Method for bioprocess of liquid immune cells or initial cell culture to obtain treated cell culture

Abstract

The present invention relates to a method for performing a biological process on a liquid immune cell or an initial cell culture to obtain a treated cell culture, where the treated cell culture is intended for autologous or allogeneic cell therapy, where the biological process is performed on an integrated biological treatment system (1), wherein the biological process comprises a series of treatment steps wherein the treatment steps each comprise at least one operation wherein the biological process system (1) comprises a base structure (3) and a preconfigurable cartridge (4) wherein the biological process system (1) performs the operation of the biological process via interaction of the base structure (3) with the cartridge (4), wherein the cartridge (4) and the base structure (3) comprise a matching standardized interface (6) for interaction of the base structure (3) with a corresponding cartridge (4), wherein the biological process system (1) performs at least two operations of the biological process inside at least two differently preconfigured cartridges (4) by interaction of the base structure (3) with the cartridges (4) via the same base structure interface (7) and / or the same base structure interface (7) and a mating cartridge interface (8).

Description

[0001] The present invention relates to a method for a bioprocess on a liquid immune cell or a primary cell culture to obtain a processed cell culture according to claim 1, to a cartridge according to claim 35, to a base structure according to claim 37, and to a bioprocessing system according to claim 38.

[0002] The term "bioprocess" currently represents a biotechnological process, in particular a biotechnological process involving the use of immune cell cultures or primary cell cultures, including stem cell cultures. One or more processing steps can be performed on each cell culture. Thus, a bioprocess in this sense can be a manufacturing process involving a series of processing steps on a cell culture, which will ultimately result in a final product.

[0003] The proposed method can be used in the field of cell and gene therapy, including allogeneic or autologous production of genetically modified immune cells. For example, the method can be applied to the production of autologous T cells modified to express a chimeric antigen receptor (CAR). These cells can be used to treat various types of blood malignancies, including different types of leukemia (blood cancer). Other cell therapies based on primary cells, in particular stem cells and their derivatives, are also of interest.

[0004] For biotechnological processes involving the use of liquid immune cells or primary cell cultures, process flexibility is particularly important. The starting material can be rather heterogeneous in its composition, for example because each patient is in a different condition (e.g., in terms of disease progression or in terms of the genetic makeup and history of their immune system). The starting material can also be heterogeneous in its composition because cell cultures from different donors are combined into a single starting material. Thus, depending on the source of the liquid cell culture, various parameters (including, for example, the type and concentration of different cell types, the total cell viability and vitality, and / or the amount and type of impurities within the liquid cell culture) can vary. Additionally, depending on the biological process to be performed, the cell culture can contain different types of immune cells (e.g., T cells, dendritic cells, or immune cells at different stages of development, including naive T cells) in different amounts. Partly for the reasons described above, the sequence of processing steps performed on each liquid immune cell culture will need to be adjusted according to the individual characteristics of the cell culture. Additionally, certain steps of the biological process may need to be flexibly adjusted and customized for each individual cell culture. For example, the type of genetic modification of the cell culture may vary because patients may respond differently to a particular genetic modification. Thus, the biological process will differ in the manner in which the genetic modification is performed. Additionally, for example, a biological process involving the genetic modification of an immune cell culture will require a sequence of processing steps different from the sequence of processing steps required in a biological process not involving the genetic modification of an immune cell culture. In addition to flexibly adjusting the steps, steps can also be completely omitted. This requires that the method of performing the biological process on the liquid immune cell culture can be adjusted in a flexible manner.

[0005] While process flexibility is highly important, cost efficiency is also an important aspect in the processing of liquid immune cells or primary cell cultures. The reason for this is that the requirements of regulatory authorities are very stringent. For example, the operators involved in the process need to receive extensive training, especially when performing manual processes. Additionally, sterility must be maintained during the manufacturing process because the treated cells need to be viable and must not contain contaminants when administered to the recipient. Partly for the reasons described above, the total cost of each biological process performed is very high. Additionally, in methods where a single device is used to perform all processing steps on the primary cell culture sequentially, the facility footprint is typically large because one device is required to process one cell culture at a time. Additionally, the throughput is reduced because only one liquid cell culture is processed within one device. Moreover, since the sequence of processing steps is typically pre-defined, for example by the installed tubing set, it is rather demanding to adapt such a device to changes in the sequence or type of processing steps performed. However, these end-to-end systems provide a system in which all media remain within a closed internal volume, which supports the maintenance of sterility.

[0006] Cost efficiency is particularly relevant to operating costs; thus, it is desirable to be able to process more than one cell culture in parallel. This also increases throughput, which is important given the fact that the processing of a single initial cell culture can take days or even weeks. However, when processing more than one cell culture in parallel, it is necessary to ensure that cross - contamination of different cell cultures does not occur.

[0007] Another important aspect is redundancy, which is also related to process robustness and process reliability. As mentioned above and especially when applied to cancer treatment, the processing of cell cultures can take a relatively long time, while patients usually urgently need treatment. Therefore, it is necessary to ensure that the process does not fail. Process failure may result in having to repeat the process, which will require more time and / or additional starting materials required. However, especially in autologous methods, it may not be possible to obtain any further starting materials from the patient.

[0008] The known prior art on which the present invention is based, namely the document WO 2021 / 212124 A1, relates to a method according to the general part of claim 1. This reference discloses a method for modular and parallel processing of liquid immune cell cultures on an integrated bioprocessing system. The method includes a series of processing steps carried out at specific unit operation stations of the bioprocessing system. Although the bioprocessing system shows a certain degree of standardization in the form of a rack that houses all the components required to carry out the unit operations, such unit operation stations are highly customized in terms of the unit operations to be carried out by each of them.

[0009] Therefore, the configuration of each complete unit operation station depends on the type of unit operation carried out at the corresponding unit operation station. Thus, the infrastructure provided at the unit operation station (such as reservoirs for raw materials and / or waste materials) also depends on the unit operation carried out at the corresponding unit operation station. In addition, the interaction between the transfer system and each unit operation station depends on the type of unit operation carried out at the corresponding unit operation station. With the resulting high degree of customization regarding unit operation stations, the flexibility regarding the definition of process steps is high; however, the potential for increasing efficiency through automation remains relatively low.

[0010] The present invention is based on the problem of improving the known method such that the potential for automation is increased without compromising the flexibility regarding the definition of process steps.

[0011] The above object is solved by the features of the characterizing part of claim 1.

[0012] The main implementation of the present invention lies in that by providing a standardized structure based on a separately preconfigured cartridge, a large number of different processing steps can be carried out in a flexible manner through an integrated bioprocessing system while maintaining sterility. The efficiency and flexibility of the entire biological process can be improved thereby. The main idea is to separate those components of the reusable system from the liquid and liquid-containing disposable components, and to provide a modular bioprocessing system capable of combining the disposable components and the reusable components as needed.

[0013] A method for performing a biological process on a liquid immune cell or a primary cell culture to obtain a processed cell culture is proposed, wherein the processed cell culture is intended for autologous or allogeneic cell therapy, wherein the biological process is carried out on an integrated bioprocessing system, wherein the biological process comprises a series of processing steps, wherein each of the processing steps comprises at least one operation, wherein the bioprocessing system comprises a base structure and a preconfigurable cartridge, wherein the bioprocessing system performs the operations of the biological process via the interaction between the base structure and the cartridge, wherein the cartridge and the base structure comprise a matching standardized interface for the interaction between the base structure and the corresponding cartridge, and wherein the bioprocessing system performs at least two operations of the biological process inside at least two differently preconfigured cartridges via the interaction between the base structure and the cartridge via the same base structure interface and / or the same base structure interface and a matching cartridge interface.

[0014] The term "different" should be understood as referring to functionally relevant differences and is not, for example, a purely optical deviation. Differently preconfigured cartridges may have different numbers of tubes, significantly different tube lengths, different functional devices, different numbers of inlets or outlets, different containers for receiving and / or providing liquids, etc.

[0015] The term "standardized" means that cartridges with different configurations for different operations can be used via the same base structure interface. Preferably, the cartridge interfaces are the same.

[0016] The term "preconfigured" means that the corresponding cartridge is configured outside the bioprocessing system, for example manually or by the cartridge manufacturer, or the cartridge is automatically configured by the bioprocessing system by adding components. Configuration should not be understood as only involving digital configuration or minimal changes or especially changes during the use of the cartridge. Preconfiguration mechanically changes the state of the cartridge from an unavailable state to an available state. In particular, the preconfiguration includes adding, especially changing (removing and adding) the fluidic structure of the cartridge.

[0017] Claims 2 to 4 relate to preferred combinations of biological processes, biological processing steps and operations carried out by a bioprocessing system.

[0018] Claims 5 and 6 describe the preferred embodiments of the said cartridge.

[0019] Claims 7 to 9 describe the preferred embodiments of the interface.

[0020] Claim 10 describes the receptacles preferably used by the said biological treatment system.

[0021] Claims 11 to 28 relate to the preferred embodiments of different cartridges suitable for multiple treatment steps.

[0022] Claims 29 to 34 relate to various details of the method.

[0023] Equally important, another teaching according to claim 36 relates to the cartridge for the proposed method.

[0024] All the explanations given for the proposed method are fully applicable.

[0025] Equally important, another teaching according to claim 38 relates to the base structure for the proposed method.

[0026] All the explanations given for the proposed method are fully applicable.

[0027] Equally important, another teaching according to claim 39 relates to the biological treatment system for the proposed method.

[0028] All the explanations given for the proposed method are fully applicable.

[0029] Hereinafter, embodiments of the present invention are explained with reference to the accompanying drawings. The accompanying drawings show: Figure 1 , a schematic diagram of the proposed integrated biological treatment system, Figure 2 , a) a perspective view of such a cartridge without the cartridge fluid structure, and b) an exploded view of the cartridge with the cartridge fluid structure and the unit operation station, Figure 3 , during the unit operation process Figure 1 the unit operation station of the biological treatment system in Figure 4 , Figure 1 the biological treatment system a) a cross-sectional view along line IV-IV and b) a cross-sectional view along line V-V, Figure 5 , during the standard routine process in the order a) to e) Figure 1 the unit operation station of the biological treatment system, Figure 6 , Figure 5The unit operation station, a) during the connection process and b) during the disconnection process, Figure 7 , Figure 5 The unit operation station, during the process of transferring the cartridge from the drive position to the cartridge waste memory in the order a) to b), Figure 8 , the closed connection process illustrated schematically in the order a) to e), Figure 9 , an example of a cartridge, and Figure 10 , a depiction of the functional interface of the cartridge and the container connectable to the functional interface.

[0030] The integrated bioprocessing system 1 shown in the figures is preferably adapted to perform a bioprocess for manufacturing genetically modified T cells. Here, the T cells are genetically modified to express a chimeric antigen receptor (CAR). Thus, the term "CAR-T cell" describes a T cell that has been genetically modified to express a CAR. The genetically modified CAR-T cells, which represent the product of the bioprocess, can be administered to a patient and used to initiate or resume cancer treatment in the patient. When performing the bioprocess, the initial immunocyte culture is gradually processed. All explanations given mainly refer to such a bioprocess. However, it can be noted that these explanations are also fully applicable to other bioprocesses.

[0031] The term "liquid immunocyte culture" should be understood in a broad sense and refers to an immunocyte culture containing at least one type of immunocyte suspended as particles in any type of liquid. As will be explained below, the liquid immunocyte culture may contain other cell types that are not immunocytes. Thus, the term "liquid immunocyte culture" refers to the liquid immunocyte culture at any stage during the bioprocess. Thus, the type and fraction of immunocytes present in the liquid immunocyte culture will change during the applied bioprocess because certain immunocytes are enriched or depleted from the liquid immunocyte culture and / or the immunocytes are genetically modified.

[0032] The term "immune cell" generally refers to different types of white blood cells. Thus, the term "immune cell" includes a variety of cells, such as but not limited to dendritic cells, T lymphocytes (also known as T cells), B lymphocytes, natural killer cells, macrophages, etc. Immune cells can also include subtypes of immune cells, such as tumor-infiltrating lymphocytes or different types of T cells. Subtypes of a certain type of immune cell can be classified based on the type of antigen present on the cell surface. Thus, the term immune cell can, for example, refer to T cells that contain the surface antigen CD4 ("CD4+ T cells"). Generally, a certain type of immune cell (such as T cells), preferably a certain subtype of immune cell (such as CD4+ T cells), will be selectively enriched by a biological process, while other immune cells (such as macrophages) and / or other cell types that are not immune cells (such as red blood cells) and / or other subtypes of immune cells (such as CD8+ T cells) will be depleted from the liquid immune cell culture. The immune cells to be enriched are called target immune cells, and all other components to be depleted from the liquid immune cell culture are called "impurities". In addition, and as described above, the target immune cells can be genetically modified.

[0033] The term "naive cell" refers to a cell that can still differentiate into different target cell types. In particular, stem cells and their derivatives that are fully differentiated into a specific cell type are naive cells. The term also includes naive immune cells.

[0034] The term "liquid" should also be understood in a broad sense and refers to any liquid and / or particulate-containing liquid processed within the integrated bioprocessing system 1. Thus, the term liquid can refer to culture media, including buffers for washing and feed media for cell expansion, waste, liquid immune cell cultures, by-products obtained during the biological process, samples, and / or naive immune cell cultures.

[0035] The term "waste" refers to any liquid and / or particulate-containing liquid obtained during the biological process, where the corresponding liquid and / or particulate-containing liquid can be discarded and not used further. However, the waste can be stored and, in some cases, reused before being discarded. For example, if the number of T cells extracted from a cell culture is too low, more T cells can be extracted from the waste.

[0036] The term "initial immune cell culture" refers to a liquid immune cell culture prior to the first processing step of the application of the biological process. The initial immune cell culture can be derived from different sources. In a method commonly referred to as "autologous cell therapy", the initial immune cell culture is obtained from a donor who is also the recipient of the product after the biological process has been fully carried out. In "allogeneic cell therapy", the initial immune cell culture can be derived from at least one donor who is not the recipient of the product. The initial immune cell culture can be derived from more than one donor and / or used for more than one recipient. In this case, immune cell cultures obtained from different donors are combined into a single initial immune cell culture.

[0037] Preferably, the initial immune cell culture is obtained in a process called "leukapheresis". In leukapheresis, immune cells are obtained from a patient. Additionally or alternatively, the initial immune cell culture can also be obtained from the tissue of the patient. As described above, the initial immune cell culture can also be obtained from one or more donors who are not the patient. Furthermore, in some cases, other cells, such as tumor cells, can be obtained from the same patient and are used to regulate the behavior of immune cells in the biological process.

[0038] Depending on the source of the initial immune cell culture and the biological process to be carried out, the initial immune cell culture, especially the impurities as well as the type, amount, and distribution of the target immune cells, may vary. Additionally, the initial immune cell culture can also be obtained from a frozen source, or the initial immune cell culture can be frozen and thawed when needed.

[0039] Currently, any initial immune cell culture used in the biological process is preferably used for a single patient or a small number of patients, such as at most 10 patients. If this is not the case, the biological process currently described will only produce cell cultures for a single patient or a small number of patients, and cell cultures for other patients are derived from different biological processes. Therefore, the proposed integrated biological processing system 1 is used for small-scale biological processes. By carrying out multiple biological processes in parallel, the biological processing system 1 itself can have a larger scale.

[0040] The term "processing step" refers to a distinct step carried out as part of a biological process involving liquid immune cell culture. The type and sequence of processing steps carried out depend on the biological process being performed on the corresponding liquid immune cell culture and on the type of immune cell culture. Depending on the parameters mentioned, different processing steps can be combined in any given order. Additionally or alternatively, the configuration of the processing steps can be different, and / or processing steps can be repeated and / or omitted. Each processing step includes at least one operation. An operation is the smallest unit step in a biological process that has a defined start and end. Typically, a processing step includes several operations such as pumping, mixing, centrifuging, etc. If one or more operations of a processing step are described herein, preferably these operations include most or all of the relevant operations of the corresponding processing step.

[0041] A method is proposed for performing a biological process on a liquid immune cell or a primary cell culture to obtain a processed cell culture. The processed cell culture can be used for cancer treatment etc. as described above. The method can also include performing multiple biological processes on multiple liquid immune cells or primary cell cultures to obtain multiple processed cell cultures. Preferably, the processed cell cultures are intended for autologous or allogeneic cell therapy. Each biological process is performed on a different cell culture, and all processing steps carried out on one cell culture should be understood as a single biological process. Multiple cell cultures can be used to treat a patient. Alternatively, multiple cell cultures can be obtained from a single input patient material to evaluate and compare different production processes. The production process identified as the best is subsequently used for subsequent therapeutic manufacturing.

[0042] The biological process is carried out on an integrated bioprocessing system 1, such as Figure 1 the integrated bioprocessing system shown in Figure 1 The integrated bioprocessing system 1 in

[0043] is merely an exemplary embodiment, and other embodiments can be significantly different, as will be apparent from the following description.

[0044] The described biological process system 1 includes a base structure 3 and a pre-configurable cartridge 4. The cartridge 4 can be pre-configured with a cartridge fluid structure 5 relative to at least one operation. The pre-configuration is preferably done outside the biological process system 1. Based on this, depending on the configuration of the cartridge fluid structure 5, almost any operation can be implemented with the pre-configured cartridge 4. In this way, each cartridge fluid structure 5 can be highly personalized for different biological processes, and especially for different liquid cell cultures as well.

[0045] Figure 2 a shows the cartridge 4 in its unconfigured state without the cartridge fluid structure 5, while Figure 2 b shows the cartridge 4 that has been pre-configured with the cartridge fluid structure 5 relative to at least one operation.

[0046] The biological process system 1 operates the biological process through the interaction between the base structure 3 and the cartridge 4. That is to say, the base structure 3 constitutes the basis for carrying out the biological process, and the cartridge 4 constitutes the basis for flexibly carrying out different biological processes. The cartridge 4 and the base structure 3 include matching standardized interfaces 6 for the interaction between the base structure 3 and the corresponding cartridge 4. Due to standardization, flexibility is achieved without having to adapt the base structure 3 to different operations.

[0047] Therefore, the biological process system 1 performs at least two operations of the biological process inside at least two different pre-configured cartridges 4 through the interaction between the base structure 3 and the cartridge 4 via the same base structure interface 7 and / or the same base structure interface 7 and the matching cartridge interface 8. The same base structure interface 7 can be used for two operations, but it is not mandatory. The cartridge interfaces 8 can be different as long as they are compatible with the base structure interface 7. For example, if the cartridge 4 in its pre-configured state does not require any mechanical energy, the cartridge 4 can simply have holes at positions where the mechanical energy transfer element can access.

[0048] The term "interface" includes all functional and at least partially mechanical connections between the base structure 3 and the cartridge 4. There is at least a base structure interface 7 that supports at least two operations. The base structure 3 can include a plurality of base structure interfaces 7 for performing operations inside the cartridge 4. These base structure interfaces 7 directly affect the actual operations. The base structure interface 7 can include an electrical connection for supplying electrical energy to the cartridge 4 and / or a cable-bonded signal connection for supplying signals to the cartridge 4 and / or a mechanical connection for supplying mechanical energy to the cartridge 4 and / or a pneumatic connection for supplying pneumatic energy to the cartridge 4.

[0049] The base structure 3 can include a plurality of different base structure interfaces 7 for performing different subsets of processing steps. Preferably, those base structure interfaces 7 are at least partially identical to each other, for example including the same electrical and / or mechanical and / or pneumatic and / or signal connectors. However, they can include additional differentiating elements such that not every operation can be performed by each base structure interface 7. In particular, functional elements can be present only at some locations as part of the base structure interface 7, and the base structure interface can be adapted to the functional interface.

[0050] There can be different additional base structure interfaces for auxiliary functions, in particular standardized transfer and placement interfaces 35. The transfer and placement interfaces 35 here and preferably include one or more transfer elements for transferring the cassette 4 and / or the receiver 15 and / or the container 30 between the base structure interfaces 7.

[0051] In addition to the biological process, the steps can be part of the biological process and be carried out by the biological process system 1.

[0052] Here and preferably, the biological process is carried out by the biological processing system 1 in at least three, preferably at least four, differently personalized cassettes 4. Preferably, no more than 8 differently individualized cassettes 4 are used in a single biological process.

[0053] The plural term "cell cultures" also includes what can be referred to in the singular as "cell culture".

[0054] The embodiments shown in the drawings will now be explained, and then other variants that are not all shown in the drawings will be discussed. Figure 1 An integrated biological processing system 1 is shown, Figure 2 A unit operation station 2 is shown, which is one way of flexibly providing the main part of the biological processing system 1. Figure 3 Unit operations being carried out on the unit operation station 2 are shown. Figure 4 How the biological processing system 1 can be constructed from a plurality of such unit operation stations 2 is shown. The unit operation station 2 together with other components such as transfer mechanisms constructs the base structure 3 and interacts with the cassette 4.

[0055] In the embodiment shown in the drawings, for performing one or more operations, a standard routine is defined. According to the standard routine, one of the cassettes 4 is transferred from the cassette storage unit 9 of the unit operation station 2 to the drive position 10 of the cassette drive unit 11 of the unit operation station 2 by the local transfer mechanism 12 of the unit operation station 2 (sequence Figure 5 a), 5b), 5c), 5d)), which is only at Figure 2shown in b. The local transfer mechanism 12 can for example include a linear actuator and / or a plurality of linear actuators and / or a combination of a linear actuator and a multi-axis robotic arm, a conveyor belt, etc. Subsequently, the cassette 4 is operatively coupled to the cassette drive unit 11. Here, the cassette drive unit 11 is a standardized interface 6 between the base structure 3 including the unit operation station 2 and the cassette 4.

[0056] Preferably, performing each and any of the unit operations includes performing the above-mentioned standard routine, which provides the transfer of the corresponding cassette 4 from the cassette storage unit 9 to the cassette drive unit 11 and the operative coupling of the cassette 4 with the cassette drive unit 11. Subsequently, the subsequent unit operations are personalized according to the pre-configuration of the cassette 4. The unit operation station 2 and the unit operations do not necessarily exist in each embodiment.

[0057] The operative coupling between the cassette 4 and the cassette drive unit 11 enables the cassette 4 to be a completely passive component without any type of actuator. Via this operative coupling, any actuation can be transferred from the cassette drive unit 11 to the cassette 4. However, it is generally possible that the cassette 4 includes additional actuators.

[0058] The term "operatively coupled" should be understood in a broad sense. Here and preferably, this means the functional engagement of the cassette drive unit 11 with the cassette 4. Thus, the term "coupled" can refer to the physical engagement between two components. Additionally or alternatively, it can also refer to an indirect connection established between two components (e.g., by magnetic actuation). It is feasible that the cassette drive unit 11 actuates the functional device 13 of the cassette 4. All of these are via the base structure interface 7 and the cassette interface 8.

[0059] According to a preferred embodiment, it is proposed that at least two, preferably all, of the cassettes 4 are identical to each other except for the corresponding cassette fluid structure 5, and the cassette fluid structure 5 can be configured for the corresponding unit operation. This means that the cassettes 4 can (but do not have to) differ from each other in terms of the corresponding cassette fluid structure 5. By using cassettes 4 that are identical in this sense, not only can the transfer of the cassettes 4 be standardized, but also the transfer of liquids into and out of the cassettes 4 can be standardized.

[0060] According to another embodiment, it is proposed that at least one unit operation station 2 includes at least one transfer position 14, shown in Figure 3 . Here and preferably, the transfer position 14 is provided by a surface or pad for receiving the receiver 15. Thus, the receiver 15 that has been pre-configured with a receiver fluid structure 16 for accommodating a liquid, preferably immune cells or an initial cell culture, is transferred to the transfer position 14 via the global transfer mechanism 17 depicted in Figure 1 so as to transfer liquids between the cassette 4 that has been transferred to the drive position 10 and the receiver 15 and / or perform corresponding unit operations on the liquid contained in the receiver 15.

[0061] Here and preferably, each unit operation station 2 includes four transfer positions 14. As Figure 1 shown and in a preferred embodiment to such an extent, each transfer position 14 has a rectangular geometry, with two transfer positions 14 positioned adjacent to each other. Preferably, two pairs of transfer positions 14 are positioned opposite each other, with the drive position 10 positioned between each pair of transfer positions 14.

[0062] As will be explained below, the receptacle 15 located at the transfer position 14 needs to be aligned with the cassette 4 located at the drive position 10. For alignment, a global transfer mechanism 17, preferably a robotic mechanism 18, can be used, or the transfer position 14 can include a positioning mechanism to align the receptacle 15 with the cassette 4.

[0063] According to one embodiment, it is proposed that at least two, preferably all, of the receptacles 15 are identical to each other except for the respective receptacle fluid structure 16, which can be configured for the respective liquid to be received. This means that the receptacles 15 can (but do not have to) differ from each other with respect to the respective receptacle fluid structure 16. The liquid to be received in the receptacle fluid structure 16 can depend on the processing step being carried out. This means that the complete operation of the receptacles 15 (including transfer, establishing fluid connections, etc.) can be standardized for all receptacles 15. Figure 3 Examples of those identical receptacles 15 are shown in

[0064] According to one embodiment, it is proposed that the integrated bioprocessing system 1 includes a plurality of unit operation stations 2, and preferably, the transfer positions 14 of the unit operation stations 2 are arranged in a first plane 19 and the receptacles 15 are transferred to and from the transfer positions 14 in the first plane 19 by a global transfer mechanism 17. The first plane 19 is here and preferably horizontally aligned. By arranging the transfer positions 14 in the first plane 19, the transfer of the receptacles 15 to and from the transfer positions 14 is simplified. In addition, as will be explained below, the receptacles 15 are then located in the same plane as the cassette 4 located at the drive position 10.

[0065] Preferably, at least a part of the plurality of unit operation stations 2 is arranged in unit operation station slices 20. Each unit operation station slice 20 preferably includes a separate transport device (such as wheels, etc.) to move the unit operation station slice 20 into and out of the integrated bioprocessing system 1. By being able to remove the unit operation station slice 20 including the plurality of unit operation stations 2 located within the unit operation station slice 20 from the integrated bioprocessing system 1, the maintenance of the unit operation stations 2 (which will be further explained below) is particularly simple. In addition, the unit operation station slice 20 can be removed from or introduced into the integrated bioprocessing system 1 without affecting the operability of the remaining unit operation stations 2 within the integrated bioprocessing system 1. This is particularly advantageous if access to a part of the integrated bioprocessing system 1 is required for maintenance.

[0066] According to one embodiment, it is proposed that at least one biological process is a closed biological process such that all the liquids involved in the corresponding biological process are kept within a closed internal volume. In the shown embodiment and preferably, such a closed structure is achieved by performing at least a part of the operations on the liquids involved in the corresponding biological process within a tube.

[0067] To facilitate the implementation of a closed biological process, it is proposed that for transferring liquids between the cartridge 4 and the receiver 15, the cartridge transfer tube 21 of the cartridge 4 and the receiver transfer tube 22 of the receiver 15 are connected in a closed connection process through a tube connection system 23. This is shown in Figure 6 a. Here and preferably, the connection process is carried out through the tube connection system, particularly through a tube welding system 24.

[0068] The connection process is shown in Figure 8 . The connection process is carried out through the tube connection system 23, particularly through a tube operating device (not shown) of the tube connection system 23. It preferably further includes the step of arranging the tubes to be connected relative to the rest of the tube connection system 23 ( Figure 8 a) to Figure 8 b) in sequence) and the subsequent step of welding the tubes to be connected through the tube connection system 23 ( Figure 8 d)). After welding, as depicted in Figure 8 e), the tubes are connected at the welding position 57. Further preferably, before the welding step, a step of trimming the tubes to be connected is provided during the connection process ( Figure 8 b). Preferably, and as depicted in Figure 8 c, the trimming of the tubes is carried out by a blade 58.

[0069] As Figure 3As depicted, the cassette transfer tubes 21 and the receiver transfer tubes 22 are provided by the cassette fluid structure 5 and the receiver fluid structure 16. Preferably, the cassette fluid structure 5 and the receiver fluid structure 16 have been pre-configured in such a way that each cassette transfer tube 21 is positioned at a predetermined cassette anchor point 25 provided by the cassette frame 26 and each receiver transfer tube 22 is positioned at a predetermined receiver anchor point 27 provided by the receiver 15. This is shown for example in Figure 3 . Preferably, the cassette anchor points 25 and the receiver anchor points 27 are arranged in such a way that when the corresponding cassette 4 is in the drive position 10 and the corresponding receiver 15 is in the transfer position 14, one cassette anchor point 25 faces one receiver anchor point 27.

[0070] Preferably, and as Figure 3 depicted, the cassette transfer tubes 21 project from the cassette anchor points 25 towards the transfer position 14 where the receiver 15 to be connected is located. It is also preferred that the receiver transfer tubes 22 project from the receiver anchor points 27 towards the cassette anchor points 25 where the cassette transfer tubes 21 are located. The welding system 24 connects the receiver transfer tubes 22 and the cassette transfer tubes 21 during the closure connection process.

[0071] Furthermore, as Figure 6 shown in b, the welding system 24 is preferably designed to also perform the disconnection process. Here and preferably, the transfer tubes to be disconnected are closed and cut at their respective ends so that the internal volume of the tubes remains sterile. It can also be noted here that the use of such a welding system 24 enables subsequent multiple weldings to be performed on the same transfer tubes. This provides flexibility since, for example, the same receiver transfer tube 22 can subsequently be connected to different cassette transfer tubes 21.

[0072] According to one embodiment, it is proposed that at least two of said biological processes are carried out at least partially simultaneously by the integrated bioprocessing system 1, preferably coordinated by the electronic process controller 28. This is shown in Figure 4 a, where two cassettes 4 of two separate unit operation stations 2 have been transferred to the respective drive positions 10.

[0073] In this shown and herein preferred embodiment, the cassette 4 includes a cassette carrier 29 that receives components of the cassette fluid structure 5. The advantage is that the cassette carrier 29 provides a standardized structure for receiving the cassette fluid structure 5. Thus, the dimensions of the cassette carrier 29 are preferably the same for all unit operation stations 2 and are thus independent of the particular unit operation being performed at the unit operation station 2. Thus, the cassette fluid structure 5 can be arranged within the cassette carrier 29 as needed, and the cassette carrier 29 provides a standardized interface 6 with the cassette frame 26 and the cassette drive unit 11. In addition, the cassette carrier 29 does not come into contact with any of the liquids being processed at the unit operation station 2. Thus, the cassette carrier 29 can be reused after the cassette 4 has been used in a unit operation. Further, using the cassette carrier 29 to receive components of the cassette fluid structure 5 ensures that any liquid that might leak from the cassette fluid structure 5, for example in the case of a breach in the cassette liquid container 30, is contained within the cassette 4 and does not contaminate other elements, such as the cassette drive unit 11 of the integrated bioprocessing system 1.

[0074] As Figure 2 depicted in Figure 2 b, the cassette carrier 29 can include a drive recess 31 to enable the drive structure of the cassette drive unit 11 to engage components of the cassette fluid structure 5. For example, and as

[0075] depicted in

[0076] a, the cassette carrier 29 can include a drive recess 31 at the location of the pump head where the peristaltic pump 32 is to be placed. To actuate components of the cassette fluid structure 5 through the interface provided by the base structure 3, it is important that the drive recess 31 in the cassette carrier 29 is aligned with the corresponding interface of the base structure 3.

[0077] All liquids involved in the biological process are herein and preferably maintained within one or more enclosed internal volumes. This ensures the sterility of all liquids is maintained. It further ensures that cross - contamination does not occur between different cell cultures. This is particularly important when multiple cell cultures are processed in parallel. Additionally, the environmental requirements regarding sterility are greatly reduced. The term "enclosed internal volume" currently refers to the volume within which all said liquids are held and directed, separated from the atmosphere. The term "atmosphere" currently denotes the volume outside the above - mentioned enclosed internal volume. This ensures that sterility is maintained within the enclosed internal volume. As explained above, maintaining sterility is a key aspect in the manufacturing process. If at least a part of the liquid handling involved in the corresponding unit operation is carried out within a tube, an enclosed internal volume can be easily achieved. Herein and preferably, the integrated biological processing system 1 includes a housing 34 within which the biological process takes place. A sterile atmosphere can be provided inside the housing 34, however, preferably, its sterility level is not as high as that of the enclosed internal volume.

[0078] According to one embodiment, it is proposed that two operations of the biological process are operations of different processing steps, and / or the biological processing system 1 performs at least two, preferably at least three, more preferably at least four operations as part of different biological processes in parallel in the same pre - configured cartridge 4.

[0079] Additionally or alternatively, the biological processing system 1 can perform at least two, preferably at least three, more preferably at least four operations as part of different biological processes, in particular as part of different processing steps of different biological processes, in parallel in different pre - configured cartridges 4.

[0080] According to one embodiment, it is proposed that the biological processing system 1 performs at least two biological processes, preferably at least three biological processes, more preferably at least five biological processes, more preferably at least ten biological processes, each biological process including at least two, preferably at least three, more preferably at least four different processing steps, in particular in parallel, wherein the biological processing system 1 performs at least one operation for each processing step, and wherein the biological processing system 1 performs those operations for each biological process in at least two, preferably at least three, more preferably at least four different pre - configured cartridges 4. Preferably, all these operations are carried out automatically without manual alteration of the base structure 3.

[0081] According to one embodiment, it is proposed that the operation includes one or more processing steps of "enrichment" and / or "selection" and / or "activation" and / or "loading" and / or "genetic modification" and / or "amplification" and / or "formulation" and / or "filling" and / or "washing" and / or "separation", and / or the plurality of processing steps include a plurality of processing steps of "enrichment" and / or "selection" and / or "activation" and / or "loading" and / or "genetic modification" and / or "amplification" and / or "formulation" and / or "filling" and / or "washing" and / or "separation".

[0082] Details of these processing steps will be given below. All explanations given for any feature or method step described herein can be applied to any one, any combination, or all of the specified biological process steps and / or biological process operations. One advantage of the proposed system is that it can be adapted to different processing steps as needed. Another advantage of the proposed system is that it can be adapted to different processing steps while a biological process is already in progress. In particular, the order of the processing steps can be changed and / or the processing steps can be repeated.

[0083] Herein and preferably, the processing steps of "enrichment" and / or "selection" and / or "activation" and / or "loading" and / or "genetic modification" and / or "amplification" and / or "formulation" and / or "filling" and / or "washing" and / or "separation" can be automatically performed and / or repeated in any order, without manual intervention as part of a biological process and by transferring the cell culture as needed between the cartridges 4. In any case, herein and preferably, at least one transfer of the cell culture from one cartridge 4 to another cartridge 4 can be performed completely automatically.

[0084] Now looking at the cartridge 4 from a general perspective, it is feasible that the biological treatment system 1 includes a single-step cartridge 4, whereby the biological treatment system 1 only operates a single processing step within the single-step cartridge 4. The fewer the processing steps combined in the cartridge 4, the easier the flexible combination and repetition of the steps become.

[0085] Additionally or alternatively, the biological treatment system 1 can include a shared cartridge 4, whereby the biological treatment system 1 operates the processing steps within the shared cartridge 4, particularly the operation of consecutive processing steps. This reduces the number of transfer steps between operations.

[0086] The operations of the processing steps of "enrichment" and / or "selection" and / or "activation" and / or "loading" and / or "genetic modification" and / or "formulation" and / or "filling" and / or "washing" and / or "separation" can be performed in the single-step cartridge 4.

[0087] As already intimated, it is possible that the preconfigured cartridge 4 includes a preconfigured cartridge fluid structure 5, and / or that the preconfigured cartridge 4 includes functional devices 13 for operations carried out inside the cartridge 4, in particular preconfigured functional devices 13, and / or that at least a part, preferably all, of the cartridges 4 for the operations are identical before being preconfigured. The preconfigured functional devices 13 are the functional devices 13 added to the cartridge as part of the preconfiguration. The functional devices 13 themselves may also have a standard configuration.

[0088] The cartridge 4 without its preconfigured contents can be regarded as an adapter between the base structure 3 providing energy and tissue and the functional devices 13 and fluid structure together carrying out the actual biological process. This abstraction layer enables generality at the base structure level and flexibility at the cartridge level to be achieved.

[0089] As already explained with respect to the preferred embodiment of the unit operation station 2, it is possible that the standardized base structure interface 7 includes an active energy transfer interface, and that the base structure 3 transfers mechanical energy and / or pneumatic energy and / or electrical energy to the cartridge 4 via the active base structure interface 7 and a matching cartridge interface 8, in particular to drive the functional devices 13 of the cartridge 4 via the transferred energy. Here and preferably, the interface includes a plug system between the base structure 3 and the cartridge 4. The plug may include a number of connectors for electrical energy and signals. In addition, a plug protruding from the base structure 3, in particular the cartridge drive unit 11, for mechanical drive may be provided on the cartridge 4.

[0090] In addition, the base structure 3 may include a transfer and placement interface 35 which here will be at the top of the unit operation station 2 together with the global transport mechanism 17, transfer positions 14, etc. Subsequently, the base structure 3 transfers the cartridge 4 via the base structure interface 7 and a matching cartridge interface 8 to the position where at least one operation is carried out inside the cartridge 4 in the biological processing system 1 and holds the cartridge 4 in that position.

[0091] It has been explained how the cartridge 4 can include functional devices 13. However, part or all of the functional devices 13 may be disposable components, and it may not be efficient to provide a large number of functional devices 13 in the cartridge 4.

[0092] According to one embodiment, there is provided the bioprocessing system 1, in particular the base structure 3, including the functional device 13. Preferably, the functional device 13 of the base structure 3 is fixed at a position close to the dedicated standardized interface 6 for performing one or more operations via the (in particular, standardized) functional interface of the functional device 13 and the functional receiving interface of the cartridge 4 (preferably standardized for different functional devices 13 of different processing steps), or the functional device 13 of the base structure 3 is transferred to a position close to the non-dedicated standardized interface 6, and the bioprocess structure performs one or more operations via the (in particular, standardized) functional interface of the functional device 13 and the functional receiving interface of the cartridge 4 (preferably standardized for different functional devices 13).

[0093] If necessary, the functional interface can be a dedicated interface. All cartridges 4 can have one or more dedicated interfaces, which are not always used according to the corresponding uses of the cartridges 4. However, it can also be the case that the cartridge 4 includes one or more standardized functional interfaces that are not dedicated to a single operation or processing step. For example, different processing steps can include applying non-contact energy to the dedicated cartridge fluid structure 5 and / or the functional device 13. The cartridge fluid structure 5 and / or the functional device 13 can be placed at standardized positions in the cartridge 4 and include additional components, such as reflectors to be further explained, to receive non-contact energy in a standardized manner through an interface, which can be, for example, a hole of a certain size in the cartridge 4 through which the non-contact energy emitting device closely contacts or is adjacent to a single cartridge fluid structure 5 and / or the functional device 13. The cartridge fluid structure 5 can include a rigid tube, etc., which can be single-use and connected to the functional device 13 to receive non-contact energy. The standardized functional interface can be the standardized interface 6.

[0094] As Figure 10 depicted in b), the functional device 13 can also be provided in the container 36, which is standardized for their interaction with the cartridge 4 and / or the base structure 3, preferably such that the base structure 3 can operate the container 36 without knowing what the content is. The container 36 and / or the receiver 15 and / or the cartridge 4 can have one or more standard sizes and / or standard transfer interfaces. The container 36 and / or the receiver 15 can have a standard interface 6 for connecting to the cartridge 4 and / or connecting to the base structure 3.

[0095] Each of the functional devices 13 of the base structure 3 or the combination of functional devices 13 (in particular, to be described later) can be fixed or placed inside the container 36.

[0096] According to one embodiment, it is proposed that the bioprocessing system 1 operates inside the cartridge 4, where the interfaces are the same between the cartridges 4, for receiving cell cultures, particularly from the receiver liquid container 56 of the receiver 15, and / or for ejecting the cell culture from the cartridge 4 after operation, particularly into the receiver liquid container 56 of the receiver 15, and / or for receiving consumables, particularly from the receiver 15. In Figure 2 and Figure 3 it can be well seen how to connect the cartridge 4 to different receivers 15 using a single type of interface. Although not shown, it is also clear that instead of the receiver 15 in Figure 3 , another cartridge 4 can be placed close to the shown cartridge 4. Similarly, the same interface can be used to transfer fluids between the receiver 15 and / or the cartridge 4. Here, the interface between the cartridge 4 and the receiver 15 includes a single tube connection. The interface between two cartridges 4 will here include one or two tube connectors. When observing Figure 3 , it is also clear that the receiver 15 connected to the cartridge 4 can be further connected to other receivers 15, which are connected to the same cartridge 4 or different cartridges 4 or not connected to a cartridge.

[0097] In another embodiment, the base structure 3 and / or the receiver 15 and / or the cartridge 4 can include a pump for pumping liquid through the interface. In particular, the pump can be part of the base structure 3 and the base structure 3 provides the interface for between the cartridges 4, between the cartridge 4 and the receiver 15 or between the receivers 15. Thus, a certain number of pumps can be used in the base structure 3 as disposable components that change with the cartridge 4 and the receiver 15. There can also be a type of standard pump for the interface and other pumps inside the cartridge 4 as needed. In one embodiment, the pump is part of the base structure 3 and the standardized base structure interface 7. It can project into the cartridge 4 in the connected state or otherwise act on the cartridge fluid structure 5.

[0098] Additionally or alternatively, the bioprocessing system 1 can operate inside the cartridge 4, where the interfaces are the same between the cartridges 4, and / or for receiving mechanical and / or pneumatic and / or electrical energy and / or cable-bound signals from the base structure 3, and / or for receiving energy from the functional device 13, and / or for providing cell culture to the functional device 13.

[0099] Generally, the cartridge 4 can include one or more fluid interfaces 37. Preferably, one or more interfaces for receiving cell culture and / or for propelling cell culture and / or for receiving consumables and / or for providing cell culture to the functional device 13 are the same fluid interface 37.

[0100] Consumables can be liquids, bags containing liquids, filters, etc.

[0101] This description of the interface can be applied to any one, any combination, or all of the different cartridges 4 and / or receivers 15 described herein. Preferably, at least 50% of the cartridges 4 and / or types of cartridges 4 include a standardized interface 6 having one or more of the described features.

[0102] The term "identical" always means identical in a functional manner. Of course, for example, the tubes can be arranged slightly differently.

[0103] The preferred manner for connecting the different cartridges 4, receivers 15, and / or functional elements is tube welding as described below. Other connection methods can also be used, such as sterile connectors. Here and preferably, at least a portion, preferably all, of the fluid interface 37 is used in a defined position relative to the base structure 3 such that the base structure 3 can interact with the interface in a standardized manner, particularly for connecting the tubes.

[0104] Here and preferably, the cartridge 4 and / or receiver 15 includes at most four inlets and outlets on all of its liquid interfaces. In particular, each fluid interface 37 includes exactly one potential fluid connection that can be used as an inlet or an outlet. For any one, any combination, or all of the one or more preconfigured cartridges 4, at least one liquid interface can be used as an inlet, and / or at least one liquid interface can be used as an outlet, and / or at least one liquid interface can be used for two different connections, particularly for sequentially connecting to two different receivers 15 and / or cartridges 4. For any one, any combination, or all of the one or more preconfigured cartridges 4, one liquid interface can be used as the sole inlet and / or one liquid interface can be used as the sole outlet and / or one liquid interface can be used as a product outlet and one liquid interface can be used as the sole waste outlet and / or exactly two liquid interfaces can be used as inlets. The product outlet is an outlet for transferring the cell culture out of the cartridge 4.

[0105] Here and preferably, the fluid interface 37 includes a portion of the tube that is also placed inside the cartridge 4 and leads directly to the functional device 13 of the cartridge 4. Here and preferably, after preconfiguring the cartridge 4, no changes are made to the fluid structure inside the cartridge 4. The interface then only changes the cartridge fluid structure 5 by connecting the cartridge fluid structure 5 to different elements, tubes, etc. outside the cartridge 4.

[0106] According to one embodiment, it is proposed that the bioprocessing system 1 includes a receiver 15 that is preconfigured with a receiver fluid structure 16 for accommodating and providing and / or receiving liquids, cell cultures, and / or consumables used in at least a portion of the operation of the bioprocessing system 1. Preferably, the receiver 15 includes a fluid interface 37 that is identical to the fluid interface 37 of the cartridge 4.

[0107] The receiver 15 can be the main way to transport liquids within the bioprocessing system 1. In particular, the cell culture can be transferred from the receiver 15 to the box 4 before one or more operations performed in the box 4, and / or after one or more operations performed in the box 4. The receiver 15 can be the only way to transport cell cultures. However, the receiver 15 can also be used (or even only used) to transport consumables such as or containing liquids (such as waste, culture medium, buffer, etc.). Here and preferably, the receiver 15, in particular the receiver liquid container 56, can be filled at the culture medium filling service station 55 of the bioprocessing system 1. The culture medium filling service station 55 can include one or more tanks with liquids such as culture medium or buffer for many biological processes. This makes it easier to input these liquids into the bioprocessing system 1, because it is not necessary to input them in small doses every time the liquid is needed.

[0108] In the following, preferred boxes 4 that can be used in the bioprocessing system 1 will be described in detail. For any one, any combination or all of the boxes 4 that will now be described, it is feasible that only the operation of the corresponding designated processing step (single-step box 4) or multiple processing steps (shared box 4) is performed inside the box 4, or only one or two operations of one or more other processing steps are performed inside the box 4. In addition, any combination of designated boxes 4 can be used by the bioprocessing system 1 for a single bioprocess and / or for different bioprocesses performed in parallel. Nevertheless, preferably, one box 4 is used for only one bioprocess.

[0109] According to one embodiment, it is proposed that the bioprocessing system 1 performs one or more or all operations of the processing step "enrichment" and / or the processing step "washing" and / or the processing step "separation" via a base structure 3 within a preconfigured centrifuge box 39, and the centrifuge box 39 has a centrifuge chamber 40 as a functional device 13 inside the centrifuge box 39.

[0110] Figure 9 The centrifuge box 39 exemplarily shown in the figure can be preconfigured by placing the centrifugal chamber 40 inside the centrifuge box 39, in particular by placing the centrifugal chamber 40 in a predetermined position. A part or all of the boxes 4 can have such a predetermined position. The predetermined position can be a position dedicated to the centrifuge or another functional device 13, or it can be a position predetermined for a functional device 13 of a specific size. For example, the predetermined position can include connecting elements, such as screws or screw openings, clamping elements, etc. The box 4 may include multiple overlapping predetermined positions of different sizes for functional elements, whereby preferably, functional elements of different sizes utilize different combinations of connecting elements according to their size and / or position. For example, the bottom plate of the box 4 can be designed as an insert plate.

[0111] The centrifugation chamber 40 can be a fluidized bed centrifugation chamber 40.

[0112] As is typically indicated by the use of “and / or”, it should be understood that different cartridges 4 for different processing steps of the same type can be used, for example, in a single bioprocessing system 1 by different pre-configured cartridges 4.

[0113] Herein and hereinafter, preferred configurations of the inlets and outlets are described. Each inlet and / or outlet is part of a fluid interface 37. Of course, the definition of the inlets and outlets is valid for the corresponding use of the pre-configured cartridge 4 and can vary with different configurations.

[0114] Preferably, the centrifuge cartridge 39 includes exactly one dedicated inlet for the cell culture and / or exactly one or exactly two dedicated inlets for the buffer. Alternatively, the centrifuge cartridge 39 can include exactly one inlet, in particular for the cell culture and the buffer. The centrifuge cartridge 39 can include exactly one waste outlet and / or exactly one product outlet. The inlet and / or outlet can be directly connected to the centrifugation chamber 40.

[0115] The centrifuge cartridge 39 can further include one or more (in particular disposable) flow sensors and / or pumps.

[0116] The cartridge interface 8 of the centrifuge cartridge 39 can include and use connections for mechanical energy and / or electrical energy and / or for control signals for the centrifugation chamber 40 and / or from the flow sensors and / or for the pumps. The centrifuge control chip that receives the sensor signals from the flow sensors and controls the centrifuge can also be placed inside the centrifuge cartridge 39 and can be powered via the cartridge interface 8.

[0117] According to one embodiment, it is proposed that the bioprocessing system 1 performs one or more or all operations of the processing step “enrichment” and / or the processing step “separation” inside a pre-configured acoustic cartridge 41 via a base structure 3, the acoustic cartridge 41 having at least one acoustic wave generator, in particular a piezoelectric element, as a functional device 13 inside the acoustic cartridge 41.

[0118] The acoustic cartridge 41 (in Figure 10Exemplary cassette 4, which is schematically and exemplarily shown as having a functional interface, can be preconfigured by placing an acoustic wave generator inside the acoustic cassette 41, in particular by placing the acoustic wave generator at a predetermined position. The acoustic wave generator can include one or two transducers, in particular interdigital transducers. The acoustic wave generator can further include an acoustic reflector. The acoustic cassette 41 can be the same as the centrifuge cassette 39 before preconfiguration. The acoustic wave generator and the eventual reflector can be accommodated in a modular cartridge 42, which can be placed inside the acoustic cassette 41 and preferably clamped into the acoustic cassette 41. The acoustic wave generator can accommodate a tube or the like and can be part of the cassette fluid structure 5. Alternatively, the tube or the like can be inserted into the cartridge 42 during preconfiguration.

[0119] Figure 9 It is also shown how the centrifuge cassette 39 has a different functional interface from the acoustic cassette 41, even if the functional interface of the centrifuge cassette 39 is not used there.

[0120] The acoustic separation of cells works by applying acoustic waves to the cassette fluid structure 5 and generating standing waves. The cell culture overflows through the fluid structure with standing waves together with the sheath flow buffer, and the cells are separated into different channels of the fluid structure based on their size.

[0121] Preferably, the acoustic cassette 41 includes exactly one dedicated inlet for the cell culture and / or exactly one dedicated inlet for the buffer. A continuous feed stream of the sheath flow can be provided via the buffer inlet during the enrichment or separation process, in particular from the receiver 15. The acoustic cassette 41 can include exactly one waste outlet and / or exactly one product outlet. The inlet and / or outlet can be directly connected to a part of the cassette fluid structure 5 to which the acoustic waves of the acoustic wave generator are applied.

[0122] The acoustic cassette 41 can further include one or more (in particular disposable) flow sensors and / or pumps and / or bubble sensors and / or temperature sensors for the acoustic wave generator and / or for the cell culture. The acoustic cassette 41 can include a cooling arrangement for the acoustic wave generator, which can be active or passive. If the cooling arrangement is an active cooling device, it can be powered via a standardized interface 6. The cooling arrangement can include one or more cooling elements, such as heat sinks and / or ventilators. The cooling arrangement can be part of the acoustic cassette 41 before preconfiguration of the acoustic cassette 41, or added to the acoustic cassette 41 as part of the preconfiguration of the acoustic cassette 41.

[0123] The cartridge interface 8 of the acoustic cartridge 41 may include and use connections for electrical energy and / or for a pump and / or a sonic generator and / or control signals from a flow sensor and / or from a temperature sensor. An acoustic control chip that receives sensor signals from a flow sensor and / or a bubble sensor and / or a temperature sensor and controls the sonic generator and / or the pump may also be placed inside the centrifuge cartridge 39 and may be powered via the cartridge interface 8. In the event that the temperature of the sonic generator or the cell culture reaches a predetermined threshold, the control chip may stop the sonic generator.

[0124] According to one embodiment, it is proposed that the bioprocessing system 1 performs one or more or all operations of the processing step “enrichment” and / or the processing step “separation” inside a preconfigured acoustic cartridge 41 via a base structure 3, the acoustic cartridge 41 having at least one sonic generator as a functional device 13 outside the acoustic cartridge 41.

[0125] Placing the sonic generator outside the cartridge 4 enables easy reuse of the sonic generator. Preferably, the sonic generator may apply sound waves to the cartridge fluid structure 5 of the acoustic cartridge 41 (in particular the flow channels of the cartridge fluid structure 5), or include a tube that forms a flow channel and is automatically replaceable and / or sterilizable and connectable to the cartridge fluid structure 5 of the acoustic cartridge 41, etc.

[0126] It is feasible that the acoustic cartridge 41 includes a functional interface to the sonic generator, the acoustic cartridge 41 includes a fluid structure, and sound waves are applied to the fluid structure from one or more sides via the functional interface. Preferably, the acoustic cartridge 41 includes a reflector for the sound waves. A part of the cartridge fluid structure 5 may include a tube or the like for applying sound waves in a defined manner and at a defined position, in particular at the edge of the acoustic cartridge 41 that is part of the functional interface. The sonic generator may be docked to the functional interface. The functional interface may include placement elements 43 that ensure precise adaptation between the cartridge 4 and the sonic generator. The reflector may be part of the acoustic cartridge 41.

[0127] The functional device 13 may be placed in a standard container 36 that has a standard connection to the cartridge 4 for different technologies such as sonic, light energy application, electromagnetic fields, etc.

[0128] The cartridge 4 may have a standard slot for an adapter cartridge 42, the adapter cartridge 42 including a fluid structure suitable for energy application, possibly a reflector or the like, and may be placed in a standard position of the cartridge 4 via, for example, a clamping mechanism ( Figure 10 a).

[0129] In use, any or all of the flow channels within the acoustic cartridge 41 may have an attached monitoring system. The monitoring system can be used to regulate the flow of liquid through the channels, for example, by changing the pumping rate. It can also be used to detect faults within the flow channels, such as blockages, air bubbles, or manufacturing issues, such as narrow channels or inadequate acoustic coupling. Exemplarily, the monitoring system would be an optical microscope focused on the flow channel, capable of detecting the presence and size of cells passing through the channel, for example, under a stroboscopic light or using low exposure.

[0130] The monitoring system can be part of the acoustic cartridge 41. Alternatively, the functional interface between the acoustic cartridge 41 and the acoustic wave generator can also be used for the monitoring system. In this case, the monitoring system can be part of the base structure and / or the container 36 that includes the acoustic wave generator.

[0131] The same concept can be applied to other operations of the same or other processing steps, particularly other operations of the separation and / or selection processing steps, to detect and / or regulate the correct operation of those operations. Thus, one or more standard containers 36 can generally include a monitoring system.

[0132] According to one embodiment, it is proposed that the biological processing system 1 performs one or more or all of the operations of the processing step "enrichment" and / or the processing step "separation" inside the preconfigured DLD cartridge 4 via the base structure 3, the DLD cartridge 4 having deterministic lateral displacement chambers as functional devices 13 inside the DLD cartridge 4.

[0133] The DLD cartridge 4 can be preconfigured by placing the deterministic lateral displacement chambers inside the DLD cartridge 4, particularly by placing the deterministic lateral displacement chambers in a predetermined position.

[0134] Preferably, the DLD cartridge 4 includes exactly one dedicated inlet for the cell culture and / or exactly one dedicated inlet for the buffer. Alternatively, the DLD cartridge 4 can include exactly one inlet, particularly for the cell culture and the buffer. The DLD cartridge 4 can include exactly one waste outlet and / or exactly one product outlet. The inlet and / or outlet can be directly connected to the deterministic lateral displacement chambers.

[0135] The DLD cartridge 4 can further include one or more (particularly disposable) flow sensors. The DLD cartridge 4 can include valves for starting and stopping the buffer flow and / or for starting and stopping the cell culture flow. Additionally or alternatively, the DLD cartridge 4 can include at least one pump to control the flow of the buffer and / or the cell culture.

[0136] Generally, other devices for liquid transfer other than pumps can also be used to direct the liquid within the tubes.

[0137] The cartridge interface 8 of the DLD cartridge 4 may include and use pneumatic connections to drive liquids and / or actuate valves and / or for controlling signals for valves and / or from flow sensors. It is to be understood that the exemplary description of the cartridge 4 is not restrictive, for example, the DLD cartridge 4 may also include electrically actuated valves and thus include electrical connections for actuating said valves.

[0138] According to one embodiment, it is proposed that the biological treatment system 1 performs one or more or all operations of the processing step "enrichment" and / or the processing step "separation" inside a preconfigured electrical and / or magnetic separation cartridge 4 via a base structure 3, the electrical and / or magnetic separation cartridge 4 having at least one sorting element, in particular an electric field and / or magnetic field generating element as a functional device 13 inside the magnetic separation cartridge 4.

[0139] Preferably, the electrical and / or magnetic separation cartridge 4 is a flow cytometry cartridge 4 and includes at least one laser and detection optics and at least one, preferably at least eight or at least sixteen sorting elements, in particular charged plates, as functional devices 13 inside the flow cytometry cartridge 4.

[0140] Alternatively, the electrical and / or magnetic separation cartridge 4 may be a negative magnetic immunoadhesion cartridge 4 and include at least one magnetic field generating element inside the cartridge 4.

[0141] Cell labeling for electrical and / or magnetic separation may be performed in the incubator service station 38 of the biological process system 1 or in the electrical and / or magnetic separation cartridge 4. Cell labeling may be performed in the electrical and / or magnetic separation cartridge 4, after which the cell culture may be transferred to the incubator location 52. The transfer may be performed by transferring the electrical and / or magnetic separation cartridge 4 or by transferring the cell culture to a receiver 15 and subsequently returning it.

[0142] Preferably, the electrical and / or magnetic separation cartridge 4 includes exactly one dedicated inlet for the cell culture and / or exactly one dedicated inlet for the buffer. A continuous feed stream of sheath flow may be provided via the buffer inlet during the enrichment or separation process, in particular from the receiver 15. The electrical and / or magnetic separation cartridge 4 may include exactly one waste outlet and / or exactly one product outlet. The inlet and / or outlet may be directly connected to the part of the cartridge fluid structure 5 to which electrical and / or magnetic separation energy is applied.

[0143] The cartridge interface 8 of the electrical and / or magnetic separation cartridge 4 may include and use connections for mechanical and / or electrical energy and / or for control signals for lasers and / or detection optics and / or sorting elements and / or magnetic field generating elements. The electrical and / or magnetic separation control chip may also be placed inside the centrifuge cartridge 39 and may be powered via the cartridge interface 8.

[0144] According to one embodiment, it is proposed that the biological treatment system 1 performs one or more or all operations of the processing step "enrichment" and / or the processing step "separation" inside a preconfigured electrical and / or magnetic separation cartridge 4 via a base structure 3, the electrical and / or magnetic separation cartridge 4 having at least one sorting element, in particular an electrical and / or magnetic field generating element, as a functional device 13 external to the cartridge 4. Preferably, the electrical and / or magnetic separation cartridge 4 is a flow cytometry cartridge 4, and the biological treatment system 1, in particular the base structure 3, includes at least one laser and detection optics and at least one sorting element, in particular a charged plate, as a functional device 13 external to the flow cytometry cartridge 4, or the electrical and / or magnetic separation cartridge 4 is a negative magnetic immunoadhesion cartridge 4, and the biological treatment system 1, in particular the base structure 3, includes at least one magnetic field generating element external to the electrical and / or magnetic separation cartridge 4.

[0145] Placing the sorting element outside the cartridge 4 enables easy reuse of the sorting element. Preferably, the sorting element can apply an electric field and / or a magnetic field to the cartridge fluid structure 5 of the electrical and / or magnetic separation cartridge 4, or includes tubes and the like that are automatically replaceable and / or sterilizable and connectable to the cartridge fluid structure 5 of the electrical and / or magnetic separation cartridge 4.

[0146] It is feasible that the electrical and / or magnetic separation cartridge 4 includes a functional interface to the sorting element. A part of the cartridge fluid structure 5 can include tubes and the like for applying an electric field and / or a magnetic field in a defined manner and a defined placement (in particular at the edge of the electrical and / or magnetic separation cartridge 4) as part of the functional interface. The sorting element can be docked to the functional interface. The functional interface can include placement elements 43 that ensure precise adaptation between the cartridge 4 and the sorting element. The laser can also be positioned outside the cartridge 4.

[0147] The cartridge 4 can have a standard slot for an adapter cartridge 42, the adapter cartridge 42 including a fluid structure suitable for electric field and / or magnetic field application.

[0148] According to one embodiment, it is proposed that the biological treatment system 1 performs one or more or all operations of the processing step "enrichment" and / or the processing step "washing" and / or the processing step "separation" inside a preconfigured filter cartridge 44 via a base structure 3, the filter cartridge 44 having at least one filter 45 as a functional device 13 inside the cartridge 4. Figure 9 The filter cartridge 44 is also shown. The shown cartridge 4 serves as an example of other feasible cartridges 4.

[0149] Preferably, the filter cartridge 44 includes exactly one dedicated inlet for the cell culture and / or exactly one dedicated inlet for the buffer. The filter cartridge 44 may include exactly one waste outlet and / or exactly one product outlet. The inlet and / or outlet may be directly connected to the filter 45.

[0150] The filter cartridge 44 may further include one or more (in particular disposable) flow sensors and / or pumps, in particular for generating the transmembrane pressure of the filter 45.

[0151] The cartridge interface 8 of the filter cartridge 44 may include and use connections for electrical energy and / or for the pump and / or control signals from the flow sensor. The filter 45 control chip that receives the sensor signal from the flow sensor and controls the pump may also be placed inside the filter cartridge 44 and may be powered via the cartridge interface 8.

[0152] Here and preferably, the filter 45 is preconfigured as part of the cartridge fluid structure 5.

[0153] According to one embodiment, it is proposed that the bioprocessing system 1 automatically connects the centrifuge cartridge 39 and / or the acoustic cartridge 41 and / or the DLD cartridge 4 and / or the electrical and / or magnetic separation cartridge 4 and / or the filter cartridge 44 to the cartridge 4 containing the cell culture and / or the receiver 15 and / or to the receiver 15 containing the buffer as a consumable after the processing step and / or to the receiver 15 for receiving the washed or separated or enriched part of the cell culture and / or automatically connects to the receiver 15 for receiving the waste part of the cell culture and / or the consumable via one of the fluid interfaces 37, preferably, the cell culture and the buffer are provided via the same fluid interface 37. A tube connection system 23, in particular a tube welding system 24, can be used for any of these connections.

[0154] Here and preferably, the centrifuge chamber 40 and / or the deterministic lateral displacement chamber and / or the filter 45 are disposable components relative to the bioprocessing system 1, meaning that they can be sterilized but must leave the bioprocessing system 1 for this purpose. The biological process may include more than one of the processing steps "enrichment", "separation" and "washing", in particular, the biological process may include at least two processing steps "washing".

[0155] It is feasible that the bioprocessing system 1 reuses a centrifuge cartridge 39 and / or a DLD cartridge 4 for multiple processing steps of the same biological process, with or without the processing step "washing" and possible disinfection steps in between.

[0156] According to one embodiment, it is proposed that one or more or all operations of the processing step "selection" of the biological treatment system 1 are carried out inside a pre-configured magnetic selection cartridge 54 via a base structure 3, the magnetic selection cartridge 54 having at least one magnetic field generating element as a functional device 13 inside or outside the cartridge 4. Preferably, the magnetic selection cartridge 54 is an electrical and / or magnetic separation cartridge 4, or the electrical and / or magnetic separation cartridge 4 and the magnetic selection cartridge 54 are combined into a shared cartridge 4. More preferably, the electrical and / or magnetic separation cartridge 4 is a magnetic separation cartridge 4 that shares one or more functional devices 13 with the magnetic selection cartridge 54 inside the shared cartridge 4.

[0157] For different processing steps, the shared functional device 13 can act on the same part or different parts of the cartridge fluid structure 5. The two processing steps can be separate processing steps, and the product can even leave the cartridge 4 therebetween, for example for coating or incubation.

[0158] All explanations given for the functional elements of the electrical and / or magnetic separation cartridge 4 are also applicable here.

[0159] Magnetic selection is preferably carried out on a cell culture incubated with magnetic beads coated with antibodies (especially antibodies targeting CD62L and / or CD4 and / or CD8 and / or CD56 and / or CD3).

[0160] As an alternative or supplement to selecting target cells by magnetic selection, unwanted cells can be selected by magnetic selection.

[0161] Preferably, the magnetic selection cartridge 54 includes exactly one dedicated inlet for a cell culture (especially a cell culture incubated with magnetic beads), and / or exactly one dedicated inlet for a liquid comprising magnetic beads. The magnetic selection cartridge 54 can include exactly one waste outlet and / or exactly one product outlet. The inlet and / or outlet can be directly connected to the functional device 13.

[0162] The cartridge interface 8 of the magnetic selection cartridge 54 can include and use connections for electrical energy and / or control signals for the magnetic field generating element. The magnetic field generating element control chip can also be placed inside the magnetic selection cartridge 54 and can be powered via the cartridge interface 8.

[0163] Preferred magnet selection is carried out by mixing the cell culture with magnetic beads, for example in a magnetic selection cassette 54 or in a mixing cassette or at a cultivator service station 38, then incubating the cell culture, then transferring the cell culture to the magnetic selection cassette 54 if desired, then flowing the cell culture through the column of the magnetic selection cassette 54, then removing or deactivating the magnetic field generating element, in particular by removing the container containing the magnetic field generating element or disabling the electromagnet, then flowing a buffer through the column (in particular through the inlet of the magnetic selection cassette 54) and capturing the residue as the cell culture, in particular behind the outlet of the magnetic selection cassette 54.

[0164] The waste can be transferred from the magnetic selection cassette 54 or any other selection cassette 4 yet to be described to a storage location after selection, in particular inside the receiver 15. The same can be done for the cassette 4 in which enrichment and / or washing and / or separation is carried out. In this way, the storage receiver can still be used, for example, to repeat the "selection" step.

[0165] If the criteria related to the number or viability of the target cells, etc. are not met, another processing step, in particular a selection step, can be carried out on the waste to obtain more target cells. Thus, the biological process can be flexibly changed to include more steps, and the waste becomes the cell culture to obtain more target cells. The further combination step of the two parts of the target cells can be carried out automatically. Alternatively, the same processing step can be carried out on the waste to repeat the step.

[0166] According to one embodiment, it is proposed that the biological processing system 1 performs one or more or all operations of the processing step "selection" inside a preconfigured buoyancy selection cassette 4 via the base structure 3, and the buoyancy selection cassette 4 has at least one centrifuge as a functional device 13 inside or outside the cassette 4. Preferably, the buoyancy selection cassette 4 is a centrifuge cassette 39, or the centrifuge cassette 39 and the buoyancy selection cassette 4 are combined into a shared cassette 4. More preferably, the centrifuge cassette 39 shares the centrifugation chamber 40 with the buoyancy selection cassette 4 inside the shared cassette 4.

[0167] Buoyancy selection is preferably carried out on a cell culture incubated with inflated lipid shell microbubbles coated with antibodies (in particular antibodies targeting CD28 and / or CD3).

[0168] Preferably, the buoyancy selection cassette 4 includes exactly one dedicated inlet for the cell culture and / or exactly one dedicated inlet for the liquid including microbubbles. The buoyancy selection cassette 4 can include exactly one waste outlet and / or exactly one product outlet. The inlet and / or outlet can be directly connected to the functional device 13.

[0169] The cartridge interface 8 of the buoyancy selection cartridge 4 may include and use connections for electrical energy and / or control signals for the centrifuge. The centrifuge control chip may also be placed inside the buoyancy selection cartridge 4 and may be powered via the cartridge interface 8.

[0170] According to one embodiment, it is proposed that the biological treatment system 1 performs one or more or all operations of the processing step "activation" inside a preconfigured activation cartridge 4 via a base structure 3, and the activation cartridge 4 preferably has at least one pump as a functional device 13 inside or outside the cartridge 4.

[0171] The activation may include adding liquid, incubation, and washing. These steps may be performed in one cartridge 4 or in separate cartridges 4. It is feasible that the activation is not performed in a dedicated activation cartridge 4.

[0172] The activation may include adding soluble antibodies or paramagnetic beads coated with or containing antibodies to the cell culture. Subsequently, the magnetic beads or nanomatrices may be removed by washing.

[0173] The activation cartridge 4 may include a cell counting sensor and / or a mixing volume and / or a pump. The cartridge interface 8 of the activation cartridge 4 may include and use connections for electrical energy and / or for the pump and / or control signals from the cell counting sensor.

[0174] The activation may be performed at the incubator service station 38. The liquid for activation may be added to the activation cartridge 4 and / or added at the incubator service station 38 and / or at the culture medium filling service station 55. The incubation may be performed inside or outside the activation cartridge 4.

[0175] According to one embodiment, it is proposed that the biological treatment system 1 performs one or more or all operations of the processing step "activation" inside a centrifuge cartridge 39 and / or an acoustic cartridge 41 and / or a DLD cartridge 4 and / or an electrical and / or magnetic separation cartridge 4 and / or a filter cartridge 44 as a shared cartridge 4 via a base structure 3.

[0176] The functional device 13 may be reused for at least one operation of the processing step "enrichment" or the processing step "washing" or the processing step "separation" and at least one operation of the processing step "selection" and / or the operation of the processing step "activation". For clarity, one step of enrichment, washing, or separation may be combined with one step of selection or activation. Other steps of other processing steps may be added.

[0177] It is feasible that the shared cartridge 4 includes a pump and / or an acoustic wave generator and / or a magnetic field generating element and / or a centrifuge as the functional device 13, or is connected to the functional device 13 via a functional interface.

[0178] Preferably, flow cytometry or microscopy can be used to monitor activation. Activation causes the diameter of the cells to change from about 6 microns to 11 microns and can thus be detected using a transmission optical microscope for unstained cells. The microscope can be part of the respective cassette 4 or of a container connected via a functional interface.

[0179] According to one embodiment, it is proposed that the biological treatment system 1 performs one or more or all operations of the processing step "genetic modification" inside a preconfigured genetic modification cassette 4 via a base structure 3. Preferably, the activation cassette 4 and the genetic modification cassette 4 are a shared cassette 4.

[0180] The shared cassette 4 can include pumps and / or centrifuges as functional devices 13. Activation and genetic modification can be carried out together in a cassette 4 shared with other processing steps as described for activation. Activation and / or genetic modification can be carried out inside the cassette 4, in particular the shared cassette 4 including a centrifuge, by rotational seeding.

[0181] According to one embodiment, it is proposed that the biological treatment system 1 performs one or more or all operations of the processing step "genetic modification" inside a centrifuge cassette 39 and / or an acoustic cassette 41 and / or a DLD cassette 4 and / or an electrical and / or magnetic separation cassette 4 and / or a filter cassette 44, which are a shared cassette 4, via a base structure 3. Preferably, the functional device 13 is reused for at least one operation of the processing step "enrichment" or the processing step "washing" or the processing step "separation" and at least one operation of the processing step "selection" and / or the operation of the processing step "genetic modification".

[0182] Furthermore, it is feasible that the biological treatment system 1 performs genetic modification by viral transduction or electroporation or nanoparticle-based delivery. A viral transduction enhancing reagent can be added via an inlet of the genetic modification cassette 4, in particular from a receiver 15. Alternatively, the viral transduction enhancing reagent can be placed inside the cassette liquid container 30 during preconfiguration. The viral transduction enhancing reagent can include RetroNectin or a cationic polymer, such as Polybrene or cationic lipids.

[0183] Electroporation includes mixing a cell culture preferably with DNA or mRNA in an electroporation buffer. The genetic modification cassette 4 can include an inlet for DNA or mRNA and / or an inlet for the buffer. Furthermore, the genetic modification cassette 4 can include one or two inlets for a highly conductive sheath medium.

[0184] The genetic modification cassette 4 can include an electroporation cuvette and / or an electric field generating element inside the cassette 4. Reuse of the electric field generating element (in particular a charged plate) of the electrical separation cassette (in particular in the shared cassette 4) or of the electric field generating element as part of the base structure 3 is feasible.

[0185] Here and preferably, one or more or all operations of the processing step "amplification" are performed by the biological processing system 1 outside the cartridge 4 and / or at the amplification location and / or inside the receptacle 15. Preferably, at least one operation of the processing step "amplification" is performed at the incubator service station 38.

[0186] According to one embodiment, it is proposed that the biological processing system 1 performs one or more or all operations of the processing steps "formulation" and "filling" inside the preconfigured formulation cartridge 4 via the base structure 3.

[0187] The formulation cartridge 4 may include an inlet for the cell culture and / or an inlet for the formulation buffer. It may include an outlet for the cell culture or not include an outlet for the cell culture, especially if it is the final processing step. The formulation cartridge 4 may contain the final product packaging, and the cell culture may be added inside the formulation cartridge 4.

[0188] According to one embodiment, it is proposed that the biological processing system 1 performs one or more or all operations of the processing steps "formulation" and "filling" inside the centrifuge cartridge 39 and / or the acoustic cartridge 41 and / or the DLD cartridge 4 and / or the electrical and / or magnetic separation cartridge 4 and / or the filter cartridge 44 and / or the activation cartridge 4 and / or the genetic modification cartridge 4, which are shared cartridges 4, via the base structure 3. Preferably, the functional device 13 repeats at least one operation of the processing step "enrichment" or the processing step "washing" or the processing step "separation" and at least one operation of the processing step "selection" and / or the operations of the processing steps "formulation" and "filling".

[0189] The biological processing system 1 may have dedicated stations for processing steps and general stations for processing steps. The dedicated stations have the functional device 13 outside the cartridge 4, and the general stations have the functional device 13 inside the cartridge 4. At the general stations, different operations of different processing steps can be performed by the biological processing system 1 at different times using different cartridges 4.

[0190] Returning to the general explanation of the proposed method, it is feasible that in the non-preconfigured state, the cartridge 4 is not yet available for any processing step or operation by the biological processing system 1.

[0191] To clarify the present invention, the first processing step of the biological process for manufacturing genetically modified CAR-T cells from a liquid immune cell culture will be described hereinafter.

[0192] From Figure 4As can best be seen, the receptacle 15 containing the initial liquid immune cell culture is introduced by the operator into the integrated bioprocessing system 1 at the input-output position 46. The receptacle 15 is transferred from the input-output position 46 to the transfer position 14 of the unit operation station 2 by the global transfer mechanism 17. In the example given, the unit operation station 2 is preconfigured for the enrichment processing step by performing a standard routine on the corresponding cassette 4 that has been preconfigured accordingly. Specifically, the preconfigured cassette 4 is transferred from the cassette storage unit 9 to the cassette drive unit 11.

[0193] In a preferred embodiment, the unit operation of the enrichment processing step at least includes a countercurrent centrifugation unit operation step. However, as described above, acoustic separation can also be used instead of countercurrent centrifugation. For countercurrent centrifugation, the cassette fluid structure 5 of the corresponding cassette 4 includes a countercurrent centrifugation chamber 40 to receive the liquid to be centrifuged. Thus and as described above, the countercurrent centrifugation chamber 40 is preferably made of a disposable material.

[0194] Before, after or during the transfer of the receiver 15 to the transfer position 14 of the unit operation station 2, the cassette 4 of the unit operation station 2 (which includes the cassette fluid structure 5 that has been preconfigured for the enrichment processing step) is operatively coupled to the cassette drive unit 11. Specifically, the countercurrent centrifugation chamber 40 of the cassette fluid structure 5 is operatively coupled to the standardized mechanical interface of the cassette drive structure 33 as part of the operative coupling. This mechanical interface can include a rotor for rotating the countercurrent centrifuge channel. As described above, the rotor is preferably designed for multiple uses.

[0195] After the receptacle 15 containing the liquid immune cell culture has been transferred to the transfer position 14 of the unit operation station 2 and the cassette 4 has been transferred to the drive position 10, one of the receptacle transfer tube 22 and the cassette transfer tube 21 is welded during a closed connection process ( Figure 6 a).

[0196] Next, the liquid immune cell culture is transferred from the receptacle 15 to the countercurrent centrifuge element of the cassette 4 via the welded connection using the fluid interface 37 and the peristaltic pump 32, so as to transfer the liquid immune cell culture to the centrifugation chamber 40 ( Figure 3 ). Similarly, the corresponding interface for engaging the peristaltic pump 32 is provided by the base structure 3, in particular by the base structure interface 7.

[0197] Next, the liquid immune cell culture is subjected to countercurrent centrifugation by the countercurrent centrifuge of cartridge 4. For this purpose, the countercurrent centrifugation chamber 40 is fluidly connected to the cartridge liquid container 30, which can receive the waste liquid from the operating steps of the countercurrent centrifugation unit. Alternatively, the countercurrent centrifugation chamber 40 is fluidly connected to the receiver 15 provided at the transfer position 14, wherein the receiver 15 includes a receiver fluid structure 16 that does not yet contain liquid. The receiver 15 can be transferred to the transfer position 14 by the global transfer mechanism 17 and can be provided from the central supply reservoir 47.

[0198] It should be noted here that after the corresponding liquid has been transferred to the receiver 15 at the medium filling position 48 of the medium filling service station 38 as described above, at least a part of the liquid required at the corresponding unit operation station 2 for performing the unit operation can also be supplied from the medium filling service station 38. In this case, the receiver 15 is transferred to the transfer position 14 of the specific unit operation station 2 by the global transfer mechanism 17, and the connection between the cartridge 4 and the receiver 15 is established during the connection process as described above.

[0199] Optionally, the washing unit operation step can be performed after the countercurrent centrifugation unit operation step (not depicted). For this purpose, the cartridge 4 can include at least one cartridge liquid container 30 containing washing liquid. The washing liquid is transferred from the cartridge liquid container 30 to the countercurrent centrifuge element. Alternatively, the washing liquid can be provided from the medium filling service station 38. In the latter case, as described above, the washing liquid is transferred from the medium storage container 36 to the receiver 15 liquid container 36. Subsequently, the receiver 15 is transferred to the transfer position 14 of the unit operation station 2 by the global transfer mechanism 17 and is connected to the cartridge 4 during the above-described closed connection process.

[0200] Again, the waste liquid from the washing unit operation step is transferred to the cartridge liquid container 30. Alternatively, the waste liquid is transferred to the receiver liquid container 56 of the receiver 15 provided at the transfer position 14. Preferably, the same liquid container that is also used to receive the waste liquid from the centrifugation of the liquid immune cell culture is used to receive the waste liquid from the washing unit operation step. However, in an alternative embodiment, the cartridge fluid structure 5 can include different cartridge liquid containers 30 to receive the waste liquid and / or different receiver liquid containers 56 can be used. After transferring the liquid waste of the washing unit operation step, the now purified liquid immune cell culture can be eluted from the countercurrent centrifuge element and transferred to a second receiver 15 provided at the second transfer position 14 of the unit operation station 2 ( Figure 3). Again, a connection is established between the receiver transfer tube 22 of the second receiver 15 and the cassette transfer tube 21 of the cassette 4 during a closed connection process. For elution, the cassette 4 may include another cassette liquid container 30 which includes an eluent such as a culture medium etc. (not depicted). The purified T cells are eluted from the countercurrent centrifuge into the receiver liquid container 56 of the second receiver 15.

[0201] After all unit operation steps of the unit operation where the enrichment processing step has been performed, the welded connection between the receiver transfer tube 22 and the corresponding cassette transfer tube 21 of the cassette 4 is disconnected during a disconnection process. Subsequently, the cassette 4 is transferred from the cassette drive unit 11 to the cassette waste storage unit 49.

[0202] After disconnection, the first receiver 15, which now includes the empty receiver liquid container 56, can be transferred to the central waste memory 50 via the global transfer mechanism 17 for discarding. The second receiver 15, which now contains the partially processed liquid immune cell culture, is transferred to the unit operation station 2 via the global transfer mechanism 17, and the unit operation station 2 is preconfigured for a selection processing step.

[0203] During the selection processing step, a certain subtype of the liquid immune cells within the liquid immune cell culture is enriched. In a preferred embodiment, the subtype of T cells is enriched. In a further preferred embodiment, the subtype of T cells expressing the antigen CD4, CD8 or CD62L is enriched. In the proposed embodiment, the unit operation of the selection processing step includes at least one magnetic separation unit operation step.

[0204] For the selection processing step, the receiver 15 containing the liquid immune cell culture after the enrichment processing step is now transferred to the transfer position 14 of a specific unit operation station 2, and the specific unit operation station 2 is preconfigured for the selection processing step by preconfiguring one of its cassettes 4. As explained for the enrichment processing step, the cassette 4 for the unit operation of the selection processing step stored in the cassette storage unit 9 of one of the unit operation stations 2 has been moved to the drive position 10 of the specific unit operation station 2.

[0205] After the connection process for establishing a fluid connection between the receiver 15 and the cassette 4, a liquid including magnetic beads coated with an antibody against an antigen on the surface of T cells is transferred into the receiver 15 containing the liquid immune cell culture during a liquid addition unit operation step. Similarly, the liquid connection is established in a closed manner via the welding system 24 connecting the corresponding transfer tubes.

[0206] As an example, magnetic beads coated with an antibody against CD4 are added to the liquid immune cell culture, and the cells within the liquid immune cell culture including the CD4 surface antigen now attach to the magnetic beads.

[0207] In a next step, the receptacle 15 comprising the liquid immune cell culture and the magnetic beads can be transferred to a cultivator service station 38 located in a second plane 51. The cultivator service station 38 comprises at least one cultivator position 52 for receiving the receptacle 15. In one embodiment and as depicted in Figure 4 , the cultivator service station 38 can be designed as a drawer system. Alternatively, the cultivator service station 38 can also be designed as a shelving system. However, other configurations are also conceivable. Again, the global transfer mechanism 17 is used for the transfer, and a lift system 53 can be used to transfer the receptacle 15 from the first plane 19 to the second plane 51 ( Figure 4 ). It should be noted that although in the examples described herein, the cultivator service station 38 comprising at least one cultivator position 52 is located in the second plane 51, it is also feasible that at least one cultivator service station 38 is located in the first plane 19.

[0208] At the cultivator service station 38, the receptacle 15 is subjected to defined process conditions for a predetermined amount of time during a cultivation step. An incubation step is carried out to enable the target immune cells (in this case CD4+ T cells) to bind to the magnetic particles via antigen-antibody bonds. Thus, T cells comprising a specific antigen corresponding to the antibody coated onto the magnetic particles bind to the magnetic particles.

[0209] After the incubation step, the receptacle 15 is transferred back from the cultivator service station 38 to the unit operation station 2 preconfigured for the selection processing step.

[0210] Next, magnetic selection of the liquid immune cell culture can be carried out by an electromagnet or a magnet of the magnetic selection cassette 54. As described above, the addition of the magnetic beads to the liquid immune cell culture can be carried out in the magnetic selection cassette 54, or it can be carried out at another cassette 4 or at the cultivator service station 38 of the bioprocessing system 1.

[0211] A liquid comprising CD4+ cells attached to magnetic beads and other cells not attached to the magnetic beads is introduced via a first inlet into a flow channel surrounded by an electromagnet serving as a functional device 13. When the cells flow through the channel, the electromagnet is switched on to hold the magnetic beads and the cells attached to the magnetic beads in the part of the flow channel affected by the electromagnet. Thus, the cells not attached to the magnetic beads leave the flow channel via a first outlet. The first outlet is fluidly connected to a cassette liquid container 30, which can receive the waste liquid from the magnetic selection operation. Alternatively, for receiving the waste liquid, the first outlet of the channel is fluidly connected to a receiver 15 provided at a transfer position 14, wherein the receiver 15 comprises a receiver fluid structure 16 that does not yet contain liquid. The receiver 15 can be transferred to the transfer position 14 by a global transfer mechanism 17 and can be provided from a central supply reservoir 47. Further, a second outlet of the magnetic channel is fluidly connected to a receiver 15 provided in a second transfer position 14, wherein the receiver 15 comprises a receiver fluid structure 16 that does not yet contain liquid. After the immunocyte culture has passed through the channel, the magnet is switched off. Now, all the previously bound magnetic beads are released and can leave the area of the electromagnet. Preferably, the magnetic beads are guided into a second receiver 15. After the target cells (CD4+ cells) are collected in the second receiver 15, the cells can be separated from the magnetic beads and subjected to an activation treatment step.

[0212] It should be noted here that after the corresponding liquid has been transferred to the receiver 15 at the medium filling position 48 of the medium filling service station 38, at least a part of the required liquid at the corresponding unit operation station 2 for performing unit operations can also be supplied by the medium filling service station 38. In this case, the receiver 15 is transferred to the transfer position 14 of a specific unit operation station 2 by a global transfer mechanism 17, and a connection between the cassette 4 and the receiver 15 is established during the connection process as described above.

[0213] As described above, all connection steps between the cassette 4 and the receiver 15 can be carried out during a closed connection process.

[0214] According to one embodiment, it is proposed that the cassette 4 and / or the receiver 15 and / or the container 36 are automatically moved by the biological treatment system 1, preferably by the same transfer mechanism, in particular a robotic arm.

[0215] According to one embodiment, it is proposed that the shared cassette 4 has walls that divide the cassette 4 into compartments for different treatment steps. Preferably, the functional device 13 is part of the wall, and / or the cell culture is transferred through a fluid structure passing through the wall.

[0216] As already explained, it is feasible that, if the criteria of the cell culture are not met during or after the processing step, the electronic process controller 28 of the bioprocessing system 1 can repeat the processing step or operation, thereby flexibly reconfiguring the bioprocess, and / or can change the processing step via the same standardized base structure interface 7 by preconfiguring the cartridge 4 differently without reconfiguring the base structure 3.

[0217] As also already explained, it is feasible that the standardized interface 6 is not fully utilized by each cartridge 4 for each processing step and is utilized differently for different processing steps.

[0218] According to one embodiment, it is proposed that the bioprocessing system 1 can move the standardized interface 6 relative to the rest of the base structure 3 and / or the cartridge 4, or the standardized interface 6 is immovable.

[0219] The bioprocess system 1 can include one or more input-output locations 46. These can be interfaces for adding consumables and / or an initial cell culture and / or removing the packaged cell culture during the use of the bioprocessing system 1.

[0220] In a preferred embodiment, the cartridge 4 does not have an energy source or only has a battery that does not drive one of the functional devices 13. Additionally or alternatively, the cartridge 4 can be partially or fully made of plastic and / or 3D printed and / or not include any fluid structures before preconfiguration.

[0221] It should be mentioned that the functional devices 13 are those that participate in the bioprocess, rather than any functional elements.

[0222] The cartridge 4 can have a wall covering its sides, especially four sides. It can have a bottom plate and can have a lid. The cartridge 4 can be provided with a defined atmosphere. The cartridge 4 can have the form of a rectangular base. The non-configured cartridge 4 can not have functional elements. Electrical connections can be provided inside the wall and / or lid and / or bottom plate of the cartridge 4.

[0223] Another equally important teaching relates to the cartridge 4 used in the proposed method.

[0224] According to one embodiment, it is proposed that the cartridge 4 is preconfigured with a sterilized and sealed fluid structure, preferably, the cartridge 4 is packaged as a ready-to-use component, especially in a sterilized package.

[0225] Another equally important teaching relates to the base structure 3 used in the proposed method.

[0226] Another equally important teaching relates to the bioprocessing system 1 used in the proposed method.

Claims

1. A method for performing a biological process on a liquid immune cell or a primary cell culture to obtain a processed cell culture, wherein the processed cell culture is intended for autologous or allogeneic cell therapy, wherein the biological process is performed on an integrated bioprocessing system (1), wherein the biological process comprises a series of processing steps, and wherein each of the processing steps comprises at least one operation, wherein the bioprocessing system (1) comprises a base structure (3) and a pre-configurable cartridge (4), and wherein the bioprocessing system (1) operates the biological process via the interaction between the base structure (3) and the cartridge (4), wherein the cartridge (4) and the base structure (3) comprise a matching standardized interface for the interaction between the base structure (3) and the corresponding cartridge (4), and wherein the bioprocessing system (1) performs at least two operations of the biological process inside at least two differently pre-configured cartridges (4) via the interaction between the base structure (3) and the cartridge (4) via the same base structure interface (7) and / or the same base structure interface (7) and a matching cartridge interface (8).

2. The method according to claim 1, characterized in that the two operations of the biological process are operations of different processing steps, and / or the bioprocessing system (1) performs at least two operations as part of different biological processes in parallel in the same pre-configured cartridge (4), and / or the bioprocessing system (1) performs at least two operations as part of different biological processes, in particular as part of different processing steps of the different biological processes, in parallel in different pre-configured cartridges (4).

3. The method according to claim 1 or 2, characterized in that the bioprocessing system (1) performs at least two biological processes, preferably at least three biological processes, more preferably at least five biological processes, more preferably at least ten biological processes, each biological process comprising at least two, preferably at least three, more preferably at least four different processing steps, in particular in parallel, wherein the bioprocessing system (1) performs at least one operation for each processing step, and wherein the bioprocessing system (1) performs those operations in at least two, preferably at least three, more preferably at least four different pre-configured cartridges (4) for each biological process.

4. The method according to any one of the preceding claims, characterized in that the operations comprise one or more processing steps of "enrichment" and / or "selection" and / or "activation" and / or "loading" and / or "genetic modification" and / or "amplification" and / or "formulation" and / or "filling" and / or "washing" and / or "separation", and / or the plurality of processing steps comprise a plurality of processing steps of "enrichment" and / or "selection" and / or "activation" and / or "loading" and / or "genetic modification" and / or "amplification" and / or "formulation" and / or "filling" and / or "washing" and / or "separation".

5. The method according to any one of the preceding claims, characterized in that The biological treatment system (1) includes a single-step cartridge (4), whereby the biological treatment system (1) operates a single treatment step only within the single-step cartridge (4), and / or the biological treatment system (1) includes a shared cartridge (4), whereby the biological treatment system (1) operates treatment steps, in particular consecutive treatment steps, within the shared cartridge (4).

6. The method according to any one of the preceding claims, characterized in that the preconfigured cartridge (4) includes a preconfigured cartridge fluid structure (5), and / or the preconfigured cartridge (4) includes functional devices (13) for operations to be performed inside the cartridge (4), in particular preconfigured functional devices (13), and / or at least a portion of the cartridges (4) for said operations are identical before being preconfigured.

7. The method according to any one of the preceding claims, characterized in that the standardized base structure interface (7) includes an active energy transfer interface, and the base structure (3) transfers mechanical energy and / or pneumatic energy and / or electrical energy to the cartridge (4) via the active base structure interface (7) and a matching cartridge interface (8), in particular to drive the functional devices (13) of the cartridge (4) via the transferred energy, and / or the base structure (3) includes a transfer and placement interface (35), and the base structure (3) transfers the cartridge (4) via the base structure interface (7) and a matching cartridge interface (8) to a position where the biological treatment system (1) performs at least one operation inside the cartridge (4) and holds the cartridge (4) in that position.

8. The method according to any one of the preceding claims, characterized in that the biological treatment system (1), in particular the base structure (3), includes functional devices (13), preferably the functional devices (13) of the base structure (3) are fixed in a position close to a dedicated standardized interface (6) for performing one or more operations via the functional devices (13) through a preferably standardized functional interface of the functional devices (13) and a function receiving interface of the cartridge 4 preferably standardized for different functional devices (13) of different treatment steps, or the functional devices (13) of the base structure (3) are transferred to a position close to a non-dedicated standardized interface (6), and the biological process structure performs one or more operations via the functional devices (13) through a preferably standardized functional interface of the functional devices (13) and a function receiving interface of the cartridge (4) preferably standardized for different functional devices (13) of different treatment steps.

9. The method according to any one of the preceding claims, characterized in that The biological treatment system (1) operates inside the cartridge (4), where the interfaces are the same between the cartridges (4) for receiving cell cultures, in particular from a receiver (15), and / or for ejecting the cell culture from the cartridge (4) after operation, in particular into the receiver (15), and / or for receiving consumables, in particular from the receiver (15), and / or for receiving mechanical energy and / or pneumatic energy and / or electrical energy and / or cable-bound signals from the base structure (3), and / or for receiving energy from the functional device (13), and / or for supplying the cell culture to the functional device (13). Preferably, the cartridge (4) includes one or more fluid interfaces (37), and more preferably, one or more interfaces for receiving the cell culture and / or for propelling the cell culture and / or for receiving consumables and / or for supplying the cell culture to the functional device (13) are the same fluid interfaces (37).

10. The method according to one of the preceding claims, characterized in that the biological treatment system (1) includes a receiver (15), which is preconfigured with a receiver fluid structure (16) for accommodating and supplying and / or receiving the cell culture and / or consumables used by the biological treatment system (1) in at least some operations. Preferably, the receiver (15) includes a fluid interface (37) that is the same as the fluid interface (37) of the cartridge (4).

11. The method according to one of the preceding claims, characterized in that the biological treatment system (1) performs one or more or all of the operations of the processing step "enrichment" and / or the processing step "washing" and / or the processing step "separation" inside a preconfigured centrifuge cartridge (39) via the base structure (3). The centrifuge cartridge (39) has a centrifuge chamber (40) as a functional device (13) inside the centrifuge cartridge (39).

12. The method according to one of the preceding claims, characterized in that the biological treatment system (1) performs one or more or all of the operations of the processing step "enrichment" and / or the processing step "separation" inside a preconfigured acoustic cartridge (41) via the base structure (3). The acoustic cartridge (41) has at least one acoustic wave generator, in particular a piezoelectric element, as a functional device (13) inside the acoustic cartridge (41).

13. The method according to one of the preceding claims, characterized in that the biological treatment system (1) performs one or more or all of the operations of the processing step "enrichment" and / or the processing step "separation" inside a preconfigured acoustic cartridge (41) via the base structure (3). The acoustic cartridge (41) has at least one acoustic wave generator as a functional device (13) outside the acoustic cartridge (41). Preferably, the acoustic cartridge (41) includes a functional interface to the acoustic wave generator. The acoustic cartridge (41) includes a fluid structure, and the acoustic wave is applied to the fluid structure from one or more sides via the functional interface. More preferably, the acoustic cartridge (41) includes a reflector for the acoustic wave.

14. The method according to one of the preceding claims, characterized in that the biological treatment system (1) performs one or more or all operations of the treatment step "enrichment" and / or the treatment step "separation" inside a preconfigured DLD cartridge (4) via a base structure (3), the DLD cartridge (4) having a deterministic lateral displacement chamber as a functional device (13) inside the DLD cartridge (4).

15. The method according to one of the preceding claims, characterized in that the biological treatment system (1) performs one or more or all operations of the treatment step "enrichment" and / or the treatment step "separation" inside a preconfigured electrical and / or magnetic separation cartridge (4) via a base structure (3), the electrical and / or magnetic separation cartridge (4) having at least one sorting element, in particular an electric field and / or magnetic field generating element as a functional device (13) inside the cartridge (4), preferably, the electrical and / or magnetic separation cartridge (4) is a flow cytometry cartridge (4) and includes at least one laser and detection optics and at least one sorting element, in particular a charged plate, as a functional device (13) inside the flow cytometry cartridge (4), or the electrical and / or magnetic separation cartridge 4 is a negative magnetic immunoadhesion cartridge (4) and includes at least one magnetic field generating element inside the cartridge (4).

16. The method according to one of the preceding claims, characterized in that the biological treatment system (1) performs one or more or all operations of the treatment step "enrichment" and / or the treatment step "separation" inside a preconfigured electrical and / or magnetic separation cartridge (4) via a base structure (3), the electrical and / or magnetic separation cartridge (4) having at least one sorting element, in particular an electric and / or magnetic field generating element as a functional device (13) outside the cartridge (4), preferably, the electrical and / or magnetic separation cartridge (4) is a flow cytometry cartridge (4), and the biological treatment system (1), in particular the base structure (3) includes at least one laser and detection optics and at least one sorting element, in particular a charged plate, as a functional device (13) outside the flow cytometry cartridge (4), or the electrical and / or magnetic separation cartridge (4) is a negative magnetic immunoadhesion cartridge (4), and the biological treatment system (1), in particular the base structure (3) includes at least one magnetic field generating element outside the electrical and / or magnetic separation cartridge (4).

17. The method according to one of the preceding claims, characterized in that the biological treatment system (1) performs one or more or all operations of the treatment step "enrichment" and / or the treatment step "washing" and / or the treatment step "separation" inside a preconfigured filter cartridge (44) via a base structure (3), the filter cartridge (44) having at least one filter (45) as a functional device (13) inside the cartridge (4).

18. The method according to one of claims 11 to 17, characterized in that The biological treatment system (1) automatically connects, in particular via one of the fluid interfaces (37), the centrifuge cartridge (39) and / or the acoustic cartridge (41) and / or the DLD cartridge (4) and / or the electrical and / or magnetic separation cartridge (4) and / or the filter cartridge (44) to the cartridge (4) containing the cell culture or the receiver (15) before the treatment step and / or automatically connects to the receiver (15) containing the buffer as a consumable after the treatment step and / or to the receiver (15) for receiving the washed or separated or enriched part of the cell culture and / or automatically connects to the receiver (15) for receiving the waste part of the cell culture and / or the consumables. Preferably, the cell culture and the buffer are provided via the same fluid interface (37).

19. The method according to one of the preceding claims, characterized in that the biological treatment system (1) performs one or more or all of the operations of the treatment step "selection" inside a preconfigured magnetic selection cartridge (54) via the base structure (3), the magnetic selection cartridge (54) having at least one magnetic field generating element as a functional device (13) inside or outside the cartridge (4). Preferably, the magnetic selection cartridge (54) is an electrical and / or magnetic separation cartridge (4), or the electrical and / or magnetic separation cartridge (4) and the magnetic selection cartridge (54) are combined into a shared cartridge (4). More preferably, the electrical and / or magnetic separation cartridge (4) is a magnetic separation cartridge (4) that shares one or more functional devices (13) with the magnetic selection cartridge (54) inside the shared cartridge (4).

20. The method according to one of the preceding claims, characterized in that the biological treatment system (1) performs one or more or all of the operations of the treatment step "selection" inside a preconfigured buoyancy selection cartridge (4) via the base structure (3), the buoyancy selection cartridge (4) having at least one centrifuge as a functional device (13) inside or outside the cartridge (4). Preferably, the buoyancy selection cartridge (4) is a centrifuge cartridge (39), or the centrifuge cartridge (39) and the buoyancy selection cartridge (4) are combined into a shared cartridge (4). More preferably, the centrifuge cartridge (39) shares the centrifuge chamber (40) with the buoyancy selection cartridge (4) inside the shared cartridge (4).

21. The method according to one of the preceding claims, characterized in that the biological treatment system (1) performs one or more or all of the operations of the treatment step "activation" inside a preconfigured activation cartridge (4) via the base structure (3), the activation cartridge (4) preferably having at least one pump as a functional device (13) inside or outside the cartridge (4).

22. The method according to one of claims 11 to 21, characterized in that the biological treatment system (1) performs one or more or all of the operations of the treatment step "activation" inside the centrifuge cartridge (39) and / or the acoustic cartridge (41) and / or the DLD cartridge (4) and / or the electrical and / or magnetic separation cartridge (4) and / or the filter cartridge (44) which are shared cartridges (4) via the base structure (3). Preferably, The functional device (13) is repeatedly used to perform at least one operation of the processing step "enrichment" or the processing step "washing" or the processing step "separation", and at least one operation of the processing step "selection" and / or the operation of the processing step "activation".

23. The method according to any one of the preceding claims, characterized in that the biological processing system (1) performs one or more or all operations of the processing step "genetic modification" inside a preconfigured genetic modification cartridge (4) via a base structure (3), preferably, the activation cartridge (4) and the genetic modification cartridge (4) are a shared cartridge (4).

24. The method according to any one of claims 11 to 23, characterized in that the biological processing system (1) performs one or more or all operations of the processing step "genetic modification" inside a centrifuge cartridge (39) and / or an acoustic cartridge (41) and / or a DLD cartridge (4) and / or an electrical and / or magnetic separation cartridge (4) and / or a filter cartridge (44) that are a shared cartridge (4) via a base structure (3), preferably, the functional device 13 is repeatedly used to perform at least one operation of the processing step "enrichment" or the processing step "washing" or the processing step "separation", and at least one operation of the processing step "selection" and / or the operation of the processing step "genetic modification".

25. The method according to claim 23 or claim 24, characterized in that the biological processing system (1) performs genetic modification by viral transduction or electroporation or nanoparticle-based delivery.

26. The method according to any one of the preceding claims, characterized in that the biological processing system (1) performs one or more or all operations of the processing step "amplification" outside the cartridge (4) and / or at an amplification location and / or inside a receiver (15).

27. The method according to any one of the preceding claims, characterized in that the biological processing system (1) performs one or more or all operations of the processing steps "formulation" and "filling" inside a preconfigured formulation cartridge (4) via a base structure (3).

28. The method according to any one of the preceding claims, characterized in that the biological processing system (1) performs one or more or all operations of the processing steps "formulation" and "filling" inside a centrifuge cartridge (39) and / or an acoustic cartridge (41) and / or a DLD cartridge (4) and / or an electrical and / or magnetic separation cartridge (4) and / or a filter cartridge (44) and / or an activation cartridge (4) and / or a genetic modification cartridge (4) that are a shared cartridge (4) via a base structure (3), preferably, the functional device (13) is repeatedly used to perform at least one operation of the processing step "enrichment" or the processing step "washing" or the processing step "separation" and at least one operation of the processing step "selection" and / or the operations of the processing steps "formulation" and "filling".

29. The method according to any one of the preceding claims, characterized in that the cartridge (4) and / or the receiver (15) and / or the container (36) are automatically moved by the biological processing system (1), preferably by the same transfer mechanism, in particular a robotic arm.

30. The method according to any one of the preceding claims, characterized in that The shared cartridge (4) has walls that divide the cartridge (4) into compartments for different processing steps. Preferably, the functional device (13) is part of the wall, and / or the cell culture is transferred through a fluid structure that passes through the wall.

31. The method according to any one of the preceding claims, characterized in that if the criteria for the cell culture are not met during or after a processing step, the electronic process controller (28) of the bioprocessing system (1) can repeat the processing step or operation, thereby flexibly reconfiguring the bioprocess, and / or can change the processing step via the same standardized base structure interface (7) by pre-configuring the cartridge (4) differently without reconfiguring the base structure (3).

32. The method according to any one of the preceding claims, characterized in that the standardized interface (6) is not fully utilized by each cartridge (4) for each processing step and is utilized differently for different processing steps.

33. The method according to any one of the preceding claims, characterized in that the bioprocessing system (1) can move the standardized interface (6) relative to the remainder of the base structure (3) and / or the cartridge (4), or the standardized interface (6) is immovable.

34. The method according to any one of the preceding claims, characterized in that the cartridge (4) does not have an energy source or only has a battery that does not drive one of the functional devices (13), and / or the cartridge (4) is partially or completely made of plastic and / or 3D printed and / or does not include any fluid structure before pre-configuration.

35. A cartridge for the method according to any one of the preceding claims.

36. The cartridge according to claim 35, characterized in that the cartridge (4) is pre-configured with a sterilized and sealed fluid structure. Preferably, the cartridge (4) is packaged as a ready-to-use component, especially in a sterilized package.

37. A base structure for the method according to any one of claims 1 to 34.

38. A bioprocessing system for the method according to any one of claims 1 to 34.

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