping unit 105 to pinch the flanges 151a, 151b of the respective tubes 150a, 150b together. Then, both parts 120a, 120b of the first jaw 120 can move apart from both parts 125a, 125b of the second jaw 125, thereby unpinching the tubes 150a, 150b and providing a continuous tube 150 through which fluid can be pumped by the pumping unit 30 Figure 16a shows two tubes 150a, 150b to be connected together, where the end of each tube 150a, 150b is located in a respective bag 220a, 220b. In figure 16b, the bags 220a, 220b are brought together, and heat is applied to weld and melt the bags 220a, 220b together The heat can be applied using any of the methods previously described. In figure 16c, a laser is used to cut a slot 230 linking the two bags 220a, 220b, and in figure 16d, the tubes 150a, 150b within the bags 220a, 220b are brought together to form a connection. The laser may also be used here to weld the tubes 150a, 150b together. In figure 16e, the reverse process occurs, where the tubes 150a, 150b are moved apart after the tubes 150a, 150b are disconnected, and in figure 12f, the slot 230 between the bags 220a, 220b is welded together again. Now, the two bags 220a, 220b can be disconnected.

Figure 17a shows an alternative apparatus for making aseptic connections, comprising a sterilisation box 230. The sterilisation box 230 provides a locally aseptic environment which means that the tubes 150a, 150b may be connected together using standard connections such as the connector 245 shown in figure 17b. The tubes 150a, 150b each have a respective duckbill valve 240a, 240b that are closed unless fluid is pumped by the pumping unit 30. To operate this apparatus, the tubes 150a, 150b are inserted into the sterilisation box 230, which sterilises the tubes 150a, 150b. Then the tubes 150a, 150b are connected together using the connector 245 immediately after the sterilisation is performed by the sterilisation box 230. The sterilisation box 230 may be an autoclave box that sterilises the tubes 150a, 150b using steam. Alternatively, the sterilisation box 230 may use other methods such as Ethanol sterilisation (Et0H) Ethylene Oxide sterilisation (Et0), gamma radiation, UV sterilisation, electron beam sterilisation, or any combination of the above.

Figure 18 depicts an alternative apparatus for making aseptic connections, comprising a "T"-piece connector 250 with a valved inlet 255 for steam. The tubes 150a, 150b to be connected together each have a valve 260a, 260b, which remains closed unless fluid is pumped by the pumping unit 30. After the tubes 150a, 150b are connected to the T-piece connector 250 while the valves 260a, 260b are closed, steam is pumped through the inlet 255 to sterilise the surfaces before the valves 260a, 260b are opened to allow fluid to flow through the tubes 150a, 150b.

Figure 19 shows a needle free connector 270 with a first part 270a and a second part 270b, than can be fixed together to form a reversible connection. Prior to attachment, the first part 270a and the second part 270b of the needle free connector are sterilised such as by using an autoclave or a laser, or by using a hot blade 275 as shown here.

Figure 20 shows two tubes 150a, 150b each with a respective septum seal 20 280a, 280b. The tubes 150a, 150b can be connected together with a needle 290 which is first heated for sterilisation, and then inserted through the septum seals 280a, 280b.

It will be appreciated that other reversible connections known in the art may be adapted for use within the cell therapy system 1. Such connections may be adapted to have features that are easily handled by the robotic device 2, such as a magnetic collar for easy alignment. It will be appreciated that any feature of a particular embodiment described herein may be applied to another embodiment, in any appropriate combination. It will also be appreciated that particular combinations of the various features described and defined in any aspects described herein can be implemented and/or supplied and/or used independently. Any apparatus feature described herein may also be incorporated as a method feature, and vice versa.

While the forgoing is directed to exemplary embodiments of the present invention, it will be understood that the present invention is described herein purely by way of example, and modifications of detail can be made within the scope of the invention. Furthermore, one skilled in the art will understand that present invention may not be limited to the embodiments disclosed herein, or to any details shown in the accompanying figures that are not described in detail herein or defined in the claims. Indeed, such superfluous features may be removed from the figures without prejudice to the present invention.

Moreover, other and further embodiments of the invention will be apparent to those skilled in the art from consideration of the specification, and may be devised without departing from the basic scope thereof, which is determined by the claims that follow.

Claims (1)

1. CLAIMS1. A bioprocessing system, comprising: a series of processing stations for performing operations for 5 bioprocessing; an automated system, comprising means for manipulating a fluid connection between a first container and a separable second container whereby to create an aseptic connection that enables a controlled transfer of fluid or cell material between the first container and the second container, and means for inspecting the fluid connection, wherein the means for manipulating a fluid connection is configured to create an aseptic connection that can be disconnected after the transfer of fluid or cell material is complete to enable a further such fluid connection to be manipulated between the first container and a separable third container; and means for controlling an automated sequence of operation of the processing stations 2. The system of claim 1, further comprising at least one sensor configured to detect fluid leakage from the aseptic connection.3. The system of claim 2, wherein the at least one sensor is configured to detect fluid leakage when fluid is pumped through the aseptic connection.4. The system of claim 2 or 3, wherein the at least one sensor comprises at least one of: a fluid sensor and a pressure sensor.The system of any of claims 1 to 4, further comprising a camera.6. The system of claim 5, wherein the camera is configured as an infra-red camera.7. The system of claim 5, wherein the camera is configured with a microscope lens to inspect the aseptic connection between the tubes.8. The system of any of claims 5 to 7, wherein the camera is configured to identify each of the containers.9. The system of any preceding claim, wherein the means for manipulating a fluid connection is further configured to apply a force on either side of the aseptic connection such that a mechanical property can be determined.10. The system of any preceding claim, wherein inspection of the fluid connection is automated.11. The system of any preceding claim, wherein the means for manipulating a fluid connection is further configured to seal a disconnected fluid connection, such that the transfer of fluid or cells to or from the first and second containers is inhibited.12. The system of any preceding claim, further comprising means for enabling the transfer of fluid or cells between aseptically connected containers.13. The system of any preceding claim, wherein the system is located within a non-sterile atmosphere.14. A method of creating a fluid connection between two aseptically joined containers for performing bioprocessing operations at one or more processing stations, comprising: manipulating, using automated means, a fluid connection between a first container and a separable second container whereby to create an aseptic connection that enables a controlled transfer of fluid or cell material between the first container and the second container; and inspecting the fluid connection manipulated by the automated means; wherein the automated means is configured to create an aseptic connection that can be disconnected after the transfer of fluid or cell material is complete to enable a further such fluid connection to be manipulated between the first container and a separable third container.15. The method of claim 14, performed on a bioprocessing system according to any of the preceding claims.