Method for performing a bioprocess on a cell culture - Patent Application 20070122997

Abstract

A method for carrying out a bioprocess on a cell culture, the bioprocess being carried out on an integrated bioprocessing system (1), wherein during the carrying out of the bioprocess, the integrated bioprocessing system (1) transfers a medium used in the bioprocess, in particular a cell culture, via a tube, the integrated bioprocessing system (1) comprising a tube connection system (2) for connecting the tubes of the integrated bioprocessing system (1) as required by welding, the first tube (4), the first tube holder (7) and a first fluid structure (12) for receiving and / or supplying the medium being carried by a movable first carrier (10), the first tube (4) being connected to the first tube holder (7) and fluidly connected to a first fluid structure (12), the first carrier (10), and the first tube (4), first tube holder (7), and first fluid structure (12) together with the first carrier (10) are transported to a welding position within the integrated bioprocessing system (1), and in a welding routine at the welding position, the tube connection system (2) connects the first tube (4) and the second tube (5) so that a tube connection (3) is formed, and the integrated bioprocessing system (1) transfers a medium from or to the first fluid structure (12) of the first carrier (10) through the tube connection (3) after welding.

Description

[Technical Field]

[0001] The present invention relates to a method for carrying out a bioprocess on a cell culture according to claim 1, an integrated bioprocessing system for carrying out a bioprocess on a cell culture according to claim 7, an integrated bioprocessing system for carrying out a bioprocess on a cell culture according to claim 17, a sealing unit according to claim 18 and a device for transporting tubes according to claim 19. [Background technology]

[0002] The term "bioprocess" encompasses processes in the broad field of biotechnology, such as those in the field of cell and gene therapy, including the production of genetically modified immune cells, whether allogeneic or autologous. In a bioprocess, a live cell culture is harvested from a patient, generated, modified, and / or used to obtain a specific desired product. The desired product may be the cells themselves and / or a product produced by the cells. For example, if a corresponding predetermined product needs to be obtained, a specific cell culture is generated and modified to thereby produce and obtain that product. Generally, different types of cell cultures may yield different types of products. In the context of this application, the term "bioprocess" should be interpreted broadly to include not only the entire process for cell culture, but also partial processes, such as the generation or modification of a cell culture or the use of a cell culture to obtain a product. A typical example of a bioprocess is the production of autologous T cells modified to express a chimeric antigen receptor (CAR). These cells may be used to treat various types of hematological malignancies, including various types of leukemia (blood cancer). Other cell therapies based on naive cells, particularly stem cells and their derivatives, are also attracting attention.

[0003] In bioprocesses involving the use of cell cultures, particularly in cell and gene therapy, process flexibility is particularly important, as the operation of the bioprocess must be adjusted and tailored to different situations. Therefore, in recent years, such bioprocesses are often carried out in integrated bioprocessing systems that are flexible and have a certain level of automation.

[0004] An example of an integrated bioprocessing system for carrying out a bioprocess is disclosed in Patent Document 1, which discloses a modularized and parallelized processing method for cell cultures on an integrated bioprocessing system.

[0005] Another integrated bioprocessing system is known from Patent Document 2. In this integrated bioprocessing system, a tube is held by a holder and welded by a tube welding system. Generally, the movement of components such as the tube and the tube welding system is performed by a robotic mechanism. It is very difficult to detect and handle a flexible tube. Controlling the tip of a robotic manipulator and detecting the position of the tube with a sufficiently low tolerance for grasping the tube requires highly advanced control and sensing capabilities. Therefore, it is necessary to reduce the degrees of freedom of the integrated bioprocessing system, particularly to completely eliminate the robotic manipulator, or at least to find a way to increase the tolerance that the tip of the robotic manipulator can have for the position of the tube so that the robotic manipulator can reliably grasp the tube.

[0006] During the execution of a bioprocess, various types of operations may be performed, which may require different types of media, such as the cell culture itself or other fluids, particularly liquids, such as culture media for cell growth, activation reagents, viral vector compositions, wash buffers, magnetic bead solutions, etc. When an integrated bioprocessing system is used to execute a bioprocess, it is essential to transfer the appropriate media, since the operations of the bioprocess may be performed at different locations within the integrated bioprocessing system or in different components of the integrated bioprocessing system. Therefore, many known integrated bioprocessing systems include connected tubing to enable the transfer of media. The connected tubing forms a tubing connection.

[0007] Even though methods for connecting different components with tubing are generally established in the art, tubing connections in known integrated bioprocessing systems are either pre-connected, e.g., by utilizing tubing sets, or manually connected by an operator, e.g., before or during the bioprocess to be performed. However, pre-connected tubing connections limit the flexibility of the integrated bioprocessing system because the transfer of media is somewhat predetermined, while manually connected tubing connections increase the risk of contamination of the cell culture. As such, known methods for performing cell culture bioprocesses using integrated bioprocessing systems are limited in terms of flexibility in the execution of the bioprocess itself or in terms of providing sterility. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2021 / 212124 [Patent Document 2] International Publication No. 2023 / 281257 Summary of the Invention [Problem to be solved by the invention]

[0009] The present invention is therefore based on the problem of providing a method for carrying out bioprocesses on cell cultures using an integrated bioprocessing system, which method is improved in terms of flexibility without compromising the sterility of the cell cultures. [Means for solving the problem]

[0010] The above-mentioned problem is solved by the features of claim 1. The main realization of the present invention is that using welding to connect tubes on an integrated bioprocessing system is a convenient way to create any number of tube connections for flexible media transfer through the integrated bioprocessing system. This allows for automation of the transfer of various media, particularly cell cultures, from or to various containers, devices, cartridges, or receptacles during bioprocessing. Sealed fluidic structures can be created and connected as needed. Concomitantly, the tube connections formed by welding are sterile, minimizing the risk of cell culture contamination, especially when the welding routine is performed automatically. Furthermore, the use of a carrier for transporting the tubes and a holder for holding the tubes makes handling the tubes within the integrated bioprocessing system easier, thereby enabling greater automation of the entire bioprocess.

[0011] In comparison to known robotic welding mechanisms, the present application presents various ways of manipulating the position of the tube by means other than a robotic manipulator, which can reduce the degrees of freedom of the integrated bioprocessing system. While it is still possible to use a robotic manipulator, such as a robotic mechanism, for welding, the tube is also handled by other means, making the robotic manipulator easier to control. In some embodiments, a robotic manipulator is not used to weld the tube.

[0012] A method for carrying out a bioprocess on a cell culture, the bioprocess being carried out on an integrated bioprocessing system, wherein during the carrying out of the bioprocess, the integrated bioprocessing system transfers a medium used in the bioprocess, in particular the cell culture, through a tube, the integrated bioprocessing system comprising a tube connection system for connecting the tubes of the integrated bioprocessing system as required by welding, the first tube, the first tube holder and the first fluid structure for receiving and / or providing the medium being carried by a movable first carrier, the first tube being connected to the first tube holder and / or the first fluid structure for receiving and / or providing the medium. A method is proposed in which the first carrier, held by a holder and fluidly connected to the first fluid structure, and the first tube, the first tube holder, and the first fluid structure together with the first carrier are transported to a welding position within the integrated bioprocessing system, and in a welding routine at the welding position, the tube connection system connects the first tube and a second tube so that a tube connection is formed, and after welding, the integrated bioprocessing system transfers the medium from or to the first fluid structure of the first carrier through the tube connection.

[0013] According to an advantageous embodiment of claim 2, the welding routine comprises different phases to be performed, namely a positioning phase, a trimming phase and a welding phase, each phase by itself, or a combination of these phases, when included in the welding routine, provides a simple sequence leading to a particularly sterile tube connection between the first tube and the second tube.

[0014] Claim 3 further identifies the trimming phase and the welding phase. During the advantageous heating step of the trimming phase, the blade is heated to a certain temperature by a blade heater of the tube cutting unit. Here, on the one hand, the blade itself is sterilized to avoid contamination when the tube is cut. On the other hand, the heated blade also facilitates smooth cutting of the tube, since the tube is often made of a plastic material that melts at a certain temperature when cut. During the advantageous alignment step of the trimming phase, the tube cutting unit is aligned so that it is positioned relative to the first tube and / or the second tube, and this alignment can ensure proper cutting of the tube. During the advantageous cutting step of the trimming phase, the first tube and / or the second tube is cut by the tube cutting unit. During the advantageous contact step of the welding phase, the tube can be axially aligned to enable proper connection of the tube when it is welded. Alternatively or additionally, during the contacting step, the tube cutting unit can be at least partially moved to facilitate contacting the tubes, and movement of the tube cutting unit can bring the tubes into contact. Alternatively or additionally, during the contacting step, the tubes can be brought into contact by axial movement of at least one of the tubes, particularly when the material of the tubes is still heated due to the cutting process, causing the tubes to fuse together. Moving only in the axial direction of the tubes prevents improper connection of the tubes, particularly when the tubes are already axially aligned.

[0015] An advantageous embodiment according to claim 4 is directed to a disconnection routine that allows the tubes to be disconnected as needed. The disconnection routine is executed by a tube disconnection mechanism. The disconnection routine can include a sealing phase in which at least one tube is sealed so that fluid communication between the tubes is interrupted. The disconnection routine can include a disconnection phase in which the tubes are cut so that the physical connection between the tubes is interrupted.

[0016] According to a preferred embodiment of claim 5, the method comprises performing an integrity test routine, wherein the integrity of the tubing connection formed by welding can be tested and, if the integrity of the tubing connection is not confirmed, an emergency routine can be initiated to protect the cell culture, which may include ensuring sterility of the tubing and / or notifying the user and / or initiating a separation routine and / or initiating another welding routine.

[0017] According to claim 6, the first tube can be connected to a third tube so that further tube connections are formed in the welding routine. Advantageous embodiments allow the first tube to be connected to different tubes as required so that the provided method provides further flexibility.

[0018] According to a further aspect, the carrier carrying the first tube holder, the first fluidic structure, and the first tube is inserted into and / or removed from the integrated bioprocessing system while the carrier is carrying the first tube holder, the first fluidic structure, and the first tube, and while the first tube holder is holding the first tube. This allows the carrier to be pre-configured with the fluidic structure. In particular, the carrier, together with the fluidic structure, is moved into and out of the integrated bioprocessing system without reconfiguring the fluidic structure within the integrated bioprocessing system, other than by tube welding.

[0019] According to a further aspect, the first tube is placed in the first tube holder outside the integrated bioprocessing system, particularly manually, before the first tube holder enters the integrated bioprocessing system. Access to and from the integrated bioprocessing system may be defined by an enclosure of the integrated bioprocessing system, which may include one or more defined interfaces for carriers to enter and exit the integrated bioprocessing system.

[0020] The equally important second teaching according to claim 7 relates to an integrated bioprocessing system for carrying out a bioprocess on a cell culture, during which a medium used in the bioprocess, in particular a cell culture, can be transported by the integrated bioprocessing system via a tube, said integrated bioprocessing system comprising a first tube and a second tube for transporting the medium, said first tube being held by a first tube holder and fluidly connected to a first fluid structure for receiving and / or providing the medium, and a movable first carrier, wherein said first tube, said first tube holder and said first fluid structure are carried by said first carrier and together with said first carrier, said first tube, said first tube holder and said first fluid structure are transported by said first carrier and The integrated bioprocessing system includes a first carrier, in which the tube holder and the first fluid structure can be transported to a welding position within the integrated bioprocessing system, and a tube connection system for connecting the first tube and the second tube at the welding position with a welding routine, so that a tube connection is formed by welding, and after welding, the medium can be transferred from or to the first fluid structure of the first carrier through the tube connection.

[0021] The proposed integrated bioprocessing system allows the proposed method to be carried out, and therefore all features and descriptions given with respect to the proposed method are fully applicable to the proposed integrated bioprocessing system and vice versa.

[0022] Claim 8 defines an advantageous embodiment that allows for easy positioning and easy handling of the second tube within the integrated bioprocessing system.

[0023] Claim 9 identifies a tube connection system for an integrated bioprocessing system, comprising: a tube positioning unit for positioning the first tube and the second tube relative to each other in at least an axial direction of the first tube and / or the second tube so that the first tube and the second tube can be cut in a positioning phase of the welding routine; and a tube cutting unit for cutting the first tube and the second tube in a trimming phase of the welding routine, the tube positioning unit being designed to bring the first tube and the second tube into contact and fuse together so that the tube connection is formed in a welding phase of the welding routine.

[0024] According to claim 10, the tube positioning unit can comprise a first tube holder and a second tube holder. The tube holders allow handling of the tubes, in particular during a welding routine. The tube positioning unit can further comprise a first and / or second holder movement mechanism, which allows moving the first tube holder and / or the second tube holder, respectively, so that the first tube and / or the second tube can be indirectly moved accordingly, in particular for placement, alignment, handling, etc. Advantageously, the first holder movement mechanism comprises a first holder guide and / or a first holder drive unit, in particular designed as a first rail unit. Alternatively or additionally, the second holder movement mechanism comprises a second holder guide and / or a second holder drive unit, in particular designed as a second rail unit. The first holder guide and / or the second holder guide enable a precise, particularly space-saving, predetermined movement of the first tube holder and / or the second tube holder. The first drive unit and / or the second drive unit enable driving the movement of the first tube holder and / or the second tube holder, particularly constrained to a rail. In particular, the combination of the respective holder guide and drive unit can result in a cost-effective, highly precise, particularly space-saving movement system for moving the respective tube holder.

[0025] Claim 11 specifies further options for moving the first tube and / or the second tube. While the above-mentioned embodiments may primarily allow for indirect movement of the tubes by moving the tube holders that hold the tubes, an advantageous embodiment according to claim 10 allows for moving the first tube and / or the second tube in a direct way. This may result in further degrees of movement, allowing for movement of the first tube and / or the second tube in at least further directions. The tube positioning unit may comprise a first tube driving unit and / or a second tube driving unit that drive the movement of the respective tubes.

[0026] Claim 12 advantageously specifies a first drive unit and a second drive unit. The respective drive rollers can provide a structurally simple but equally effective option for moving the respective tubes, particularly in the axial direction of the tubes. The respective drive lockers can lock the drive rollers to prevent further movement of the respective tubes, particularly in the axial direction of the tubes. The respective passive rollers can position the respective tubes in the drive unit so that they contact the drive rollers. A pretensioning mechanism can preload the tubes against the drive rollers and vice versa, improving the drive roller's grip on the tube.

[0027] To achieve greater flexibility in terms of the relative movement of the tube and the tube cutting unit, the tube connection system advantageously comprises a tube connection head as defined in claim 13. The first tube holder and / or the second tube holder can be designed separately from the tube connection head. Here, the tube connection head can comprise the tube cutting unit so that the tube cutting unit can be moved relative to the first tube holder and / or the second tube holder, and thus relative to the first tube held by the first tube holder and / or the second tube held by the second tube holder. In a preferred embodiment, the tube connection head comprises a first tube receptacle and / or a second tube receptacle. Here, the first tube receptacle and / or the second tube receptacle can be designed as grippers of the tube connection head so that the first tube and / or the second tube are gripped by the first tube receptacle and / or the second tube. Alternatively, the first tube receiver and / or the second tube receiver may be designed as a tube holder having one or several features of the first tube holder and the second tube holder. The tube cutting unit may be part of the tube connection head or may be designed separately, in either case the tube can be moved relative to the tube cutting unit by the tube connection head.

[0028] According to the embodiment of claim 14, the first tube and / or the second tube can be guided, in particular when moving. Since the tubes are often flexible, the first guiding mechanism and / or the second guiding mechanism can prevent bending of the first tube and / or the second tube, thus leading to more accurate movement of the respective tube. Advantageously, the first guiding mechanism comprises a first funnel and / or the second guiding mechanism comprises a second funnel, each funnel providing a constructionally simple yet reliable and robust guiding option for the respective tube. By means of the respective funnel, the guided tube is guided along its axis.

[0029] An advantageous embodiment according to claim 15 relates to position determination within a tube connection system. In particular, due to the highly flexible movement of the tubes, tube holders and / or tube connection heads, in particular the carrying carriers, the position determination mechanism can achieve a higher precision during operation of the tube connection system. The position determination mechanism can comprise a position sensor or multiple position sensors, which are commonly known in the art in a wide variety for countless applications and can therefore be used with relatively cost-effective development costs.

[0030] According to an embodiment of claim 16, the tube connection system comprises a robotic mechanism. The robotic mechanism transports the tube connection head so that it can be moved in at least one direction. According to another embodiment of claim 16, the tube connection system additionally or alternatively comprises a conveyor mechanism, and the first carrier and / or the second carrier are movable by the conveyor mechanism. For example, if the first carrier, the first tube, the first tube holder, and the first fluidic structure are part of a cartridge in which a unit operation is performed, and the second carrier, the second tube, the second tube holder, and the second fluidic structure are part of a receptacle in which a cell culture is transported, the conveyor mechanism can directly move the cartridge and / or the receptacle. The respective tubes, respective tube holders, and respective fluidic structures are transported by the respective carriers and are therefore moved indirectly. In particular, the combination of the robotic mechanism and the conveyor mechanism can realize a highly effective tube connection system, especially for use in integrated bioprocessing systems.

[0031] The third teaching according to claim 17, which is equally important, relates to an integrated bioprocessing system for carrying out a bioprocess on a cell culture, wherein a medium used in the bioprocess, in particular a cell culture, can be transported by the integrated bioprocessing system via a tube during the carrying out of the bioprocess, the integrated bioprocessing system comprising a first tube for transporting a medium and a second tube for transporting a medium, the first tube and the second tube being connected by a tube connection and arranged at separate positions within the integrated bioprocessing system, the first tube being held by a first tube holder and fluidly connected to a first fluid structure for receiving and / or supplying the medium via the first tube, and a movable first carrier for transporting the first tube, the first tube holder and the second tube. the tube holder and the first fluid structure are carried by the first carrier; and a tube separation mechanism for separating the first tube and the second tube at the separation position in a separation routine so that the first tube and the second tube are fluidically and / or physically separated, wherein the first carrier and the first tube, the first tube holder and the first fluid structure together with the first carrier can be transported from the separation position after the first tube and the second tube are separated.

[0032] The proposed integrated bioprocessing system allows the proposed method to be carried out, and therefore all features and descriptions given with respect to the proposed method are fully applicable to the proposed integrated bioprocessing system according to claim 17, and vice versa. Furthermore, all features and descriptions given with respect to the proposed integrated bioprocessing system according to claim 7 are fully applicable to the proposed integrated bioprocessing system according to claim 17, and vice versa.

[0033] A fourth teaching, of equal importance, relates to a tube separation mechanism for separating a first tube and a second tube of an integrated bioprocessing system in a separation routine in which the first tube and the second tube are fluidically and / or physically separated, wherein the tube separation mechanism comprises a sealing unit for sealing the first tube and / or the second tube in a sealing phase so that a first seal and / or a second seal are formed, the sealing unit comprising at least one sealing surface designed to crimp the first tube and / or the second tube along the axial direction of the respective tube so that the first tube and / or the second tube are self-sealed.

[0034] The proposed tube separation mechanism can be used in the proposed method, and therefore all features and explanations given with respect to the proposed method are fully applicable to the proposed tube separation mechanism, and vice versa. The proposed tube separation mechanism can be used in the proposed integrated bioprocessing system according to claim 7 and / or the proposed integrated bioprocessing system according to claim 17, and therefore all features given with respect to the integrated bioprocessing system are fully applicable to the proposed tube separation mechanism, and vice versa.

[0035] The fifth teaching according to claim 18, which is equally important, relates to a sealing unit, in particular of a tube separation mechanism in an integrated bioprocessing system, for sealing a first tube and / or a second tube in a sealing phase so that a seal is formed, the sealing unit comprising at least one sealing surface designed to crimp the first tube and / or the second tube along the axial direction of the respective tube so that the first tube and / or the second tube are self-sealed.

[0036] The proposed sealing unit can be used in the proposed method, and therefore all features and explanations given with respect to the proposed method are fully applicable to the proposed sealing unit, and vice versa. The proposed sealing unit can be used in the proposed tube separation mechanism, the integrated bioprocessing system according to claim 7, and / or the integrated bioprocessing system according to claim 17, and therefore all features given are fully applicable to the proposed sealing unit, and vice versa.

[0037] The sixth teaching as set forth in claim 19 relates to a device for transporting tubes, particularly within an integrated bioprocessing system, the device comprising a carrier, a tube, a tube holder and a fluid structure, the carrier carrying the tube, the tube holder and the fluid structure so that the tube, the tube holder and the fluid structure can be transported together with the carrier, and the tube holder holding the tube in a defined position.

[0038] The proposed device relates to the proposed method, the proposed integrated bioprocessing system according to claim 7, the proposed integrated bioprocessing system according to claim 17, the proposed tube separation mechanism and the proposed sealing unit according to claim 18. Accordingly, all features and explanations given are fully applicable to the proposed tube holder and vice versa.

[0039] An equally important seventh teaching proposes a method for carrying out a bioprocess on a cell culture, said bioprocess being carried out on an integrated bioprocessing system, said integrated bioprocessing system transporting a medium used in said bioprocess, in particular a cell culture, through tubes during the carrying out of said bioprocess, said integrated bioprocessing system comprising a tube connection system for connecting, if necessary by welding, the tubes of said integrated bioprocessing system, said first tube, said first tube holder and said first fluid structure for receiving and / or supplying said medium being connected to said integrated bioprocessing system. The integrated bioprocessing system is part of an integrated bioprocessing system, wherein the first tube is held by the first tube holder and fluidly connected to the first fluid structure, the first tube holder is positioned at the welding position by a positioning mechanism separate from the tube connection system, and in a welding routine at the welding position, the tube connection system connects the first tube and a second tube to form a tube connection, and after welding, the integrated bioprocessing system transfers the medium from or to the first fluid structure of the first carrier via the tube connection.

[0040] Any statements made with respect to other teachings are applicable and vice versa.

[0041] The tube connection system may interact with the tubes by specifically only roughly aiming at known weld locations that may be defined relative to the integrated bioprocessing system regardless of the actual location of the tubes, and the tube connection system may be positioned at the weld locations in a repeatable process;

[0042] In one embodiment, the first carrier is positioned at the welding position, thereby positioning the first holder at the welding position. In another embodiment, the first holder is then further repositioned so that it is more accurately positioned relative to the welding position. In another embodiment, only then does the tube connection system interact with the tube. In another embodiment, only then does the tube connection system further reposition the tube for welding, specifically by repositioning the tube holder or without repositioning the tube holder.

[0043] Over time, a tube connection system may interact with multiple, possibly tens or even hundreds of, tube holders at the same weld location, as carriers and tube holders may be frequently replaced.

[0044] According to one embodiment, the positioning mechanism can position the tube holders at one time or all the time in one or two dimensions, in particular only in a direction parallel to the floor. When the first tube holder is positioned along the direction of gravity, the positioning mechanism preferably includes separate mechanisms for positioning the first tube holder along the direction of gravity and a direction perpendicular thereto. Preferably, the positioning mechanism is configured to simultaneously move the first tube holder in two or fewer dimensions, preferably one or fewer dimensions. Exemplarily, the positioning mechanism can be a conveyor for moving the carrier or a rail unit for moving the tube holders.

[0045] An equally important eighth teaching proposes a method for carrying out a bioprocess on a cell culture, said bioprocess being carried out on an integrated bioprocessing system, wherein during the carrying out of said bioprocess, said integrated bioprocessing system transfers a medium used in said bioprocess, in particular a cell culture, through tubes, said integrated bioprocessing system comprising a tube connection system for optionally connecting tubes of said integrated bioprocessing system by welding, said first tube, a first tube holder and a first fluid structure for receiving and / or supplying said medium. The integrated bioprocessing system includes a first tube holder, a first tube holder that fluidly occludes, particularly pinches, the first tube, particularly reversibly, and a tube connection system that connects the first tube and a second tube at the welding position to form the tube connection. After welding, the integrated bioprocessing system transfers media to or from the first fluid structure of the first carrier via the tube connection. The tube holder can be used in this manner as an additional function by providing extra security against incorrect welding. After welding is confirmed, the occlusion can be released. If welding is not confirmed, the user can, for example, remove the fluid structure from the integrated bioprocessing system while the tube remains occluded.

[0046] Any statements made with respect to other teachings are applicable and vice versa.

[0047] A ninth teaching of equal importance proposes a method for carrying out a bioprocess on a cell culture, said bioprocess being carried out on an integrated bioprocessing system, said integrated bioprocessing system transferring a medium used in said bioprocess, in particular a cell culture, during the carrying out of said bioprocess, said integrated bioprocessing system comprising a tube connection system for connecting, by welding as required, tubes of said integrated bioprocessing system, said first tube, first tube holder and first fluidic structure for receiving and / or supplying said medium being connected to said integrated bioprocessing system. The integrated bioprocessing system is part of a system, the first tube being held by a first tube holder and fluidly connected to a first fluid structure, the first tube holder particularly pushing the first tube into the tube connection system prior to any interaction between the first tube and the tube connection system, the tube connection system connecting the first tube and a second tube in a welding routine at the welding position so as to form a tube connection, and the integrated bioprocessing system transferring a medium from or to the first fluid structure of the first carrier via the tube connection after welding. This is a further method of handling the tubes by means other than the tube connection system to reduce the complexity of the tube connection system.

[0048] Any statements made with respect to other teachings apply and vice versa.

[0049] An equally important tenth teaching proposes a method for carrying out a bioprocess on a cell culture, the bioprocess being carried out on an integrated bioprocessing system, which during the carrying out of the bioprocess transfers a medium used in the bioprocess, in particular a cell culture, through tubes, the integrated bioprocessing system comprising a tube connection system for connecting the tubes of the integrated bioprocessing system as required by welding, a first tube, a first tube holder and a first fluid structure for receiving and / or supplying the medium being part of the integrated bioprocessing system, the first tube being held by the first tube holder and the first The first tube holder is fluidly connected to a fluidic structure of the first carrier, and the first tube holder holds the first tube at a predefined angle or range of angles that is defined relative to the integrated bioprocessing system itself and / or the tube connection system and / or the second tube prior to any interaction between the first tube and the tube connection system; during a welding routine at the welding position, the tube connection system connects the first tube and the second tube to form a tube connection; and after welding, the integrated bioprocessing system transfers the medium from or to the first fluidic structure of the first carrier through the tube connection. Having a defined angle or range of angles, and thus at least some orientation, of the tube allows the tube connection system to more easily interact with the tube. It may be the case that the tube connection system cannot be rotated perpendicular to the ground, or even at all, so that a predetermined orientation of the tube is required. For example, moving the tube connection system in the direction of a Cartesian coordinate system to a number of predefined weld locations without rotating the tube connection system greatly simplifies control of the tube connection system.

[0050] Any statements made with respect to other teachings apply and vice versa.

[0051] An eleventh teaching is directed to a method for welding, particularly sealing, a tube at least partially along its length, particularly in an integrated bioprocessing system.

[0052] Any statements made with respect to other teachings apply and vice versa.

[0053] All features described herein can be combined with further teachings, and all features of all teachings can be combined. Any device, component, method step, etc. described is a preferred embodiment in any combination. In particular, a carrier is not a required feature in all embodiments of the invention. Other methods of improving tube handling and tube welding as described herein are also preferred.

[0054] Hereinafter, an embodiment of the present invention will be described with reference to the drawings. [Brief explanation of the drawings]

[0055] [Figure 1] FIG. 1 is a schematic diagram of a provided integrated bioprocessing system, including an expanded view of the tubing connections. [Figure 2] 2a)-e) are schematic diagrams of the welding routine in top view. [Figure 3] 3a)-3d) are schematic diagrams of the tube connection system provided in the welding routine corresponding to FIGS. 2a)-2e). [Figure 4] 4a)-d) are schematic diagrams of the separation routine in top view. [Figure 5] FIG. 5 is a top view of one embodiment of a provided tube holder having a first guide mechanism and a second guide mechanism disposed on the tube holder, including an enlarged view of a cross-sectional view of the tube holder. [Figure 6]FIG. 6 illustrates a further embodiment of a tube connection system provided. [Figure 7] FIG. 7 is a schematic diagram of the integrity check routine. [Figure 8] 8a) and b) are schematic illustrations of the provided tube separation mechanism during the tube separation routine, particularly the sealing phase. [Figure 9] FIG. 9 illustrates an embodiment of a tube connection system that includes first and second guide mechanisms as part of the tube connection head. DETAILED DESCRIPTION OF THE INVENTION

[0056] Methods for carrying out bioprocesses on cell cultures are provided. The bioprocesses carried out may be the same, but may also be different and / or distinct bioprocesses. However, each bioprocess may include at least one unit operation, i.e., elementary step, performed to achieve a particular physical or chemical effect. The cell cultures on which the bioprocesses are carried out may be of the same type or different types. Preferably, the bioprocesses may be carried out at least partially simultaneously.

[0057] Preferably, the cell culture herein is a liquid immune cell culture or a naive cell culture.

[0058] The term "liquid immune cell culture" should be interpreted broadly and refers to an immune cell culture containing at least one type of immune cell suspended as particles in any type of liquid. As explained below, a liquid immune cell culture may contain other types of cells that are not immune cells. Therefore, the term "liquid immune cell culture" refers to a liquid immune cell culture at any phase of a bioprocess. As a result, the types and proportions of immune cells present in a liquid immune cell culture may change during the course of a bioprocess due to the enrichment or removal of certain immune cells from the liquid immune cell culture and / or genetic modification of the immune cells.

[0059] The term "immune cells" generally refers to various types of white blood cells. Thus, the term "immune cells" includes, but is not limited to, various cells, such as dendritic cells, T lymphocytes (also known as T cells), B lymphocytes, natural killer cells, and macrophages. Immune cells can also include subtypes of immune cells, such as tumor-infiltrating lymphocytes or different types of T cells. Certain immune cell subtypes can be classified based on the type of antigen present on the cell surface. Thus, the term "immune cells" can refer to, for example, T cells containing the surface antigen CD4 ("CD4+ T cells"). Typically, specific types of immune cells, such as T cells, and preferably specific subtypes of immune cells, such as CD4+ T cells, are selectively enriched by bioprocessing, while other immune cells, such as macrophages, and / or other cell types that are not immune cells, such as erythrocytes, and / or other subtypes of immune cells, such as CD8+ T cells, are removed from the liquid immune cell culture. The enriched immune cells are referred to as target immune cells, and all other components removed from the liquid immune cell culture are referred to as "impurities." Additionally, as mentioned above, the target immune cells may be genetically modified.

[0060] The term "naive cells" refers to cells that are still capable of differentiating into different target cell types. In particular, stem cells and their derivatives are naive cells before they have fully differentiated into a specific cell type. This term also includes naive immune cells.

[0061] The term "liquid" should also be interpreted broadly and refers to any liquid and / or particulate-containing liquid being processed within an integrated bioprocessing system. Thus, the term liquid may refer to media, waste, liquid immune cell cultures, by-products obtained during a bioprocess, samples, and / or initial immune cell cultures.

[0062] 1 exemplarily shows a preferred embodiment of the proposed integrated bioprocessing system 1. The provided methods can be implemented using the respectively adapted proposed integrated bioprocessing system 1.

[0063] The term "integrated bioprocessing system" refers to a system that allows for the performance of multiple bioprocesses, whereby the bioprocesses are preferably carried out at least partially simultaneously. The integrated bioprocessing system 1 can provide central electronic process control for controlling the execution of all bioprocesses. Additionally, the integrated bioprocessing system 1 can provide shared infrastructure elements such as transport elements, media supplies, consumable supplies, and / or dedicated unit operation stations 1a for performing at least one, some, or all unit operations of each bioprocess.

[0064] During the performance of a bioprocess, in particular to perform an operation or operations on a cell culture, the integrated bioprocessing system 1 transports the medium or media used in the bioprocess through tubes 4, 5. This medium may in particular be the cell culture in which the respective bioprocess is to be performed.

[0065] Thus, within the integrated bioprocessing system 1, multiple tubing connections 3 may be provided for transferring media, particularly cell cultures, within the integrated bioprocessing system 1. For example, media may be received and transported by movable receptacles 1b between different unit operation stations 1a. One or more unit operations may be performed at the unit operation stations 1a. The unit operations themselves may be performed using cartridges 1d, which are individually tailored depending on the unit operation being performed. To transfer the respective media from one of the receptacles 1b to one of the cartridges 1d, or vice versa, they must be fluidly connected. Such connections may be provided by connectable tubes 4, 5 of the receptacles 1b and cartridges 1d. However, within the integrated bioprocessing system 1, several other tubing connections 3 may be present, which allow fluidic connection between components to transfer any kind of media, particularly liquids, such as liquid cell cultures, reagents, culture media, buffers, mixtures thereof, and the like.

[0066] Currently, connections between components, especially via tubing, are often made manually, which carries the risk of contamination and misconnections due to tubing mix-ups. In addition, connections between components are often pre-configured, limiting the flexibility of known systems.

[0067] It is proposed that the integrated bioprocessing system 1 comprises a tube connection system 2 for connecting the tubes of the integrated bioprocessing system 1 as needed, in particular by aseptic welding. Thus, welding is performed on demand, for example, when an individual unit operation is performed. The tubes to be connected may have a circular cross section.

[0068] The integrated bioprocessing system 1 comprises a first tube 4, a first tube holder 7, and a first fluid structure 12 for receiving and / or supplying a medium via the first tube 4. The first tube 4 is held in a defined position by the first tube holder 7 and is fluidly connected to the first fluid structure 12 such that a fluid, in particular a medium, can be guided to and from the first fluid structure 12 by the first tube 4. The first fluid structure 12 can hold a medium, in particular a cell culture, and / or can perform a unit operation on the medium, in particular a cell culture.

[0069] The term "fluidic structure" includes any type of fluidic structure capable of receiving and / or supplying a medium, in particular a cell culture. The fluidic structure may be designed as a reservoir capable of storing a medium, or as an operational structure capable of performing unit operations.

[0070] The first tube 4, the first tube holder 7 and the first fluid structure 12 are carried by a movable first carrier 10. The first carrier 10 may in particular be designed as a container of which the first fluid structure is a part, or as a carrier on which the first tube 4, the first tube holder 7 and the first fluid structure 12 are arranged and in particular attached, as exemplarily depicted in Fig. 1 . The first tube 4 is in particular carried as a whole by the first carrier 10. The first carrier 10 may enable the first tube 4 to be transported to the welding position independently from the tube cutting unit 9 and / or the tube connection head 43.

[0071] In particular, the first carrier 10 simplifies transportation within the integrated bioprocessing system 1. The first carrier 10, and together with it the first tube 4, first tube holder 7, and first fluid structure 12, are transported to a welding position within the integrated bioprocessing system 1. At the welding position, welding is performed. The integrated bioprocessing system 1 may comprise multiple welding positions where welding can be performed by the tube connection system 2. Transporting the first carrier 10 together with the first tube 4, first tube holder 7, and first fluid structure 12 can be performed automatically by the integrated bioprocessing system 1, in particular by a robotic mechanism 52 or preferably by a conveyor mechanism 53.

[0072] At the welding position, in a welding routine, the tube connection system 2 connects the first tube 4 and the second tube 5 such that a particularly sterile tube connection 3 is formed by welding. The second tube 5 may be part of an apparatus for performing a unit operation, comprising a second fluid structure 13 and optionally a second tube holder 8. Alternatively, the second tube 5 may be carried by a second carrier 11. The second carrier 11 may carry the second tube 5 as well as the second tube holder 8 and the second fluid structure 13, as exemplarily depicted in FIG. 1 .

[0073] After welding, the integrated bioprocessing system 1 transfers the medium from or to the first fluid structure 12 of the first carrier 10 via the tube connection 3. In this way, previously unconnected tubes 4, 5, in particular fluid structures 12, 13, can be connected, in particular automatically, while maintaining sterility.

[0074] The tubing connections 3 are used to carry out a bioprocess. Preferably, multiple tubing connections 3 are used to carry out each bioprocess. More preferably, different unit operations of each bioprocess are performed, and between unit operations, tubing connections 3 are formed and / or separated as described below. Illustratively, one unit operation is performed, then tubing connections 3 are formed, particularly to transport a cell culture to a location for the next unit operation; then, medium, particularly the cell culture, is transferred through the tubing connections 3; the tubing connections 3 are separated; then, another unit operation, particularly on the cell culture, can be carried out, for example, by means of a fluidic structure 13 connected to one of the tubings 4, 5. Between two unit operations, the tubings 4, 5 can be transported within the integrated bioprocessing system 1, particularly by moving the respective carriers 10, 11.

[0075] 1, preferably, a first tube 4 and a second tube 5 are connectable to form a tube connection 3. The tube connection 3 fluidly connects components of the integrated bioprocessing system 1, such as a first fluid structure 12 and a second fluid structure 13. A medium, particularly a fluid such as a liquid, preferably a cell culture, can be transferred via the tube connection 3.

[0076] In the exemplary and preferred embodiment shown, the first carrier 10, the first tube 4, the first tube holder 7, and the first fluid structure 12 are part of a receptacle 1b. Within the receptacle 1b, and in particular within the first fluid structure 12, media and other fluids can be transported within the integrated bioprocessing system 1. Preferably, the second carrier 11, the second tube 5, the second tube holder 8, and the second fluid structure 13 are part of a cartridge 1d. Within the cartridge 1d, and in particular within the second fluid structure 13, unit operations can be performed on media, in particular cell cultures. Preferably, the first tube 4 and the second tube 5 are designed as flexible tubes. More preferably, the first tube 4 and the second tube 5 are designed identically, in particular with respect to tube diameter, tube wall thickness, and / or tube material, and / or circular cross section.

[0077] However, the term "tube" in the context of the present application must be interpreted broadly, so that "tube" includes not only flexible tubes, but also rigid tubes such as pipes, tube elements of different designs capable of transporting fluids, such as tube connectors, etc. In general, a tube can be any medium-conducting element, preferably an elongated, more preferably a cylindrical element. Preferably, the tube is made of a plastic material, preferably a thermoplastic material, more preferably a thermoplastic elastomer.

[0078] It should be generally noted that in the context of the present application, the term "second" in combination with a respective component of the integrated bioprocessing system 1 or the tube connection system 2, such as "second tube 5," does not necessarily require that the embodiment be understood to include at least two of the respective component. Furthermore, the term "second" is chosen for distinguishing purposes, such as to distinguish between the first tube 4 and the second tube 5. Thus, the integrated bioprocessing system 1 may include a second component but not the corresponding first component. The same applies to the term "third."

[0079] Advantageously, the welding routine is performed at least partially automatically by the tube connection system 2. An automatically performed welding routine, or an automatically performed phase of a welding routine, may or may not require manual input, operation, or interaction from a user. Thus, contamination risks are reduced and the overall bioprocess may be further automated. Preferably, the welding routine is performed fully automatically.

[0080] The welding routine may comprise different phases: a positioning phase, a trimming phase and / or a welding phase. The welding routine is exemplarily shown in detail in Figures 2a) to 2e). These different phases may be performed simultaneously, preferably at least partially simultaneously, and / or sequentially. It is particularly preferred that the trimming phase immediately follows the welding phase.

[0081] In a preferred embodiment, the welding routine includes a positioning phase. During the positioning phase, the first tube 4 and the second tube 5 are positioned relative to each other at the welding position. Generally, the relative positioning of the first tube 4 and the second tube 5 is achieved by direct or indirect movement of at least one of the tubes 4, 5. Direct movement can be achieved by pushing or pulling back the respective tube. Indirect movement can be achieved by movement of the respective tube holders 7, 8 or by movement of the first carrier 10 and / or the second carrier 11 with the respective tubes 4, 5. Here, preferably, the first tube 4 and / or the second tube 5 are moved only in the axial direction of the first tube 4 and / or the second tube 5, in particular.

[0082] Preferably, as exemplarily shown in FIG. 2a), during the positioning phase, the first tube 4 is moved, preferably pushed or pulled back, in its axial direction, particularly automatically, and / or the second tube 5 is moved, preferably pushed or pulled back, in its axial direction, particularly automatically. The axial directions of the first tube 4 and the second tube 5 are preferably opposite to each other, particularly when the first tube 4 is in the first cutting position and the second tube 5 is in the second cutting position. In FIG. 2a), the tubes 4 and 5 are moved in the x-dimension, with the first tube 4 being moved in a direction opposite to the direction of movement of the second tube 5. Preferably, as shown in FIG. 2a), during the positioning phase, the first tube 4 is held by a first tube holder 7 and the second tube 5 is held by a second tube holder 8.

[0083] Furthermore, the first tube 4 can be moved laterally, in particular perpendicularly, to its axis and / or the second tube 5 can be moved laterally, in particular perpendicularly, to its axis. In Figure 2a), the perpendicular direction of the axes of the first tube 4 and the second tube 5 lies in the y dimension.

[0084] The positioning phase can be at least partly performed by the tube positioning unit 6, which in particular comprises the first tube holder 7 and / or the second tube holder 8. The movement of the first tube 4 and / or the second tube 5 can be performed directly, i.e., by directly moving the respective tubes 4, 5, for example by pushing and / or pulling them by the tube moving mechanisms 27, 28, and / or indirectly, i.e., by moving the respective tube holders 7, 8, for example by the holder moving mechanisms 21, 22, thereby moving the respective tubes 4, 5 in their axial and / or lateral directions. The first tube 4 and / or the second tube 5 can be moved laterally by the respective tube holders 7, 8 before the first tube 4 and / or the second tube 5 are moved axially by the tube moving mechanisms 27, 28. Thus, the respective tubes 4, 5 can be roughly positioned.

[0085] In the positioning phase, the first tube 4 and / or the second tube 5 can be moved to the first cutting position and / or the second cutting position, respectively. In FIG. 2b), the first tube 4 and the second tube 5 are in their respective cutting positions. When the first tube 4 is in the first cutting position and the second tube 5 is in the second cutting position, the first tube 4 and the second tube 5 are preferably positioned adjacent to each other, in particular parallel to each other. Preferably, when the tubes 4, 5 are in their respective cutting positions, the first tube 4 and the second tube 5 at least partially overlap each other. The first tube 4 and the second tube 5 may be positioned alongside each other at their respective cutting positions.

[0086] Preferably, the reaching of the respective cutting positions is confirmed by a sensor. By way of example, the tube connection system 2 may comprise one or more sensors that detect the position of the tubes 4, 5, in particular whether the tubes 4, 5 are in the respective cutting positions. The sensor or sensors may also indicate whether the pushing or retraction of the tubes 4, 5 has been successfully initiated. Suitable sensors, for example photoelectric sensors, are well known in the art.

[0087] Furthermore, the method preferably includes temporarily occluding the first tube 4 and / or the second tube 5 before the welding routine is performed. The first tube 4 and / or the second tube 5 may be temporarily occluded by one or more occlusion elements 60, such as clamps. Preferably, one tube occlusion element 60 is installed on either tube 4, 5. Preferably, the tube occlusion elements 60 are installed such that a tube connection 3 is formed between them. In this context, each tube occlusion element 60 is preferably installed between a tube connection 3 and a respective tube holder 7, 8.

[0088] A tube closure element 60 for closure of the first tube 4 and / or the second tube 5 may be provided by the first tube holder 7 and / or the second tube holder 8, respectively. Preferably, the first tube holder 7 and / or the second tube holder 8 may each comprise a closure element 60. Alternatively, one or more closure elements 60 may be designed separately, for example as separate clamps, etc., and may be attached during the welding routine, for example by the robotic mechanism 52, preferably after the tubes 4, 5 have been placed in their respective cutting positions.

[0089] After the welding routine is performed, an integrity test routine is preferably performed to verify the integrity of the tubing connection 3. This verification check determines whether the tubing connection 3 formed by the welding is intact or unsafe. Intact means that the interior of the tubing remains isolated from the outside atmosphere, thereby maintaining the sterility of the liquid within the tubing. Unsafe means that the tubing is not properly connected, specifically that the interior of the tubing is not completely sealed from the outside atmosphere. An incomplete seal could allow potential contaminants from the outside air to enter the tubing, compromising the sterility of the liquid being transferred thereto. Preferably, after the welding routine, an integrity check routine is performed, and once the integrity of the tubing connection 3 is detected, the temporary occlusion is removed. Even if the welding fails, the temporary occlusion maintains the sterility of the occluded portion of the tubing 4, 5. In this case, a separation routine can be performed, as described in more detail below. Preferably, the sealing phase of the separation routine is performed before removing the occlusion element 60. In this context, it is preferred to seal the first tube 4 and / or the second tube 5 between the first tube holder 7 and the corresponding closure element 60 and / or, more appropriately, between the second tube holder 8 and the corresponding closure element 60. In this way, sterility of the tubes 4, 5 can be ensured.

[0090] The integrity check routine may be performed by a weld verification device 49, described below.

[0091] Depending on the results of the integrity check routine, if the integrity of the tube connections is confirmed, the temporary occlusion of the first tube and / or the second tube is preferably removed. Here, media can then be transferred from the first tube to the second tube or vice versa via the tube connection 3. However, if the integrity of the tube connection 3 is not confirmed, an emergency routine to protect the cell culture is initiated. In the emergency routine, the temporary occlusion is not removed, thereby preventing contamination of the cell culture via the unsafe tube connection 3. Thus, the sterility of the tubes, and therefore of the liquids in the tubes and the liquids to which the tubes connect, can be ensured. The emergency routine may include reporting a notification to the user and / or initiating a separation routine and / or initiating a separation routine followed by another welding routine. In particular, portions of the first tube 4 and / or the second tube 5, each of which may be exposed to the external environment, can remain occluded by an occlusion element 60, e.g., a clamp. Furthermore, the portions of the first tube 4 and / or the second tube 5 that may be exposed to the external environment can be sealed, in particular cut, for example by performing a separation routine. As will be explained in more detail below, after sealing the tubes 4, 5 in the separation routine, the closure element 60 can be removed. After the separation routine has been performed, another welding routine can be performed.

[0092] Alternatively or additionally, the welding routine includes a trimming phase, in which the first tube 4 and the second tube 5 are cut at the welding location. The trimming phase preferably follows the positioning phase, such that the tubes 4, 5 are cut at their cutting locations. Preferably, the tubes 4, 5 are cut using a hot cutting procedure. The trimming phase is at least partly performed by a tube cutting unit 9, which in particular comprises a blade 9a, a blade mount 9b and / or a blade heater 9c.

[0093] Preferably, the tube connection system 2 comprises a tube cutting unit 9, which comprises a blade 9a and preferably a blade heater 9c.

[0094] In connection with the trimming phase, it is preferred that the trimming phase includes a heating phase during which the blade heater 9c heats the blade 9a to a cutting temperature. In this high-temperature cutting procedure, high temperature means above 150°C, preferably above 250°C, and even more preferably above 350°C, providing decontamination during the welding routine. Furthermore, cutting of the tubes 4, 5, which are preferably plastic tubes, can be simplified since they are melted during cutting by the heated blade 9a.

[0095] Preferably, the trimming phase herein includes an alignment step in which the tube cutting unit 9 is aligned relative to the first tube 4 and / or the second tube 5. The alignment of the tube cutting unit 9 relative to the first tube 4 and / or the second tube 5 can be performed by moving the tube cutting unit 9 and / or by moving the first tube 4 and / or the second tube 5. Preferably, when the alignment step is performed, the first tube 4 is in the first cutting position and / or the second tube 5 is in the second cutting position. Here, the tube cutting unit 9 can be moved for alignment. It is preferred that the alignment step follows the heating step, or that the heating step follows the alignment step, or that the alignment step and the heating step are performed at least partially simultaneously, or vice versa.

[0096] FIG. 2b) exemplarily illustrates the heating and alignment steps of the trimming phase in a preferred embodiment. The first tube 4 and the second tube 5 are in their respective first and second cutting positions. The tubes 4, 5 are held by the tube holders 7, 8. The tube cutting unit 9 is aligned relative to the tubes 4, 5, and the tube cutting unit 9 itself is moved during the alignment step (compare FIGS. 2a and 2b). The tube cutting unit 9 is aligned so that the blade 9a is oriented transversely, particularly perpendicularly, to the first tube 4 and / or the second tube 5. The blade 9a is heated by the blade heater 9c of the tube cutting unit 9 during the heating step. Another example of the alignment step is illustrated in FIG. 3a), where the tube cutting unit 9 is moved relative to the tubes 4, 5 as exemplarily indicated by the arrows in FIG. 3a). FIG. 3b) exemplarily illustrates the heating step, where the blade 9a is heated by the blade heater 9c.

[0097] More preferably, the trimming phase includes a cutting step, in which the first tube 4, particularly in the first cutting position, and / or the second tube 5, particularly in the second cutting position, are cut by a tube cutting unit 9, particularly a blade 9a. During the cutting step, the tubes 4, 5 are cut. Preferably, the first tube 4 and the second tube 5 are cut at least partially, preferably completely, simultaneously. The cutting step preferably follows a heating step and / or an alignment step. More preferably, the blade 9a is heated to a certain temperature by a blade heater 9c during the cutting step. The tubes 4, 5 can be at least partially melted during the cutting step. In the trimming phase, the first tube 4 and / or the second tube 5 are squeezed in a squeezing direction, and cutting can be performed transversely, particularly perpendicularly, to the squeezing direction. In this way, cutting can be optimized and simplified. By squeezing the tubes 4, 5, the cross section of each tube 4, 5 temporarily includes a short side and a long side, and cutting can be simplified by cutting along the long side.

[0098] FIG. 2c) exemplarily illustrates the cutting step of the trimming phase in a preferred embodiment. A heated blade 9a at least partially cuts the first tube 4 and the second tube 5 simultaneously. During the cutting step, the first tube 4 and the second tube 5 are generally open, but the blade 9a seals the openings of the tubes 4, 5 against the surrounding atmosphere. As a result, contamination, particularly due to the temperature of the blade 9a, can be prevented. Another example of the cutting step is exemplarily illustrated in FIG. 3c), in which the blade 9a cuts the tubes 4, 5. Thus, the tube cutting unit 9 preferably includes a cutting table 9d facing the blade 9a. The cutting table 9d can support the cutting process by the blade 9a.

[0099] In addition to or as an alternative to the trimming phase, the welding routine includes a welding phase. In the welding phase, the first tube 4 and the second tube 5 are brought into contact with each other and fused together at the welding position so as to form the tube connection 3. The welding phase preferably follows the positioning phase and / or the trimming phase. In particular, the welding phase immediately follows the trimming phase, so that the first tube 4 and the second tube 5 are brought into contact with each other and fused together in the welding phase after the first tube 4 and the second tube 5 are cut in the trimming phase. The welding phase is particularly partially performed by the tube positioning unit 6 and the tube cutting unit 9. The contact and fusion of the tubes 4 and 5 is preferably performed by the first tube holder 7 and / or the second tube holder 8, which, for example, pushes the first tube 4 and / or the second tube 5 into contact. The welding phase is exemplarily shown in FIGS. 2c, 2d, and 2e.

[0100] In conjunction with the welding phase, the welding phase advantageously includes a contacting phase. Preferably, during the contacting step, the first tube 4 and the second tube 5 are axially aligned. The axial alignment of the tubes 4, 5 can be performed along the tube cutting unit 9, in particular along the blade 9a. Here, the openings of the tubes 4, 5 to be cut can be covered by the blade 9a. Preferably, the first tube 4 and the second tube 5 are axially aligned by movement of the first tube holder 7 and / or the second tube holder 8, respectively, in particular by the first holder moving mechanism 21 and / or the second holder moving mechanism 22. The first tube holder 7 and / or the second tube holder 8 may be movable independently of the tube connection head 43 and the tube cutting unit 9.

[0101] Alternatively or additionally, during the contacting step, the tube cutting unit 9 is moved at least partially, in particular laterally, preferably orthogonally, relative to the tubes 4, 5 so that the first tube 4 and the second tube 5 can be brought into contact. Preferably, the blade 9a is moved, in particular laterally, preferably orthogonally, relative to the tubes 4, 5 so that the first tube 4 and the second tube 5 can be brought into contact. This movement of the tube cutting unit 9 is preferably performed after axial alignment of the tubes 4, 5. Furthermore, alternatively or additionally, during the contacting step, the first tube 4 and the second tube 5 can be brought into contact, in particular by moving the first tube 4 and / or the second tube 5 axially, preferably by the first tube moving mechanism 27 and / or the second tube moving mechanism 28. This can be done after axial alignment of the tubes 4, 5 and / or after movement of the tube cutting unit 9. Preferably, the axial movement of the first tube 4 is performed by movement of the first tube holder 7 and / or the movement of the second tube 5 is performed by movement of the second tube holder 8. Alternatively, and also preferably, the axial movement of the first tube 4 is performed by the first tube holder 7 such that the first tube 4 is pushed out and / or pulled back, and / or the axial movement of the second tube 5 is performed by the second tube holder 8 such that the second tube 5 is pushed out and / or pulled back. During the contacting step, the first tube 4 and the second tube 5 are brought into contact and fused, in particular because the tubes 4, 5 are heated by the heating blade 9a during the trimming phase. During the contacting step, a particularly sterile tube connection 3 is formed.

[0102] 2c), 2d), and 2e) exemplarily depict the welding phase. Here, the first tube 4 and the second tube 5 are preferably aligned axially by horizontally moving the first tube holder 7 and / or the second tube holder 8. The movement of the first tube holder 7 and / or the second tube holder 8 can be performed transversely, particularly perpendicularly, to the axis of the first tube 4 and / or the second tube 5. During the axial alignment, the blade 9a is held in place, so that the first tube 4 and / or the second tube 5 moves along the blade 9a, particularly while contacting the blade 9a during this movement. After the axial alignment, the blade 9a is moved transversely, particularly perpendicularly, relative to the tubes 4 and 5 so that they can come into contact. In FIG. 2d), the blade is moved vertically upwards. In Fig. 2e), the first tube 4 and the second tube 5 are brought into contact and fused by axial movement of at least one of the tubes 4, 5. In this way, a tube connection 3 is formed. The welding phase is further exemplarily depicted in Fig. 3c) and Fig. 3d).

[0103] After welding has been performed, the tube connection 3 can be opened. The tube connection 3 can be opened by an external force applied to the tube connection 3 on the outer surfaces of the first tube 4 and the second tube 5. The external force can be applied by a tube cutting unit 9, a tube welding head 43, or another robot, etc. The external force can be applied perpendicular to the axis of the tubes 4, 5. Alternatively, the tube connection 3 can be opened by applying internal pressure to the tubes 4, 5. This can be achieved by a pumping mechanism 54.

[0104] The method further preferably includes temporarily occluding the first tube 4 and / or the second tube 5 before the welding routine or phase is performed. The first tube 4 and / or the second tube 5 can be occluded by a clamp, particularly a clamp designed independently of the tube connection head 43. After the welding routine or phase is performed, an integrity check routine is preferably performed to verify the integrity of the tube connection, as exemplarily shown in FIG. 7 . This check determines whether the tube connection 3 formed by welding is intact or unsafe. Depending on the result of the integrity check routine, if the integrity of the tube connection is confirmed, the temporary occlusion of the first tube 4 and / or the second tube 5 is removed. Thereafter, medium can be transferred through the tube connection 3. However, if the integrity of the tube connection 3 is not confirmed, an emergency routine to protect the cell culture is initiated. Here, the temporary occlusion is not removed to prevent contamination of the cell culture through the unsafe tube connection 3. The emergency routine may include notifying the user and / or initiating a detachment routine and / or initiating another welding routine.

[0105] More preferably, the tube connection system 2 comprises a tube separation mechanism 14. The tube separation mechanism 14 preferably comprises a sealing unit 15 and / or a separation unit 17.

[0106] In a further preferred embodiment, the method includes a separation routine in which the first tube 4 and the second tube 5 are separated. The separation routine can fluidically and / or physically separate the tubes 4, 5. "Fluidically separated" means that the tubes 4, 5 are sealed, for example, so that fluid cannot be transferred through the tubes 4, 5. "Physically separated" means that the tubes 4, 5 are completely separated and can be handled, e.g., moved, independently of each other. The separation routine is performed by a tube separation mechanism 14 of the tube connection system 2.

[0107] The separation routine preferably includes a sealing phase, during which the currently connected first tube 4 and / or second tube 5 are sealed to form a first seal 56 and / or a second seal 57. This is exemplarily depicted in FIG. 4. In the sealing phase, the first tube 4 and / or the second tube 5 are preferably sealed by compression and heat. Here, the first tube 4 and / or the second tube 5 are compressed and heated, particularly transversely to their respective tube axes, so that the first tube 4 and / or the second tube 5 are partially melted and sealed, particularly self-sealed. The sealing phase can be performed by the tube separation mechanism 14, particularly by a sealing unit 15 of the tube separation mechanism 14. The sealing unit 15 can include a sealing surface 16 for compression and heating. The sealing unit 15 can be designed independently of the tube cutting unit 9. The sealing surface 16 can be designed independently of the separating blade 18.

[0108] Advantageously, the separation routine includes a separation phase, in which the first tube 4 and / or the second tube 5 are cut, in particular between the first seal 56 and the second seal 57. It is also possible to cut the first tube 4 or the second tube 5 within the respective seal 56, 57. In this way, the tubes 4, 5 are physically separated. The separation phase can be performed by the tube separation mechanism 14, in particular by the separation unit 17 of the tube separation mechanism 14.

[0109] FIGS. 4a, 4b, 4c, and 4d exemplarily illustrate the separation routine. Preferably, the first tube 4 and the second tube 5 are first physically and fluidly connected, as exemplarily depicted in FIG. 4a. Preferably, during the separation routine, the first tube 4 and the second tube 5 are at least partially sealed simultaneously by the sealing unit 15 of the tube separation mechanism, as shown in FIG. 4b. However, sealing can also be performed sequentially, i.e., one at a time. The sealing unit 15 includes two sealing surfaces 16, which compress the tubes 4 and 5 and are heated to self-seal them, as exemplarily shown in FIG. 4c. As a result, a first seal 56 and a second seal 57 are formed. After sealing the tubes 4 and 5 in the sealing phase, the tubes 4 and 5 are cut in the separation phase by the separation unit 17, particularly the separation blade 18, as exemplarily shown in FIG. 4c. Preferably, the separation blade 18 is heated to facilitate cutting. Preferably, the sealing phase is performed before the separating phase. Alternatively, the sealing phase can be performed after the separating phase, for example, if the separating blade 18 cuts the tubes 4, 5 and temporarily seals the resulting opening. Preferably, the separating blade 18 cuts the first tube 4 and the second tube 5 with a cutting plane perpendicular to the axis of the tubes 4, 5. The cutting plane can be oriented transversely to the sealing surface 16 and / or the first sealing portion 56 and / or the second sealing portion 57.

[0110] Preferably, the method further includes connecting the first tube 4 or the second tube 5 to a third tube 19 of the integrated bioprocessing system 1 by the tube connection system 2, such that a further tube connection 20 is formed, the further tube connection 20 being formed in a welding routine. The welding routine may be performed as previously described with respect to the tube connection 3 of the first tube 4 and the second tube 5. In particular, the same tube connection system 2 is used to connect the first tube 4 or the second tube 5 to the third tube 19. It is also possible to weld the first tube 4 or the second tube 5 multiple times to different tubes 4, 5, 19. This is an interesting advantage of using a welding system, since the tubes 4, 5, 19 can be easily cut and welded multiple times, provided there is sufficient tube length.

[0111] The third tube 19 may be carried by a third carrier. The third carrier may carry a third tube holder and a third fluid structure. The third carrier, the third tube 19, the third tube holder and the third fluid structure may also be part of the receptacle 1b or the cartridge 1d.

[0112] Different tubes 4, 5, 19 may originate from different cartridges 1d and / or different receptacles 1b. It is therefore possible that a cartridge 1d can be connected to different receptacles 1b, particularly in sequence. It is also possible that a receptacle 1b can be connected to different cartridges 1d, preferably in sequence. It is also possible that a cartridge 1d comprises multiple tubes 4, 5, 19 connected to the tubes 4, 5, 19 of a receptacle 1b or to the tubes 4, 5, 19 of multiple receptacles 1b. Here, a cartridge 1d may be connected to a receptacle 1b via multiple tube connections 3, 20, or to multiple receptacles 1b via multiple tube connections 3, 20.

[0113] For example, cartridge 1d includes tubes 4, 5, 19, which are connected to tubes 4, 5, 19 of receptacle 1b to form tube connections 3, 20. Media can be transferred through the tube connections 3, 20, and a unit operation can be performed on cartridge 1d. The tubes 4, 5, 19 can then be separated, particularly by performing a separation routine. Cartridge 1d and / or receptacle 1b can then be transported to another location in the integrated bioprocessing system 1, particularly to another welding location. Another tube connection 3, 20 can then be formed by connecting the tubes 4, 5, 19 of the cartridge to another tube 4, 5, 19 of receptacle 1b or another tube 4, 5, 19 of another receptacle 1b, particularly by performing a welding routine.

[0114] First, a first receptacle 1b containing a liquid immune cell culture can be connected to cartridge 1d using a first set of tube holders 7, 8, and tubes 4, 19 of the first receptacle 1b can be connected to tubes 5, 19 of cartridge 1d. The first receptacle 1b can include a first fluidic structure 12 that initially contains a medium, in particular a cell culture. Cartridge 1d, in particular its fluidic structure 13, can receive the medium from the first receptacle 1b. Subsequently, for example, to perform counterflow centrifugation in the fluidic structure 13 of cartridge 1d, tubes 4, 19 of a second receptacle 1b with a further fluidic structure containing a buffer can be connected to cartridge 1d using second tubes 5, 19 of cartridge 1d located in a different holder 8 of cartridge 1d.

[0115] Alternatively, the tubes 4, 19 of the second receptacle 1b may be connected to the first tubes 5, 19 of the cartridge 1d when the tube connections 3, 20 between the first receptacle 1b and the cartridge 1d are subsequently separated. After the unit operation is performed, the liquid immune cell culture may be transferred from the second fluidic structure 13 of the cartridge 1d to a third receptacle 1b, particularly to a further fluidic structure in the third receptacle 1b, while waste may be transferred from the cartridge 1d to the fourth receptacle 1b. Here, two or more holders 8 may be arranged on the same rail. It is also possible for the receptacle 1b to include multiple tubes 4, 19 that are sequentially connected to the tubes 5, 19 of the cartridge 1d. Thus, the receptacle 1b may contain different media, e.g., different media contained in different containers of the fluidic structure, which can be transferred to the cartridge 1d through different tubes 4, 19. Exemplarily, receptacle 1b may include a first container containing a liquid (e.g., a cell washing buffer) and a second container for receiving a liquid (e.g., waste from the cell washing step). In this case, each container may include a tube 4, 19, which may be placed in a holder 7. Both holders may be placed on the same rail of receptacle 1b. In a first step, buffer solution may be transferred from the first container to the centrifugation unit of fluidic structure 13 placed in cartridge 1d by utilizing first tubes 5, 19 of cartridge 1d. After or during centrifugation, waste from the centrifugation may be transferred from cartridge 1d by utilizing second tubes 5, 19 of cartridge 1d. These second tubes 5, 19 may be connected to the tubes 4, 19 belonging to the second container of receptacle 1b.

[0116] Preferably, the multiple tube connections 3, 20 are formed by multiple welding routines, in particular one (especially the same) or multiple tube connection systems 2 performing the welding routines within the integrated bioprocessing system 1. The welding routines are preferably performed before, during and / or after the execution of the bioprocess.

[0117] It is particularly preferred that the welding routine be performed at least once during a bioprocess on a cell culture, preferably at least once for each unit operation performed on the cell culture. During the welding routine, the cartridge 1d and the receptacle 1b may be connected, particularly by a tubing connection 3. Preferably, after performing the welding routine, at least one unit operation of the bioprocess is performed, particularly on the cartridge 1d. The receptacle 1b may contain a medium, particularly a liquid immune cell culture, used in the bioprocess, particularly a unit operation, and transferred to the cartridge 1d. After performing the at least one unit operation, a separation routine is performed, particularly to separate the cartridge 1d and the receptacle 1b. The cartridge 1d and / or the receptacle 1b may then be moved within the integrated bioprocessing system 1. Illustratively, the receptacle 1b containing the liquid immune cell culture may be moved to another unit operation station 1a, particularly to perform another unit operation on the liquid immune cell culture using a different cartridge 1d.

[0118] In general, it is also possible for the tube connection 3 to be formed to extend the first tube 4, where the second tube 5 is designed as an extension tube and is welded to the first tube 4 as described above. It is also possible for the tube connection 3 to be formed to extend the second tube 5, where the first tube 4 is designed as an extension tube and is welded to the second tube 5 as described above. However, in one embodiment, the tubes 4, 5 can also be extended during a separation routine. For this, before separation, the position of the tube connection 3 is changed, in particular by the tube holders 7, 8, so that one tube 4, 5 is extended with a portion of the other tube 4, 5. The other tube 4, 5 is therefore shortened. The integrated bioprocessing system 1 can include a welding strategy including steps for shortening and lengthening the tubes 4, 5 by successive welding and separation, such that a target length spacing of the tubes 4, 5 is maintained.

[0119] As a second teaching, an integrated bioprocessing system 1 is provided, as exemplarily depicted in Figure 1. Since the integrated bioprocessing system 1 is adapted to carry out the provided method, all of the descriptions and features made above are fully applicable. Conversely, all of the descriptions and features below are fully applicable to the proposed method.

[0120] The integrated bioprocessing system 1 is adapted to perform a bioprocess on a cell culture, in particular automatically, during which a medium used in the bioprocess, in particular a cell culture, can be transported through tubes 4, 5 by the integrated bioprocessing system 1. The bioprocessing system 1 comprises a first tube 4 for transporting a medium, in particular a fluid, and a second tube 5 for transporting a medium, in particular a fluid. The first tube 4 is held by a first tube holder 7 and is fluidly connected to a first fluid structure 12 for receiving and / or supplying the medium. The first tube holder 7 preferably holds a single tube 4.

[0121] The integrated bioprocessing system 1 comprises a movable first carrier 10, and the first tube 4, the first tube holder 7, and the first fluid structure are carried by the first carrier 10. The first carrier 10, and together with the first carrier 10, the first tube 4, the first tube holder 7, and the first fluid structure, can be transported to a welding position within the integrated bioprocessing system 1. In this way, the first carrier serves as a transport vehicle for the first tube 4, and the integrated bioprocessing system 1 includes a tube connection system 2 for connecting the first tube 4 and the second tube 5 in a welding routine at the welding position so that a particularly sterile tube connection 3 is formed by welding, after which a medium can be transferred from or to the first fluid structure 12 of the first carrier 10 through the tube connection 3. Here, preferably, a medium is transferred via the tubes 4, 5 and the tube connection 3 as part of a bioprocess.

[0122] The integrated bioprocessing system 1 preferably includes a robotic mechanism 52. The robotic mechanism 52 may be part of the tube connection system 2. The robotic mechanism 52 may be involved in welding routines, but may also be involved in other operations in the integrated bioprocessing system 1, among others.

[0123] The second tube 5 is preferably held by a second tube holder 8 and fluidly connected to a second fluid structure 13 for receiving and / or supplying a medium. The second tube holder 8 preferably holds a single tube 5. After welding, a medium can be transferred from or to the second fluid structure 13 of the second carrier via the tube connection 3. When the first tube 4 and the second tube 5 are connected, a medium can be transferred between the first fluid structure 12 and the second fluid structure 13.

[0124] The second tube 5 may be part of an apparatus for performing a unit operation. In this case, the second tube 5 may be held by, for example, a second tube holder 8 disposed on or attached to the apparatus. The apparatus may also include a second fluidic structure 13. However, it is more preferred that the integrated bioprocessing system 1 comprises a movable second carrier 11, and the second tube 5, second tube holder 8, and second fluidic structure 13 are carried by the second carrier 11. The second carrier 11, second fluidic structure 13, second tube 5, and second tube holder 8 may be part of a receptacle 1b or, in particular, a cartridge 1d. The second carrier 11, and the second tube 5, second tube holder 8, and second fluidic structure 13 together with the second carrier 11, can be transported to the welding position. The second carrier 11 can be transported independently from the first carrier 10 and / or the tube connection head 43 and / or the tube cutting unit 9.

[0125] Furthermore, the integrated bioprocessing system 1 may also include a conveyor mechanism 53. The conveyor mechanism 53 may be part of the tube connection system 2. The conveyor mechanism 53 may be involved in the welding routine, but may also be involved in other operations in the integrated bioprocessing system 1. The conveyor mechanism 53 may transport the first carrier 10 and / or the second carrier 11, and / or the cartridge 1d and / or the receptacle 1b within the integrated bioprocessing system 1, particularly to the welding position.

[0126] Alternatively or additionally, the robot mechanism 52 is designed to transport the cartridge(s) 1 d and / or the receptacle 1 b within the integrated bioprocessing system 1. In particular, the robot mechanism 52 can handle the cartridge(s) 1 d and / or the receptacle 1 b by picking, moving, and releasing. The robot mechanism 52 can be designed as a rail robot mechanism 52 including different movement axes for linear movement in one, two, or three dimensions (Cartesian robot mechanism). The robot mechanism 52 can alternatively be designed as a robot arm.

[0127] The tube connection system 2 of the integrated bioprocessing system 1 preferably includes a tube positioning unit 6 for positioning the first tube 4 and the second tube 5 relative to each other, at least in the axial direction of the first tube 4 and / or the second tube 5, so that the first tube 4 and the second tube 5 can be cut during the positioning phase of the welding routine. Preferably, the first tube 4 and the second tube 5 are positioned one-dimensionally or two-dimensionally during the positioning phase. The first tube 4 and / or the second tube 5 are preferably moved at least in the axial direction of the first tube 4 and / or the second tube 5. This positioning is preferably performed automatically. The tube connection system 2 further includes a tube cutting unit 9 for cutting the first tube 4 and the second tube 5 during the trimming phase of the welding routine. Preferably, the tube positioning unit 6 is designed to bring the first tube 4 and the second tube 5 into contact and fuse with each other during the welding phase of the welding routine, so that the tube connection 3 is formed.

[0128] In the context of this application, "dimension" refers to a three-dimensional Cartesian coordinate system, such as x, y, and z dimensions. "One-dimensional," "two-dimensional," and "three-dimensional" refer to the ability to move in one, two, or three dimensions.

[0129] The tube connection system 2 connects a first tube 4 and a second tube 5 of the integrated bioprocessing system 1 in a welding routine, and a tube connection 3 is formed by welding. The tube connection system 2 includes a tube positioning unit 6 that positions the first tube 4 and the second tube 5 relative to each other at least in the axial direction of the first tube 4 and / or the second tube 5 so that the first tube 4 and the second tube 5 can be cut in a positioning phase of the welding routine. The tube connection system 2 further includes a tube cutting unit 9 that cuts the first tube 4 and the second tube 5 in a trimming phase of the welding routine. The tube positioning unit 6 brings the first tube 4 and the second tube 5 into contact with each other and fuses them together in the welding phase of the welding routine so that the tube connection 3 is formed. The tube positioning unit 6 is preferably designed separately from the tube cutting unit 9. Therefore, positioning of the tubes 4 and 5 can be performed independently of the tube cutting unit 9.

[0130] The tube positioning unit 6 and the tube cutting unit 9 are preferably designed such that the welding routine is performed at least partially, preferably completely, automatically. Thus, the risk of contamination is reduced and the tube connection process can be further automated. Furthermore, an automatically executable welding routine may provide advantages when the provided tube connection system 2 is applied to the provided integrated bioprocessing system 1, since the automation of the integrated bioprocessing system 1 may be improved. In particular, the first carrier 10 and / or the second carrier 11 enable automatic transport of the first tube 4 and / or the second tube 5 within the integrated bioprocessing system 1.

[0131] In a preferred embodiment, the tube positioning unit 6 includes a first tube holder 7 for holding the first tube 4 and a second tube holder 8 for holding the second tube 5. The first tube holder 7 and / or the second tube holder 8 are part of the tube positioning unit 6. As exemplarily shown in FIGS. 2a-2e, and preferably, the first tube holder 7 holds the first tube 4 at least during the entire welding routine. The same is true for the second tube holder 8, which holds the second tube 5 at least during the entire welding routine. Typically and preferably, the first tube holder 7 and the second tube holder 8 are designed so that the first tube 4 and the second tube 5 can be presented for performing a welding routine on the tubes 4, 5 to form the tube connection 3. The first tube holder 7 is preferably arranged on or attached to the first carrier 10, and / or the second tube holder 8 is preferably arranged on or attached to the second carrier 11, so that the tube holders 7, 8 hold the tubes 4, 5 in their respective defined positions, in particular before and after the welding routine is performed.

[0132] The tube positioning unit 6 preferably further comprises a first holder movement mechanism 21 for moving the first tube holder 7, preferably one-dimensionally, two-dimensionally, or three-dimensionally, more preferably transversely, preferably perpendicular to the axial direction of the first tube. The first holder movement mechanism 21 may enable the first tube holder 7 to be moved, in particular horizontally, and the first tube 4 may be moved together with the first tube holder 7. Additionally or alternatively, the tube positioning unit 6 comprises a second holder movement mechanism 22 for moving the second tube holder 8, preferably one-dimensionally, two-dimensionally, or three-dimensionally, more preferably transversely, preferably perpendicular to the axial direction of the second tube 5. The second holder movement mechanism 22 may enable the second tube holder 8 to be moved, in particular horizontally, and the second tube 5 may be moved together with the second tube holder 8, as exemplarily depicted in FIG. 2c).

[0133] With respect to the first holder movement mechanism 21 and / or the second holder movement mechanism 22, the first holder movement mechanism 21 preferably includes a first holder guide 23, and / or the second holder movement mechanism 22 preferably includes a second holder guide 24. The holder guides 23, 24 enable predetermined guided movement of the respective tube holders 7, 8. The first holder guide 23 and / or the second holder guide 24 can each be designed as a rail unit. As shown exemplarily in FIGS. 1 and 2a)-2e), and preferably, at least one of the tube holders 7, 8 is movably mounted on the holder guide 23, 24, each designed as a rail unit, so that at least one of the tube holders 7, 8 can be moved horizontally in one dimension (see, for example, FIG. 2c). In the example shown in FIG. 2c), the second tube holder 8 is movable in the y-direction of a Cartesian coordinate system, i.e., transversely relative to the second tube 5. The holder guides 23, 24, which are designed as rail units, may each comprise one or two rails. The first tube holder 7 and / or the second tube holder 8 can be attached to the first carrier 10 via the first holder guide 23 or to the second carrier 11 via the second holder guide 24. The holder guides 23, 24 can therefore perform a dual function.

[0134] Preferably, the first holder moving mechanism 21 comprises a first holder drive unit 25, and / or the second holder moving mechanism 22 comprises a second holder drive unit 26. The holder drive units 25, 26 drive the movement of the tube holders 7, 8, respectively, in particular on the holder guides 23, 24. The first holder drive unit 25 can be at least partially, in particular completely, arranged on the first tube holder 7, and / or the second holder drive unit 26 can be at least partially, in particular completely, arranged on the second tube holder 8. Thus, the tube holders 7, 8 can be self-driven. Alternatively, in another preferred embodiment, the first holder drive unit 25 and / or the second holder drive unit 26 are designed separately from the first tube holder 7 and / or the second tube holder 8. It is also possible that the first holder drive unit 25 and / or the second holder drive unit 26 can be temporarily connectable to the respective tube holders 7, 8 so that the first tube holder 7 and / or the second tube holder 8 can be driven, in particular so that the respective tube holders 7, 8 can be moved on the holder guides 23, 24. The first holder drive unit 25 and / or the second holder drive unit 26 can be moved to the first tube holder 7 and / or the second tube holder 8 as needed, in particular by the robot mechanism 52. In another embodiment, the first holder drive unit 25 and / or the second holder drive unit 26 can be part of the robot mechanism 52 so that the first tube holder 7 and / or the second tube holder 8 are moved by the robot mechanism 52.

[0135] It is particularly preferred that the first holder drive unit 25 and / or the second holder drive unit 26 can be used to drive a plurality of different first tube holders 7 and / or a plurality of different second tube holders 8 within the integrated bioprocessing system 1. The different first tube holders 7 and / or different second tube holders 8 may be part of different cartridges 1d and / or different receptacles 1b.

[0136] Generally, a single second carrier 11 can carry multiple second tube holders 8. Also, a single cartridge 1d can include multiple second tube holders 8. Each second tube holder 8 can hold a second tube 5, such that the second carrier 11 carries multiple second tubes 5, or the cartridge 1d includes multiple second tubes 5. Generally, a single first carrier 10 can carry multiple first tube holders 7, in which case each first tube holder 7 carries a first tube 4. A single receptacle 1b can include multiple first tube holders 7, each holding a first tube 4. Thus, multiple first tubes 4 and / or multiple second tubes 5 can be connected in sequence to transport media such as liquid immune cell culture, washing buffer, waste, etc.

[0137] In general, multiple tube connections 3 can be formed as needed. The multiple tube connections 3 can be formed simultaneously, partially simultaneously, or sequentially. The tube connections 3 can be formed between multiple different first tubes 4 and multiple different second tubes 5, which are held, in particular, by multiple different first tube holders 7 and multiple different second tube holders 8. The different first tubes 4 can be mounted on a single first carrier 10. In particular, the different first tubes 4 can have different functions, such as inflow and outflow of a medium, respectively. The different second tubes 5 can be mounted on a single second carrier 11. In particular, the different second tubes 5 can have different functions, such as inflow and outflow of a medium, respectively.

[0138] Besides the moving design of the tube holders 7, 8, it has proven advantageous if the tube positioning unit 6, in particular the first tube holder 7, comprises a first tube moving mechanism 27 for moving the first tube 4 held by the first tube holder 7 at least in one dimension, in particular in its axial direction. Preferably, the first tube 4 held by the first tube holder 7 can be moved relative to the first tube holder 7 and the first carrier 10. Alternatively or additionally, the tube positioning unit 6, in particular the second tube holder 8, comprises a second tube moving mechanism 28 for moving the second tube 5 held by the second tube holder 8 in one dimension, preferably in its axial direction; preferably, the second tube 5 held by the second tube holder 8 is moved relative to the second tube holder 8 and the second carrier 11. Preferably, the first tube 4 can be pushed and / or pulled back by a first tube moving mechanism 27, and / or the second tube 5 can be pushed and / or pulled back by a second tube moving mechanism 28. For example, as depicted in FIGS. 2a) and 4d), and preferably, the first tube 4 is pushed or pulled back horizontally by a first tube holder 7. In the embodiment shown in FIGS. 2a) and 4d), the first tube 4 is pushed or pulled back one-dimensionally in the x-direction of a Cartesian coordinate system. The second tube 5 is pushed or pulled back horizontally by a second tube holder 8. In the embodiment shown in FIGS. 2a) and 4d), the second tube 5 is pushed or pulled back one-dimensionally in the x-direction of a Cartesian coordinate system. To drive this movement of the respective tubes 4, 5, the first tube movement mechanism 27 preferably comprises a first tube drive unit 29 and / or the second tube movement mechanism 28 preferably comprises a second tube drive unit 30. It is also possible that the first tube movement mechanism 27 and / or the second tube movement mechanism 28 can be operated automatically. Furthermore, the first tube drive unit 29 and / or the second tube drive unit 30 may be self-driven or may be externally powered, for example by a robotic mechanism 52.The first tube drive unit 29 may be part of the first tube holder 7 and / or the second tube drive unit 30 may be part of the second tube holder 8 .

[0139] Regarding the design of the tube drive units 29, 30, it is preferred that the first tube drive unit 29 comprises a rotatably mounted first drive roller 31 and / or the second drive unit 30 comprises a rotatably mounted second drive roller 32. Rotation of the respective drive roller 31, 32 can cause axial movement, in particular pushing or pulling back, of the respective tube 4, 5. As can be seen exemplarily in FIG. 5 , and preferably, each tube 4, 5 is arranged tangentially to the respective drive roller 31, 32, such that rotational movement of the drive roller 31, 32 causes axial movement of the tube 4, 5. The rotation axis of each drive roller 31, 32 is arranged vertically.

[0140] In a preferred embodiment, the tube drive units 29, 30 are self-driven. Here, the respective drive rollers 31, 32 can be rotated as needed to push or retract the respective tubes 4, 5 accordingly. However, in another preferred embodiment, the first tube drive unit 29 and / or the second tube drive unit 30 can be externally powered. Here, the first tube drive unit 29 can be driven by a first tube drive unit drive 61, and / or the second tube drive unit 30 can be driven by a second tube drive unit drive 62. The first tube drive unit drive 61 and / or the second tube drive unit drive 62 can be designed separately from the respective tube drive units 29, 30, or can be temporarily connected to the respective tube drive units 29, 30 as needed. The first tube drive unit drive 61 and / or the second tube drive unit drive 62 can be transported to the first tube drive unit 29 and / or the second tube drive unit 30 by a robotic mechanism 52 in the integrated bioprocessing system 1. It is particularly preferred that the first tube drive unit drive 61 and / or the second tube drive unit drive 62 can be used to drive a plurality of different tube drive units 29, 30, in particular different cartridges 1d and / or different receptacles 1b. It is also possible that the first holder drive unit drive and / or the second holder drive unit drive are part of the tube connection head 43.

[0141] The first tube drive unit 29 preferably comprises a first drive rocker 33 for locking the first drive roller 31 so that the first tube 4 is immobile relative to the first tube drive unit 29. Additionally or alternatively, the second tube drive unit 30 comprises a second drive rocker 34 for locking the first drive roller 31 so that the second tube 5 is immobile relative to the second tube drive unit 30. The drive rockers 33, 34 may lock the drive rollers 31, 32 after axial positioning of the tubes 4, 5, as exemplarily shown in Figures 2a) and 2b).

[0142] Advantageously, the first tube drive unit 29 comprises a rotatably mounted first passive roller 35 and / or the second tube drive unit 30 comprises a rotatably mounted second passive roller 36. Preferably, each passive roller 35, 36 is positioned relative to the respective drive roller 31, 32 such that the respective tube 4, 5 is located therebetween, as shown, for example, in Figure 5. The axis of rotation of each passive roller 35, 36 is vertically arranged.

[0143] Furthermore, it is preferred that the first tube drive unit 29 comprises a first preloading mechanism 37 for preloading the first passive roller 35 onto the first tube 4, and / or the second tube drive unit 30 comprises a second preloading mechanism 38 for preloading the second passive roller 36 onto the second tube 5. The respective preloading mechanisms 37, 38 make it possible to increase the grip of the respective drive roller 31, 32 on the respective tube 4, 5, thus preventing slippage of the respective tube 4, 5. In the exemplary and preferred embodiment of FIG. 5, the preloading mechanisms 37, 38 comprise at least one spring that preloads the respective passive roller 35, 36 towards the respective drive roller 31, 32. The spring may be a compression spring, as in the embodiment according to FIG. 5.

[0144] In a further preferred embodiment, as depicted in FIG. 5 , the tube positioning unit 6 includes a first guide mechanism 39 for guiding the first tube 4 and / or a second guide mechanism 40 for guiding the second tube 5. Because the tubes 4 and 5 may be flexible, the guide mechanisms 39 and 40 can improve the accuracy of positioning of each of the tubes 4 and 5. It is preferred that the first guide mechanism 39 is part of the first tube holder 7 and / or the second guide mechanism 40 is part of the second tube holder 8. As exemplarily depicted in FIG. 5 , it is particularly preferred that the first guide mechanism 39 includes a first funnel 41 and / or the second guide mechanism 40 includes a second funnel 42. Each of the tubes 4 and 5 can be pushed and / or pulled back through the respective funnels 41 and 42. The first funnel 41 is preferably arranged on the first tube holder 7, and / or the second funnel 42 is preferably arranged on the second tube holder 8, wherein more preferably the first funnel 41 is arranged such that the first tube 4 can move through the first funnel 41, and / or the second funnel 42 is arranged such that the second tube 5 can move through the second funnel 42. The first funnel 41 and / or the second funnel 42 may be arranged such that the first tube 4 and / or the second tube 5 can be pushed or pulled back through the respective funnels 41, 42.

[0145] Alternatively, as schematically depicted in FIG. 9 , the first and second guide mechanisms 39, 40 can be part of a tube connection head 43, in particular part of a first tube receiver 58, 59. The tube connection head 43 will be described in more detail below. It is particularly preferred that the first guide mechanism 39 comprises a first funnel 41 and / or the second guide mechanism 40 comprises a second funnel 42. Each tube 4, 5 can be pushed and / or pulled back through each funnel 41, 42. Preferably, the first and second funnels 41, 42 guide the first and second tubes 4, 5 into the tube connection head 43 as they are pushed out so that a welding routine can be performed. The first funnel 41 and the second funnel 42 can be arranged on the tube connection head 43, and more preferably, the first funnel 41 is arranged so that the first tube 4 can move through the first funnel 41, and / or the second funnel 42 is arranged so that the second tube 5 can move through the second funnel 42.

[0146] As explained above, each funnel 41, 42 may be equipped with a sensor to confirm that the tube extrusion process has been successfully initiated and additionally to indicate that the tube has been successfully retracted.

[0147] When the first and second guide mechanisms 39, 40 are part of the tube connection head 43, the first and second funnels 41, 42 preferably have first and second funnel openings extending along the axis of the funnels 41, 42 and on their outer circumferential surfaces (shell surfaces). Through the first and second funnel openings, the first and second tubes 4, 5 can be removed transversely to the funnels 41, 42, particularly after the tube connection 3 has been formed and the tubes 4, 5 have been connected to one another. Alternatively, the first and second funnels 41, 42 can each be designed as at least two parts, so that the first and second tubes 4, 5 can be removed from the funnels 41, 42, particularly after the tube connection 3 has been formed. The first and second funnel openings, or at least two part funnels 41, 42, can receive the first tube 4 and the second tube 5 when the tube connection 3 has already been formed. This may be beneficial if the welding and separation routines are performed by the tube cutting unit 9 and the tube separation mechanism 14 of the tube connection system 2, respectively.

[0148] Preferably, as exemplarily shown in FIG. 1, the first tube holder 7 is an anchor point 1c, preferably an anchor point for a receptacle or an anchor point for a cartridge, and / or the second tube holder 8 is an anchor point 1e, preferably an anchor point for a receptacle or an anchor point for a cartridge.

[0149] Preferably, as exemplarily shown in FIG. 1, the first tube 4 is a transfer tube, preferably a receptacle transfer tube or a cartridge transfer tube, and / or the second tube is a transfer tube, preferably a receptacle transfer tube or a cartridge transfer tube.

[0150] Advantageously, the tube connection system 2 comprises a tube connection head 43, which is preferably movable one-, two-, or three-dimensionally. Preferably, the tube positioning unit 6, in particular the first tube holder 7 and / or the second tube holder 8, are designed to be separate from and independently movable with respect to the tube connection head 43, as exemplarily shown in FIGS. 3c and 3d. Alternatively, at least a part of the tube positioning unit 6, in particular the first tube receptacle 58 and / or the second tube receptacle 59, may be arranged on the tube connection head 43, as exemplarily shown in FIG. 6. Preferably, the tube receptacles 58 and 59 are designed as tube holders having the same or at least partially the same features as the tube holders 7 and 8. More preferably, the tube cutting unit 9 is designed separately from the tube connection head 43, or at least a part of the tube cutting unit 9 is arranged on the tube connection head 43, as exemplarily shown in FIGS. 3c and 6.

[0151] FIG. 3c) exemplarily shows a preferred embodiment in which the tube connection head 43 is equipped with a tube cutting unit 9. The tube positioning unit 6, i.e., the first tube holder 7 and the second tube holder 8, are designed separately from the tube connection head 43. Thus, the tube connection head 43 can be moved relative to the tube holders 7, 8. Here, the tube cutting unit 9 can be moved to a specific location within the integrated bioprocessing system 1 to perform a welding routine. Multiple welding routines can be performed, for example, at different unit operation stations, to connect different tubes 4, 5.

[0152] 6 exemplarily illustrates another preferred embodiment, in which a tube connection head 43 includes a tube cutting unit 9 and at least a part of a tube positioning unit 6, i.e., a first tube receptacle 58 for receiving a tube, particularly for receiving the first tube 4, and a second tube receptacle 59 for receiving a tube, particularly for receiving the second tube 5. Here, the first tube receptacle 58 and the second tube receptacle 59 are movable together with the tube connection head 43. The tube connection head 43 can be moved to a specific location within the integrated bioprocessing system 1 to perform a welding routine. Preferably, the welding routine includes an insertion phase in which the tubes 4 and 5 are inserted or threaded into the tube receptacles 58 and 59, respectively. It is also possible for the first tube receptacle 58 and / or the second tube receptacle 59 to be designed like the tube holders 7 and 8. The receptacles 58 and 59 may be designed, in particular, like the previously described tube holders 7 and 8. Here, the positioning phase can be performed at least in part by movement of the tube connection head 43.

[0153] The tube cutting unit 9 preferably includes a blade 9a for cutting the first tube 4 and / or the second tube 5, and the blade 9a is heatable. Preferably, the tube cutting unit 9 includes a blade heater 9c for heating the blade 9a and / or a blade mount 9b, and the blade 9a is detachably and / or ejectably attached to the blade mount 9b. After the welding routine is performed, the blade 9a can be automatically ejected by the blade mount 9b. As exemplarily shown in FIGS. 3c and 6, the blade 9a and / or the blade heater 9c and / or the blade mount 9b are preferably disposed on the tube connection head 43. Alternatively, the tube cutting unit 9 can include an alternative cutting element, such as a laser, for cutting the tubes 4 and 5. The cutting element may be single-use (disposable) or multiple-use (reusable) and / or non-contact.

[0154] To replace the blades 9a, the tube connection system 2 advantageously comprises a blade storage 44 for storing a plurality of blades 9a, preferably comprising a plurality of blades 9a that can be individually, in particular fully automatically, mounted on blade mounts 9b. The blades 9a are preferably detachably, in particular ejectably, mounted on the blade mounts 9b, so that the entire blade replacement process of replacing a used blade 9a with an unused blade 9a can be carried out automatically. Here, the used blade 9a is removed, for example by ejection after a welding routine has been performed, and an unused blade 9a, which may be located in the blade storage 44, is installed.

[0155] Alternatively, the blade 9a may be replaced by an operator, in which case the tube cutting unit 9 may be moved to a position on the integrated bioprocessing system 1 that is accessible to the operator.

[0156] In a further preferred embodiment, the tube connection system 2 comprises a tube identification mechanism 45 for identifying the first tube 4 held by the first tube holder 7 and / or the second tube 5 held by the second tube holder 8. Preferably, the tube identification mechanism 45 is at least partially arranged on the first tube holder 7 and / or at least partially arranged on the second tube holder 8 and / or at least partially arranged on the tube connection head 43. More preferably, the tube identification mechanism 45 comprises at least one, in particular optical, identification sensor 46. The tubes 4, 5 to be welded can be identified by the tube identification mechanism 45. In an exemplary embodiment, the means for tube identification can be a color pattern or the like. A welding routine can be executed according to the identified tubes 4, 5.

[0157] Preferably, the tube connection system 2 comprises a position determination mechanism 47 for determining the position of the first tube 4 and / or the second tube 5, and / or the first tube holder 7 and / or the second tube holder 8, and / or the tube connection head 43, and / or the first carrier 10 and / or the second carrier 11. Determining the position of each component of the tube connection system 2, in particular of the integrated bioprocessing system 1, may be important for performing welding routines, in particular in an automated manner. It is particularly preferred that the position of the first tube 4 in the integrated bioprocessing system 1 is determined by determining the position of the first carrier 10 and / or that the position of the second tube 5 in the integrated bioprocessing system 1 is determined by determining the position of the second carrier 11. Preferably, the positioning mechanism 47 is arranged at least partially on the first tube holder 7 and / or at least partially on the second tube holder 8 and / or at least partially on the tube connection head 43 and / or at least partially on the first carrier 10 and / or the second carrier 11. Further preferably, the positioning mechanism 47 comprises at least one position sensor 48, in particular optical or electrical, or a plurality of position sensors 48, in particular optical and / or electrical.

[0158] For verification reasons, in a further embodiment, the tube connection system 2 preferably comprises a weld verification mechanism 49 for verifying the tube connection 3. The tube connection 3 can be verified by an integrity test routine. The integrity test routine can be performed as described above in connection with the proposed method. Preferably, the weld verification mechanism 49 comprises one or more tube closure elements 60, such as clamps, for temporarily occluding the first tube 4 and / or the second tube 5. The tube closure elements 60 can be part of the first tube holder 7 and / or the second tube holder 8. Preferably, the weld verification mechanism 49 comprises at least one verification sensor 50, in particular optical or pressure-measuring, or multiple verification sensors 50, in particular optical and / or pressure-measuring. Preferably, the weld verification mechanism 49 comprises at least one tube pressurization unit 51 for applying pressure to the first tube 4 and / or the second tube 5, in particular after welding.

[0159] More preferably, the weld verification mechanism 49 comprises a tube pressurization unit 51. The tube pressurization unit 51 may comprise one or more actuators, in particular linear actuators, each compressing one of the tubes 4, 5. Compression on both sides of the tube connection 3 is preferred. Preferably, compression is performed by applying pressure to the tubes 4, 5, preferably by the tube pressurization unit 51, in particular by compressing the first tube 4 by one of the linear actuators and the second tube 5 by another of the linear actuators. The compression can be performed according to a predefined compression pattern.

[0160] The weld verification mechanism 49 preferably comprises at least one, in particular optical, force or pressure measuring verification sensor 50 or a plurality of, in particular optical, force or pressure measuring verification sensors 50 .

[0161] Preferably, the weld verification mechanism 49 comprises at least one verification sensor 50 on either side of the tube connection 3 in order to verify the integrity of the tube connection 3. Preferably, the at least one verification sensor 50 is designed as a force measuring sensor, which is used to monitor the force required to compress each tube 4, 5 to a certain extent. Preferably, the force measuring sensor(s) are part of the tube pressurizing unit 51. In particular, each linear actuator comprises a force measuring sensor. Alternatively or additionally, each tube holder 7, 8 may be equipped with one force measuring sensor.

[0162] Preferably, to verify the integrity of the tubing connections 3, the sensor signals obtained over time as each tube 4, 5 is compressed are compared with sensor signals obtained for a tubing connection 3 known to be intact and / or for a tubing connection 3 known to be unsafe. Verification of the integrity of the tubing connections 3 can be done, for example, by analyzing the peak force measured by any verification sensor 50, in particular any force-measuring sensor, for a given compression. Additionally or alternatively, multivariate data analysis approaches such as principal component analysis or machine learning approaches such as neural networks can be used to analyze the sensor signals and determine whether the tubing connection 3 is intact or unsafe.

[0163] It has proven advantageous if the tube connection system 2 comprises a waste disposal mechanism for disposing of waste material while the first tube 4 and the second tube 5 are cut. Preferably, the waste disposal mechanism comprises at least a waste disposal collector and / or at least a waste disposal suction unit. More preferably, the waste disposal collector is movable relative to the first tube holder 7 and / or the second tube holder 8, and / or the waste disposal suction unit is arranged on the tube connection head 43. Alternatively, and preferably, the waste disposal collector can be moved, preferably under automatic control, using the same mechanism that moves the tube connection system 2, e.g., a robotic mechanism 52, to a location where the waste material can be deposited for further disposal, such as incineration.

[0164] Furthermore, it is preferred that the tube connection system 2 comprises a robot mechanism 52, and that the tube connection head 43 is attached to the robot mechanism 52 so that the tube connection head 43 is preferably movable in one, two, or three dimensions. The robot mechanism 52 can be designed as a robot arm, such as a multi-axis robot, or as a linear robot having one, two (also known as an xy robot mechanism) or three (also known as a Cartesian (orthogonal) robot mechanism) movement axes. In Fig. 1, for example and preferably, the robot mechanism 52 is designed as a linear robot having three movement axes so that the robot mechanism 52 can move the tube connection head 43 in three dimensions, i.e., in the x-, y-, and z-directions.

[0165] Additionally or alternatively, the tube connection system includes a conveyor mechanism 53, and the first carrier 10 and / or the second carrier 11 are movable one-, two-, or three-dimensionally by the conveyor mechanism 53. In general, the robot mechanism 52 may be designed such that the first carrier 10, particularly the receptacle 1b, and / or the second carrier 11, particularly the cartridge 1d, are movable by the robot mechanism 52 within the integrated bioprocessing system 1. In Figure 1, for example and possibly, the conveyor mechanism 53 may move the first tube 4 and the second tube 5 by moving the first carrier 10, or more appropriately the receptacle 1b, and the second carrier 11, or more appropriately the cartridge 1d, respectively, in a horizontal plane depicted in the x and y directions exemplarily shown in Figure 1.

[0166] In another preferred embodiment, the tube connection system 2 comprises a tube separation mechanism 14 for separating the first tube 4 and the second tube 5. The separation of the first tube 4 and the second tube 5 may be performed in a separation routine, as described above in connection with the proposed method. The tube separation mechanism 14 preferably comprises at least a sealing unit 15 and / or a separation unit 17. More preferably, the tube separation mechanism 14 is at least partially arranged on the tube connection head 43. Figures 4b) and 4c) exemplarily show a tube separation mechanism 14 comprising a sealing unit 15 and a separation unit 17.

[0167] In this context, it is preferred that the sealing unit 15 has two sealing surfaces 16, between which the first tube 4 and / or the second tube 5 and / or the tube connection 3 can be arranged for sealing, and the sealing surfaces 16 can be moved relative to each other for sealing. It is also possible that at least one of the sealing surfaces 16 is heatable. The sealing phase can be carried out by the sealing unit 15. In FIG. 4b), for example, the sealing unit 15 has four sealing surfaces 16, more suitably two pairs of sealing surfaces 16. Here, and preferably, the sealing surfaces 16 are each designed as a plane, thereby forming planar seals 56, 57. Here, and preferably, the planar seals 56, 57 are arranged transversely to the axes of the tubes 4, 5.

[0168] However, it is particularly preferred if the sealing unit 15 comprises a sealing surface 63 which is designed to crimp the first tube 4 and / or the second tube 5 along the axial direction of the respective tube 4, 5, such that the first tube 4 and / or the second tube 5 are self-sealing, in particular if the sealing surface 63 is heated when the respective tubes 4, 5 are crimped. An example of such an embodiment is shown in Figures 8a) and 8b).

[0169] Here, and preferably, the sealing surface 63 comprises a crimping element 64 designed as a pin 65, in particular an elongated pin 65. As shown exemplarily in FIG. 8a), the elongated pin 65 extends in the axial direction of the tubes 4, 5 to be sealed. The sealing surface 63 preferably forms a seal that is U-shaped in cross section, in particular in cross section along the main axis of the sealed tubes 4, 5, as exemplarily depicted in FIG. 8b). The cross section can extend in the axial direction of the tubes 4, 5 over at least the length of the original diameter of the sealed tubes 4, 5, preferably at least twice the original diameter of the sealed tubes 4, 5. Furthermore, the cross section of the seal can include at least a subsection spanning an angular range of at least 180°, preferably at least 235°, within which the original diameter of the sealed tubes 4, 5 can be maintained. As shown in FIG. 8b, and preferably, the seal formed by the sealing surface 63 includes a periphery with at least one inflection point, preferably at least two inflection points.

[0170] It is particularly preferred that the sealing surface 63 is a first sealing surface 66, and that the sealing unit 15 comprises a second sealing surface 67 designed to receive the tubes 4, 5 to be sealed. The second sealing surface 67 is designed to correspond to the tubes 4, 5 to be sealed. The second sealing surface 67 in particular comprises a cylindrical groove 68 for receiving the respective tubes 4, 5. Here, and preferably, the sealing unit 15 comprises four sealing surfaces, with pairs of sealing surfaces 66, 67 corresponding to each other. Each pair of sealing surfaces 67, 66 is located on either side of a cutting position 69 where the cutting is performed. It is preferred that the crimp element 64 of one of the first sealing surfaces 66 is aligned to coincide with the center of the corresponding groove 68 of the second sealing surface 67, so that the crimp element 64 compresses the tubes 4, 5 at their centers, compressing and sealing the tubes 4, 5 without changing their diameter.

[0171] Alternatively or additionally, the cutting unit 17 comprises a separation laser or a separation blade 18, which can be heated, and the first tube 4 and / or the second tube 5 and / or the tube connection 3 can be cut by the separation laser or separation blade 18, which is preferably attached, in particular detachably and / or ejectably, to a blade mount 9b of the tube connection head 43. The separation blade 18 or separation laser can be used to perform the separation phase. The separation blade 18 can in particular be a blade 9a included in the tube cutting unit 9. The tube cutting unit 9 can also be the separation unit 17. In general, the tube separation mechanism 14, in particular the separation unit 17, can preferably share components such as the blades 9a, 18, the blade mount 9b and / or the blade storage 44 with the tube connection system 2, in particular the tube cutting unit 9.

[0172] Furthermore, it can be advantageous if the tube connection system 2 comprises a pumping mechanism 54, which is designed to be able to transport a medium, in particular a fluid, preferably a liquid, through the first tube 4 and the second tube 5 after welding and / or to push the medium in the first tube 4 and / or the second tube 5 and minimize dead volumes in the first tube 4 and / or the second tube 5. Preferably, the pumping mechanism 54 comprises a peristaltic pump and / or a pressure unit. It is also possible for the pumping mechanism 54 to evacuate the first tube 4 and / or the second tube 5 before welding, in particular before the welding phase.

[0173] In a preferred embodiment, the tube connection system 2 comprises a data reporting unit 55 for reporting welding and / or separation data, preferably data relating to the first tube 4 and / or the second tube 5 and / or the tube connection 3 and / or the first tube holder 7 and / or the second tube holder 8 and / or the tube connection head 43 and / or the blade 9a and / or the blade heater 9c and / or the blade mount 9b and / or the blade storage section 44 and / or the robot mechanism 52 and / or the conveyor mechanism 53 and / or the tube separation mechanism 14 and / or the sealing unit 15 and / or the separation unit 17 and / or the end of the first tube 4 and / or the end of the second tube 5, in particular movement data, position data, temperature data, time data and / or pressure data.

[0174] As a third teaching, an integrated bioprocessing system 1 for performing a bioprocess on a cell culture is provided, wherein during the performance of the bioprocess, a medium used in the bioprocess, in particular the cell culture, can be transported through tubes 4, 5 by the integrated bioprocessing system 1. The integrated bioprocessing system 1 includes a first tube 4 for transporting the medium and a second tube 5 for transporting the medium, the first tube 4 and the second tube 5 being connected by a tube connection 3 and disposed at a separation position within the integrated bioprocessing system 1. The separation position may be a welding position. The integrated bioprocessing system 1 may include multiple separation positions.

[0175] The first tube 4 is held by a first tube holder 7 and is fluidly connected to a first fluid structure 12 for receiving and / or supplying a medium via the first tube 4. Furthermore, the integrated bioprocessing system 1 comprises a movable first carrier 10, which carries the first tube 4, the first tube holder 7 and the first fluid structure 12.

[0176] The integrated bioprocessing system 1 includes a tube separation mechanism 14 for separating the first tube 4 and the second tube 5 at a separation position during a separation routine so that the first tube 4 and the second tube 5 are fluidly and / or physically separated.

[0177] The first carrier 10, and together with the first carrier 10 the first tube 4, the first tube holder 7 and the first fluid structure 12, can be transported from the separated position after the first tube 4 and the second tube 5 are separated.

[0178] The proposed method can be implemented in conjunction with the proposed integrated bioprocessing system according to the third teaching, and therefore all features and descriptions made with respect to the proposed method are fully applicable to the proposed integrated bioprocessing system according to the third teaching, and vice versa. Furthermore, all features and descriptions made with respect to the proposed integrated bioprocessing system according to the second teaching are fully applicable to the proposed integrated bioprocessing system according to the third teaching, and vice versa.

[0179] As a fourth teaching, a tube separation mechanism 14 is provided for separating a first tube 4 and a second tube 5, particularly in an integrated bioprocessing system 1, in a separation routine in which the first tube 4 and the second tube 5 are fluidly and / or physically separated, wherein the tube separation mechanism 14 includes a sealing unit 15 for sealing the first tube 4 and / or the second tube 5, and in the sealing phase, a first sealing portion 56 and / or a second sealing portion 57 are formed, and the sealing unit 15 includes at least one sealing surface 63, which is designed to crimp the first tube 4 and / or the second tube 5 along the axial direction of each tube 4, 5, thereby causing the first tube 4 and / or the second tube 5 to self-seal.

[0180] The proposed tube separation mechanism 14 can be used in the proposed method, and therefore all features and descriptions made with respect to the proposed method are fully applicable to the proposed tube separation mechanism 14, and vice versa. The proposed tube separation mechanism 14 can be used in the proposed integrated bioprocessing system 1 according to the second teaching and / or in the proposed integrated bioprocessing system according to the third teaching, and therefore all features made with respect to the integrated bioprocessing system are fully applicable to the proposed tube separation mechanism 14, and vice versa.

[0181] As a fifth teaching, there is provided a sealing unit 15, particularly of a tube separation mechanism 14 in an integrated bioprocessing system 1, for sealing a first tube 4 and / or a second tube 5 in a sealing phase to form seals 56, 57. The sealing unit 15 comprises at least one sealing surface 63, which is designed to crimp the first tube 4 and / or the second tube 5 along the axial direction of the respective tubes 4, 5, so that the first tube 4 and / or the second tube 5 are self-sealed.

[0182] One embodiment of the sealing unit 15 is exemplarily depicted in Figures 8a) and 8b) and has been previously described in connection with the tube separation mechanism 14 of the integrated bioprocessing system, and all features are therefore fully applicable.

[0183] The proposed sealing unit 15 can be used in the proposed method, and therefore all features and explanations made with respect to the proposed method are fully applicable to the proposed sealing unit 15, and vice versa. The proposed sealing unit 15 can be used in the proposed integrated bioprocessing system 1 according to the second teaching, and / or in the proposed integrated bioprocessing system according to the third teaching, and / or in the tube separation mechanism 14 according to the fourth teaching, and therefore all features made are fully applicable to the proposed sealing unit 15, and vice versa.

[0184] As a sixth teaching, a device for transporting tubes 4, 5, particularly within an integrated bioprocessing system 1, is provided, the device comprising carriers 10, 11, tubes 4, 5, tube holders 7, 8 and fluid structures 12, 13, the carrier transports the tubes 4, 5, tube holders 7, 8 and fluid structures 12, 13 so that the tubes 4, 5, tube holders 7, 8 and fluid structures 12, 13 can be transported together with the carriers 10, 11, and the tube holders 7, 8 hold the tubes 4, 5 in a defined position.

[0185] The device can be designed as a cartridge 1d or a receptacle 1b. The carriers 10, 11, tubes 4, 5, tube holders 7, 8 and / or fluidic structures 12, 13 can be designed as described above. All descriptions and features made above are fully applicable. Conversely, all descriptions and features relating to the device are fully applicable to the proposed method, the proposed integrated bioprocessing system 1, the proposed tube separation mechanism 14, and the proposed sealing unit 15.

[0186] An equally important seventh teaching proposes that the first tube holder 7 is positioned at the welding position by a positioning mechanism separate from the tube connection system 2 .

[0187] An equally important eighth teaching proposes that the first tube holder 7 fluidly occludes, in particular pinches, the first tube 4, in a particularly reversible manner.

[0188] According to the equally important ninth teaching, it is proposed that the first tube holder 7 pushes the first tube 4 into the tube connection system 2, in particular before any interaction of the first tube 4 with the tube connection system 2.

[0189] Equally important, the tenth teaching proposes that the first tube holder 7 holds the first tube 4 at a predetermined angle or range of angles defined with respect to the integrated bioprocessing system 1 and / or defined with respect to the tube connection system 2 and / or defined with respect to the second tube 5 prior to any interaction between the first tube 4 and the tube connection system 2. Figure 2 shows the defined angle of the first tube and the second tube 5. Figure 3 shows how this angle is advantageous in interaction with the tube connection system 2.

[0190] The eleventh teaching is directed to a method for welding, particularly sealing, a tube at least partially along its length, particularly in an integrated bioprocessing system 1.

Claims

1. A method for carrying out a bioprocess on a cell culture, the bioprocess being carried out on an integrated bioprocessing system (1), wherein during the carrying out of the bioprocess, the integrated bioprocessing system (1) transports a medium used in the bioprocess, in particular the cell culture, through tubes, the integrated bioprocessing system (1) comprising a tube connection system (2) for connecting the tubes of the integrated bioprocessing system (1) as required by welding, a first tube (4), a first tube holder (7) and a first fluid structure (12) for receiving and / or supplying the medium are carried by a movable first carrier (10), the first tube (4) is connected to the first tube holder (7) the first carrier (10) is held and fluidly connected to the first fluid structure (12), and the first carrier (10) and the first tube (4), the first tube holder (7), and the first fluid structure (12) together with the first carrier (10) are transported to a welding position within the integrated bioprocessing system (1), and during a welding routine at the welding position, the tube connection system (2) connects the first tube (4) and a second tube (5) to form a tube connection (3), and the integrated bioprocessing system (1) transfers the medium from or to the first fluid structure (12) of the first carrier (10) through the tube connection (3).

2. 2. The method according to claim 1, characterized in that the welding routine comprises a positioning phase, in which the first tube (4) and the second tube (5) are positioned relative to each other, preferably at least in the axial direction of the first tube (4) and / or the second tube (5), and / or a trimming phase, in which the first tube (4) and the second tube (5) are cut, and / or a welding phase, in which the first tube (4) and the second tube (5) are brought into contact and fused so as to form the tube connection (3).

3. 3. The method according to claim 1, wherein the tube connection system (2) comprises a tube cutting unit (9), the tube cutting unit (9) comprising a blade (9a) and preferably a blade heater (9c), and wherein the trimming phase preferably comprises a heating step during which the blade heater (9c) heats the blade (9a) to a cutting temperature; and / or the trimming phase comprises an aligning step in which the tube cutting unit (9) is aligned relative to the first tube (4), in particular in the first cutting position, and / or the second tube (5), in particular in the second cutting position; and / or the trimming phase comprises a cutting step in which the first tube (4), in particular in the first cutting position, and / or the second tube (5), in particular in the second cutting position, are cut by the tube cutting unit (9), in particular by the blade (9a).

4. 4. The method according to claim 1, wherein the tube connection system (2) comprises a tube separation mechanism (14), preferably the tube separation mechanism (14) comprises a sealing unit (15) and / or a separation unit (17), further preferably the method comprises a separation routine in which the first tube (4) and the second tube (5) are separated, further preferably the separation routine comprises a sealing phase in which the first tube (4) and / or the second tube (5) are sealed by the sealing unit (15) so that a first seal (56) and / or a second seal (57) are formed, and / or a separation phase in which the first tube (4) and the second tube (5) are cut by the tube separation unit (17), in particular between the first seal (56) and the second seal (57).

5. 5. The method according to claim 1, further comprising temporarily occluding the first tube (4) and / or the second tube (5) before the welding routine or before the welding phase is performed, and performing an integrity test routine after the welding routine or after the welding phase has been performed to verify the integrity of the tube connection (3), and depending on the result of the integrity test routine, removing the temporary occlusion of the first tube (4) and / or the second tube (5) if the integrity of the tube connection (3) is confirmed, or initiating an emergency routine to protect the cell culture if the integrity of the tube connection (3) is not confirmed.

6. The method according to any one of claims 1 to 5, characterized in that the method comprises connecting the first tube (4) or the second tube (5) of the integrated bioprocessing system (1) to a third tube (19) by means of the tube connection system (2) so as to form a further tube connection (20), the further tube connection (20) being formed by a welding routine.

7. An integrated bioprocessing system for carrying out a bioprocess on a cell culture, wherein during the carrying out of the bioprocess, a medium used in the bioprocess, in particular the cell culture, can be transported by the integrated bioprocessing system (1) through a tube, the integrated bioprocessing system (1) comprising a first tube (4) for medium transport and a second tube (5) for medium transport, the first tube (4) being held by a first tube holder (7) and fluidically connected to a first fluid structure (12) for receiving and / or supplying the medium, the integrated bioprocessing system (1) comprising a movable first carrier (10), the first tube (4), the first tube holder (7) and the first fluid structure (12) being The integrated bioprocessing system is transported by the first carrier (10), and the first carrier (10), together with the first tube (4), the first tube holder (7), and the first fluid structure (12) can be transported to a welding position within the integrated bioprocessing system, the integrated bioprocessing system (1) comprising a tube connection system (2) for connecting the first tube (4) and the second tube (5) in a welding routine at the welding position so that a tube connection (3) is formed by welding, and after welding, the medium can be transferred from the first fluid structure (12) of the first carrier (10) or to the first fluid structure (12) of the first carrier (10) through the tube connection (3).

8. The integrated bioprocessing system of claim 7, characterized in that the second tube (5) is held by a second tube holder (8) and is fluidly connected to a second fluid structure (13) for receiving and / or supplying the medium, preferably the integrated bioprocessing system (1) comprises a movable second carrier (11), the second tube (5), the second tube holder (8) and the second fluid structure (13) are carried by the second carrier (11), and the second carrier (11), and the second tube (5), the second tube holder (8) and the second fluid structure (13) together with the second carrier (11) can be transported to the welding position.

9. 9. The integrated bioprocessing system of claim 7, wherein the tube connection system (2) comprises a tube positioning unit (6) for positioning the first tube (4) and the second tube (5) relative to one another at least in the axial direction of the first tube (4) and / or the second tube (5) so that the first tube (4) and the second tube (5) can be cut in a positioning phase of the welding routine, and a tube cutting unit (9) for cutting the first tube (4) and the second tube (5) in a trimming phase of the welding routine, wherein the tube positioning unit (6) is preferably designed such that the first tube (4) and the second tube (5) are brought into contact and fused together in a welding phase of the welding routine so that the tube connection (3) is formed.

10. The first tube holder (7) and / or the second tube holder (8) are part of the tube arrangement unit (6), and preferably the tube arrangement unit (6) comprises a first holder moving mechanism (21) for moving the first tube holder (7), in particular perpendicular to the axial direction of the first tube (4), and / or a second holder moving mechanism (22) for moving the second tube holder (8), in particular perpendicular to the axial direction of the second tube (5), and more preferably the first holder moving mechanism (21) comprises a first holder moving mechanism (22) for guiding the movement of the first tube holder (7). and / or the second holder moving mechanism (22) comprises a second holder guide (24) for guiding the movement of the second tube holder (8), and / or the first holder moving mechanism (21) comprises a first holder drive unit (25), and / or the second holder moving mechanism (22) comprises a second holder drive unit (26), preferably the first holder guide (23) is designed as a first rail unit and / or the second holder guide (24) is designed as a second rail unit.

11. The tube arrangement unit (6), in particular the first tube holder (7), comprises a first tube moving mechanism (27) for moving the first tube (4) held by the first tube holder (7), in particular in one dimension and / or in the axial direction of the first tube (4), preferably for moving the first tube (4) held by the first tube holder (7) relative to the first tube holder (7); and / or the tube arrangement unit (6), in particular the second tube holder (7), comprises a first tube moving mechanism (27) for moving the first tube (4) held by the first tube holder (7), in particular in one dimension and / or in the axial direction of the first tube (4), preferably for moving the first tube (4) held by the first tube holder (7) relative to the first tube holder (7).

11. An integrated bioprocessing system as described in claim 9 or 10, characterized in that the tube holder (8) of the first tube holder (8) comprises a second tube moving mechanism (28) for moving the second tube (5) held by the second tube holder (8) in one dimension, in particular in the axial direction of the second tube (5), and / or the first tube moving mechanism (27) comprises a first tube drive unit (29) and / or the second tube moving mechanism (28) comprises a second tube drive unit (30).

12. The first tube drive unit (29) comprises a rotatable first drive roller (31), and / or the second drive unit (30) comprises a rotatable second drive roller (32), the first drive roller (31) moving the first tube (4) in the axial direction of the first tube (4) when rotated, and / or the second drive roller (32) moving the second tube (5) in the axial direction of the second tube (5) when rotated, preferably the first tube drive unit (29) comprises a first drive locker (33) for locking the first drive roller (31) so that the first tube (4) is immobile relative to the first tube drive unit (29), and / or the second tube drive unit (30) comprises a first drive locker (33) for locking the first drive roller (31) so that the first tube (4) is immobile relative to the first tube drive unit (29), and / or the second tube drive unit (30) comprises a second drive locker (33) for locking the second tube (5) in the axial direction of the second tube (5).

12. The integrated bioprocessing system of claim 11, wherein the first tube drive unit (29) comprises a second drive locker (34) for locking the first drive roller (31) so that the first tube drive unit (29) is immobile relative to the second tube drive unit, and / or the first tube drive unit (29) comprises a rotatable first passive roller (35), and / or the second tube drive unit (30) comprises a rotatable second passive roller (36), preferably the first tube drive unit (29) comprises a first pre-load mechanism (37) for pre-loading the first passive roller (35) onto the first tube (4), and / or the second tube drive unit (30) comprises a second pre-load mechanism (38) for pre-loading the second passive roller (36) onto the second tube (5).

13. 13. An integrated bioprocessing system according to any one of claims 7 to 12, characterized in that the tube connection system (2) comprises a tube connection head (43), in particular a movable one, preferably comprising a first tube receiver (58) for receiving a tube, in particular the first tube (4), and / or a second tube receiver (59) for receiving a tube, in particular the second tube (5), and further preferably at least a part of the tube cutting unit (9) is arranged on the tube connection head (43).

14. The tube arrangement unit (6) comprises a first guiding mechanism (39) for guiding the first tube (4) and / or a second guiding mechanism (40) for guiding the second tube (5), preferably the first guiding mechanism (39) is part of the first tube holder (7) and / or the second guiding mechanism (40) is part of the second tube holder (8), or the first guiding mechanism (39) and the second guiding mechanism (40) are part of the tube connection head (43), in particular the first tube receiver (58) and the second tube receiver ( 14. The integrated bioprocessing system of claim 7, wherein the first guide mechanism (39) comprises a first funnel (41) and / or the second guide mechanism (40) comprises a second funnel (42), the first funnel (41) being arranged such that the first tube (4) is movable through the first funnel (41) and / or the second funnel (42) being arranged such that the second tube (5) is movable through the second funnel (42).

15. 15. The integrated bioprocessing system according to claim 7, wherein the tube connection system (2) comprises a positioning mechanism (47) for determining the position of the first tube (4) and / or the second tube (5) and / or the first tube holder (7) and / or the second tube holder (8) and / or the tube connection head (43) and / or the first carrier (10) and / or the second carrier (11), preferably wherein the positioning mechanism (47) comprises at least one or more, in particular optical or electrical, position sensors (48), which are at least partially arranged on the first tube holder (7) and / or the second tube holder (8) and / or the tube connection head (43) and / or the first carrier (10) and / or the second carrier (11).

16. 16. An integrated bioprocessing system according to any one of claims 7 to 15, characterized in that the tube connection system (2) comprises a robot mechanism (52), in particular an xy robot mechanism or a Cartesian robot mechanism, such that the tube connection head (43) is movable at least one-dimensionally, preferably two-dimensionally or three-dimensionally, and / or the tube connection system (2) comprises a conveyor mechanism (53), such that the tube connection head (43) is attached to the robot mechanism (52), and the first carrier (10) and the first tube holder (7), and / or the second carrier (11) and the second tube holder (8) are movable by the conveyor mechanism (53) at least one-dimensionally, preferably two-dimensionally or three-dimensionally.

17. An integrated bioprocessing system for carrying out a bioprocess on a cell culture, wherein during the carrying out of the bioprocess, a medium used in the bioprocess, in particular the cell culture, can be transported by the integrated bioprocessing system (1) through a tube, the integrated bioprocessing system (1) comprising a first tube (4) for medium transport and a second tube (5) for medium transport, the first tube (4) and the second tube (5) being connected by a tube connection (3) and arranged at separate positions within the integrated bioprocessing system (1), the first tube (4) being held by a first tube holder (7) and fluidically connected via the first tube (4) to a first fluid structure (12) for receiving and / or supplying the medium, the integrated bioprocessing system (1) being movable. The integrated bioprocessing system (1) comprises a first carrier (10) capable of transporting the first tube (4), the first tube holder (7), and the first fluidic structure (12) are carried by the first carrier (10), the integrated bioprocessing system (1) comprises a tube separation mechanism (14) for separating the first tube (4) and the second tube (5) in a separation routine at the separation position so that the first tube (4) and the second tube (5) are fluidically and / or physically separated, and the first carrier (10) and the first tube (4), the first tube holder (7), and the first fluidic structure (12) together with the first carrier (10) are transportable from the separation position after the separation of the first tube (4) and the second tube (5), in particular the integrated bioprocessing system according to any one of claims 7 to 16.

18. A sealing unit, particularly of a tube separation mechanism (14) in an integrated bioprocessing system (1), for sealing a first tube (4) and / or a second tube (5) in a sealing phase so that a seal (56, 57) is formed, the sealing unit (15) comprising at least one sealing surface (63) designed to crimp the first tube (4) and / or the second tube (5) along the axial direction of each of the tubes (4, 5) so that the first tube (4) and / or the second tube (5) are self-sealed.

19. 17. A device for transporting tubes (4, 5), comprising carriers (10, 11), tubes (4, 5), tube holders (7, 8) and fluidic structures (12, 13), wherein the carriers (10, 11) carry the tubes (4, 5), the tube holders (7, 8) and the fluidic structures (12, 13) so that the tubes (4, 5), the tube holders (7, 8) and the fluidic structures (12, 13) can be transported together with the carriers (10, 11), and the tube holders (7, 8) hold the tubes (4, 5) in a defined position, in particular a device for transporting tubes (4, 5) within an integrated bioprocessing system (1) according to any one of claims 7 to 16.

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