Method for performing a bioprocess on immune or naive cell cultures

Abstract

The present invention relates to the field of bioprocessing of a cell culture, particularly on immune or naive cell cultures by a bioprocessing system in which the handling and cultivation of the patient cells and the media is simplified. Specifically, the invention provides a bioprocessing system as well as a bioreactor module for performing a bioprocess on a cell culture. The invention further provides a method for performing a bioprocess on a cell culture. The invention further provides a method for manufacturing a cell therapy product. The invention further provides uses of the bioreactor module.

Description

[0001] METHOD FOR PERFORMING A BIOPROCESS ON IMMUNE OR NAIVE CELL CULTURES

[0002] TECHNICAL FIELD OF THE INVENTION

[0003] The present invention relates to the field of bioprocessing of a cell culture, particularly on immune or naive cell cultures by a bioprocessing system in which the handling and cultivation of the patient cells and the media is simplified. Specifically, the invention provides a bioprocessing system as well as a bioreactor module for performing a bioprocess on a cell culture. The invention further provides a method for performing a bioprocess on a cell culture. The invention further provides a method for manufacturing a cell therapy product. The invention further provides uses of the bioreactor module.

[0004] BACKGROUND OF THE INVENTION

[0005] The term "bioprocess" presently represents a biotechnological process, here a biotechnological process involving the use of immune cell cultures or naive cell cultures. One or more processing steps might be performed on each cell culture. Hence, a bioprocess in this sense might refer to a manufacturing process that involves a sequence of processing steps performed on a cell culture which ultimately will lead to a final product.

[0006] Here, the bioprocess is in the area of cell and gene therapy, for example to manufacture autologous T cells that are modified to express a chimeric antigen receptor (CAR). These cells might be used for the treatment of various types of cancer, including different types of leukemia (blood cancer). Other cell therapies based on naive cells, in particular stem cells and their derivatives, are also of interest.

[0007] It is currently not fully known which factors contribute significantly to the success of automation in cell and gene therapy cell manufacturing. There is a need to devise a bioprocessing system with an extremely high tolerance to errors with the goal of always protecting the cells but at the same time achieving a high grade of automation to reduce manual labor costs and human mistakes. There is also a need to devise a bioprocessing system with a high flexibility and at the same time planning the components and workflows such that the automation is not hindered by complex mechanisms, complex parts or the like. At the same time, with the unknown sources for success of an automated bioprocessing system, there are still many problems to be solved. The wrong type of bioreactor for example may work only for a fraction of the emerging processes, possibly dooming a bioprocessing system or necessitating many individual solutions.

[0008] In bioprocesses in the area of cell and gene therapy with allogenic or autologous production of genetically modified immune cells, compliance of the bioprocess with regulatory demands is also important and the bioprocess is typically highly regulated and needs to be approved by regulatory authorities.

[0009] One specific problem that still needs an improved solution is the handling of media like agents and feed medium. On the one hand, several types of media, some in larger quantities, are needed during the bioprocess, on the other hand, the cells are moved through the bioprocessing system such that in most solutions media containers are placed stationary. That has the disadvantage that the media containers need to be connected to a bioreactor at an expansion location (incubator) or the like or the cells need to be brought to a media location very often to transfer a medium into the bioreactor. It is also conceivable to transport all needed media with the cells to different locations within the bioprocessing system, however that places significant complexity on a transport mechanism.

[0010] It is an object of the present invention to provide an improved bioprocessing system, in particular by simplifying existing bioprocessing system. It is a further object to improve on the known prior art by providing a method for performing a bioprocess on immune or naive cell cultures by a bioprocessing system in which the handling and cultivation of the patient cells and the media is simplified.

[0011] SUMMARY OF THE INVENTION

[0012] The present invention addresses these above-described objects. Specifically, the invention provides a bioprocessing system for performing a bioprocess on a cell culture which allows to simplify the handling of multiple bioreactor modules in parallel. The bioprocessing system comprises forthis purpose at least one exchangeable bioreactor module comprising a cell vessel area, wherein in the cell vessel area a cell vessel can be located, and a media supply area, wherein in the media supply area a media container can be located. Furthermore, the bioprocessing system comprises a framework, and a transport mechanism for automatically transporting the bioreactor module. By automatically transporting the bioreactor module the bioprocessing system advantageously allows to transport the bioreactor module between different positions for performing a bioprocess without a requirement for the user or operator to interfere.

[0013] The main realization of the present invention is furthermore that a bioreactor module which comprises a cell vessel for the cells and a media supply area for a media container allows adding media to the cell vessel whenever necessary without having to move the cell vessel to a media station or the like and without having to be able to connect the cell vessel to a media container at an expansion location. To make the handling of the bioreactor module simpler, not all needed media are transported together with the cell vessel. Instead, the medium is replenished, either by refilling the media container or by adding a new media container. As such, the complexity and size of the bioreactor module are reduced. If the medium needs certain storage conditions, it may be possible to refill the media container often enough to eliminate the need for providing these storage conditions at the media supply area.

[0014] The combination of having a media container and replenishing the medium provides for a less complex transport mechanism and allows functional grouping in the bioprocessing system. For example, a connection system, in particular a tube welder, may be used at a central zone in the bioprocessing system and the bioreactor module can be transported there for replenishing without this transport having to happen too often, thereby reducing the complexity of the bioprocessing system. In addition, with transport less often required, it might be possible to run more bioprocesses in parallel on a single bioprocessing system.

[0015] Further advantages and embodiments of the bioprocessing systems are described herein.

[0016] According to a first aspect of the invention, a bioprocessing system for performing a bioprocess on a cell culture is provided, wherein the bioprocessing system comprises: i. at least one exchangeable bioreactor module comprising a cell vessel area, wherein in the cell vessel area a cell vessel can be located, and a media supply area, wherein in the media supply area a media container can be located; ii. a framework, and iii. a transport mechanism for automatically transporting the bioreactor module. According to a second aspect of the invention, a bioreactor module for performing a bioprocess on a cell culture is provided, comprising: a cell vessel area, wherein in the cell vessel area a cell vessel can be located, and a media supply area, wherein in the media supply area a media container can be located; wherein the bioreactor module including the cell vessel and the media container is adapted to be automatically transported by a transport mechanism.

[0017] According to a third aspect of the invention, a method for performing a bioprocess on a cell culture is provided, wherein the method comprises: a) providing a. a cell culture, preferably an immune or naive cell culture; b. a bioreactor module (2) according to one or more of claims 38 to 58 and / or a bioprocessing system according to one or more of claims 1 to 37; c. a cell vessel (6); d. a media container (7); and e. optionally, a waste container (12), preferably, wherein a life support container (14) is provided comprising the media container (7) and the waste container (12); b) optionally, transferring the cell culture into the cell vessel (6); and c) expanding the cell culture in the cell vessel (6), located in the cell vessel area (4), preferably wherein expanding involves transferring liquid medium of the media container (7) into the cell vessel (6).

[0018] According to a fourth aspect of the invention, a method for manufacturing a cell therapy product is provided, wherein the method comprises: a) providing a. a cell culture, preferably an immune or naive cell culture; b. a bioreactor module (2) according to one or more of claims 38 to 58 and / or a bioprocessing system according to one or more of claims 1 to 37; c. a cell vessel (6); d. a media container (7); and e. optionally, a waste container (12), preferably, wherein a life support container (14) is provided comprising the media container (7) and the waste container (12); b) transferring the cell culture into the cell vessel (6); and c) expanding the cell culture in the cell vessel (6), located in the cell vessel area (4), preferably wherein expanding involves transferring liquid medium of the media container (7) into the cell vessel (6), for manufacturing a cell therapy product.

[0019] According to a fifth aspect of the invention, a use of the bioreactor module disclosed herein and / or the bioprocessing system disclosed herein for manufacturing a cell therapy product is provided. Preferably wherein the manufacturing comprises at least one of the following: activating cells, preferably activating T cells; transducing cells, preferably transducing T cells; transfecting cells, preferably transfecting T cells; and / or expanding cells, preferably T cells, more preferably genetically modified T cells.

[0020] According to a sixth aspect of the invention, a use of the bioreactor module disclosed herein and / or the bioprocessing system disclosed herein in a method disclosed herein is provided.

[0021] According to a further aspect of the invention, an expanded cell culture is provided obtained by the method disclosed herein.

[0022] According to a further aspect of the invention, a cell therapy product is provided obtained by the method disclosed herein.

[0023] BRIEF DESCRIPTION OF THE FIGURES

[0024] In the following, embodiments of the invention are explained with respect to the drawing. The drawing shows in

[0025] Fig. 1 a bioprocessing system with bioreactor modules and a close-up view of tube holders for tube welding,

[0026] Fig. 2 a first embodiment of a bioreactor module,

[0027] Fig. 3 a second embodiment of a bioreactor module,

[0028] Fig. 4 the cell vessel of the second embodiment of the bioreactor module,

[0029] Fig. 5 the total cell number (see 1) and daily fold expansion (see 2) of T cells using the bioprocessing system (BRO3) compared to a reference cell culture (BRO2), and

[0030] Fig. 6 the viable cell density using the bioprocessing system (BRO3) compared to a reference cell culture (BRO2) during the whole culture (see 1) and the perfusion culture only (see 2). DETAILED DESCRIPTION

[0031] The following description serves to deepen the understanding of the present disclosure and shall be understood to complement and be read together with the description of exemplary embodiments of the present disclosure as provided in the above section of this description. It is to be understood that this invention is not limited to the particular embodiments, methodologies, protocols and reagents described herein as these may vary within the scope set by the claims. It is also to be understood that terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention which is defined by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0032] In the following description, certain elements of the present invention will be described. These elements may be discussed with specific embodiments, however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples, features and particular embodiments should not be construed to limit the present invention to only the explicitly described embodiments or to the explicitly described combination of features. This description should be understood to disclose and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by this description unless the context indicates otherwise.

[0033] Bioprocessing system according to a first aspect of the invention

[0034] According to a first aspect of the invention, a bioprocessing system for performing a bioprocess on a cell culture is provided, wherein the bioprocessing system comprises: i. at least one exchangeable bioreactor module comprising a cell vessel area, wherein in the cell vessel area a cell vessel can be located, and a media supply area, wherein in the media supply area a media container can be located; ii. a framework, and iii. a transport mechanism for automatically transporting the bioreactor module. As disclosed herein, the bioprocessing system according to the present disclosure advantageously allows for simplified handling of the at least one exchangeable bioreactor module. By automatically transporting the bioreactor module the bioprocessing system advantageously allows to transport the bioreactor module between different positions for performing a bioprocess without a requirement for the user or operator to interfere. For simplified handling, the cell culture media supply is transported together with the cell vessel, wherein the media is replenished, either by refilling the media container or by adding a new media container. As such, the complexity and size of the bioreactor module are reduced. If the medium needs certain storage conditions, it may be possible to refill the media container often enough to eliminate the need for providing these storage conditions at the media supply area. The combination of having a media container and replenishing the medium provides for a less complex transport mechanism and allows functional grouping in the bioprocessing system.

[0035] Transport mechanism

[0036] The bioprocessing system according to the present disclosure comprises a transport mechanism for automatically transporting the bioreactor module. The "transport mechanism" may also be referred as a transport unit. It advantageously allows for automatically transporting the bioreactor module between different positions. Preferably, the bioreactor module comprises the cell vessel and the media container during the automated transportation. As a result, the different system features required for cell culture handled together as a single unit which can be handled by the transport mechanism of the bioprocessing system. Indeed, the present disclosure has the object to provide more than one bioreactor module which can be consecutively (or simultaneously) transported in an automated manner using the transport mechanism disclosed herein. For instance, in Fig. 1 it is further the case that the bioprocessing system comprises a transport mechanism, for example a movable tray mounted on rails (located outside the visible area on the right side in Fig. 1) or a robotic arm, for automatically moving the bioreactor module. The transport mechanism may transport the cell vessel and the media container at the same time and together as both are connected fluidically.

[0037] According to a preferred embodiment, the transport mechanism is configured to automatically transfer the bioreactor module between different positions, preferably between an expansion location and at least one further position, which can be the refill location, the emptying location, and / or the swapping location. At the different positions, specific bioprocessing steps can be performed such that the functions of different positions within the bioprocessing system can be optimized for the respective purpose. For instance, the transport mechanism may transport the bioreactor module in an automated manner to the refill location, the emptying location, and / or the swapping location, all of which may be the same or different positions. In one preferred embodiment, the refill location, the emptying location, and the swapping location correspond to a single position. At this position, the bioreactor module may be equipped with a suitable consumable, e.g. including the cell vessel, as well as a media container and waste container (or alternatively the life support container). In addition, different bioprocessing steps may be performed, including inoculation of the cell vessel, activation and transduction, but optionally, also filling of the media container with fresh cell culture media. Afterwards, the bioreactor unit may be transported by the transport mechanism to another location, such as the expansion location, whereat the cell culture undergoes expansion. In case during expansion the media container does not contain a sufficient volume for the whole culture, the media container may be transported to the refill location, the emptying location, and / or the swapping location by the transport mechanism. Here, the media container may be swapped with a new media container (automatically or manually) or the media container may be connected to a media supply container and fresh media may be filled into the media container, essentially "refilling'' the container. Similarly, the waste container may be swapped or emptied in case throughout culture the waste container volume is insufficient to store the complete permeate / waste volume.

[0038] According to a preferred embodiment, the transport mechanism comprises a transport element that is adapted to hold a bioreactor module and movable in at least one direction. Preferably, the transport element is movable in at least one linear direction, such as vertically. In another embodiment, the transport element is movable in more than one direction. For instance, the transport mechanism may be movable horizontally and vertically. This may be advantageous in case the expansion locations are present in stack of shelves arranged next to each other. In another embodiment, the transport mechanism is movable in all three dimensions.

[0039] The transport mechanism can be an elevator, such that the bioreactor module can be elevated into different positions in respect to the height, e.g. allowing for moving the bioreactor module into different positions provided by the framework of the bioreactor module.

[0040] According to a preferred embodiment, the transport mechanism further comprises a further transport element for pushing the bioreactor module into the expansion location and / or for retrieving the bioreactor module from the expansion location. Such further transport element advantageously allows for moving the bioreactor module into the respective expansion location but also retrieving the bioreactor module from an expansion location in order to transport the bioreactor module to another location, e.g. the refill location, the emptying location, and / or the swapping location. Bioreactor module

[0041] The bioprocessing system according to the present disclosure comprises at least one exchangeable bioreactor module comprising a cell vessel area, wherein in the cell vessel area a cell vessel can be located, and a media supply area, wherein in the media supply area a media container can be located.

[0042] The term "exchangeable" is well-known in the art and recognized by the skilled person. It can be understood in that the complete bioreactor module is exchangeable with another bioreactor module. It may also be understood as one or more parts of the bioreactor module are exchangeable with one or more of the respective parts. For instance, the cell vessel and the media container (and optionally the waste container) may be exchangeable with another cell vessel and the media container (and optionally the waste container). According to the present disclosure, "exchangeable" also means that the bioreactor module may be changed in position with another bioreactor module. For instance, in a first bioprocess run a first bioreactor module may be at a certain position where expansion is performed (expansion location), whereas a second bioreactor module is located at another expansion location. In a second run, the first bioreactor module may be located at the another expansion location, whereas the second bioreactor module may be located at the expansion location, where the first bioreactor module was originally located. In a further example, the bioreactor modules may be multi-use and may be exchanged after some time or with an updated version or the like. It is conceivable to also have bioreactor modules which are not part of such a group, i.e. to provide some bioreactor modules which are non-exchangeable (next to at least one exchangeable bioreactor module).

[0043] A "cell vessel area" is well-known in the art and recognized by the skilled person. Herein, it specifically refers to a dedicated area of the bioreactor module, whereat the cell vessel can be located. Preferably, the cell vessel is a consumable (or alternatively multi-use vessel) in which the cells can be cultured. Hence, it is in particularthe case that the cell vessel can be exchanged, such that in one bioprocess, cells are cultured in a first cell vessel and being located at the cell vessel area, whereas in a second bioprocess other cells are cultured in a second cell vessel located at the very same cell vessel area. Hence, the cell vessel area is a defined area of the bioreactor module configured to receive the cell vessel.

[0044] As disclosed herein, the cell vessel can be located "in the cell vessel area". Specifically, this means that the cell vessel can be located "at" or "on" the cell vessel area. Whenever herein it is referred to a certain object (e.g. cell vessel, media container, waste container, or life support container) being located "in" a certain area of the bioreactor module, the skilled person well understands that this means that such object is located "at" or "on" such area. When being located "in", "at", or "on" such area, it does not mean that such object needs to cover the complete area, but it is sufficient that are least part of such object covers such area. Although indeed for efficient configuration of the bioreactor module the areas are usually well covered by such objects. This may also change throughout the process, e.g. if throughout an expansion process the cell vessel is filled with more and more cell culture media, the cell vessel area may be covered more at the end of such bioprocess compared to coverage at the beginning of the expansion process.

[0045] As disclosed herein, the media container can be located "in the media supply area". Specifically, this means that the media container can be located "at" or "on" the media supply area, as is well understood by the person skilled in the art.

[0046] Accordingly, the bioreactor module may comprise the cell vessel and / or media container, especially when the bioreactor module is equipped with such consumable(s). But an empty or unequipped bioreactor module not comprising or being equipped with a consumable may also be provided without such cell vessel and / or media container - but nevertheless, must be configured for receiving such cell vessel and media container and supporting the respective processes. In an alternative embodiment, the bioreactor module is equipped with the cell vessel and / or media container, wherein such cell vessel and / or media container may be multi-use compounds of the bioreactor system.

[0047] As also disclosed herein, the bioreactor module may be re-used with a different single-use cell vessel, however, presently only a single use is described. If the cell vessel is replaced and cells of a new patient or cells either from one donor or pooled from several donors are introduced in a new cell vessel, that starts a new cell culture cycle.

[0048] The cell vessel area may hold exactly one cell culture. However, it is not excluded that the bioreactor module comprises a second cell vessel area and possibly further cell vessel areas, in particular at least three, at least four, at least five or more.

[0049] According to a preferred embodiment, the bioreactor module further comprises a support structure, wherein due to the support structure the bioreactor module can be handled as a unit. In particular, due to the support structure the bioreactor module can be automatically transported by the transport mechanism. Preferably, due to the support structure the bioreactor module can be handled as a unit together with the cell vessel, the media container and, optionally, a waste container.

[0050] According to a preferred embodiment, the support structure of the bioreactor module comprises a life support area. In the life support area, a life support container can be placed. The life support container may also be placed in the life support area by being mounted on or placed on a life support tray. As disclosed herein, the life support container or life support tray can be located "in" the life support area. Specifically, this means that the life support container or life support tray can be located "at" or "on" the life support area, as is well understood by the person skilled in the art.

[0051] Providing a life support container, e.g. mounted on a life support tray, has the advantage that it can be handled as a single piece. Such life support container advantageously comprises a media container and a waste container, such that the media container and waste container do not need to be placed at different locations and handled as two individual objects. Rather, one single object, i.e. the life support container, can be handled. It may also be within the scope of the present disclosure that further containers are provided by the life support container, which may also be mounted or placed on the life support tray.

[0052] In case a life support area is provided, preferably the media supply area would essentially overlap with the life support area. Preferably, also the waste area would essentially overlap with the life support area.

[0053] Hence according to one preferred embodiment, the bioprocessing system further comprises a cell vessel located in the cell vessel area, a media container located in the media supply area, optionally a waste container located in a waste area.

[0054] Preferably in such embodiment, the bioreactor module may not comprise a life support area. Alternatively, the bioreactor module comprises a life support area, which comprises the media supply area and the waste area.

[0055] According to another preferred embodiment, the bioprocessing system further comprises a cell vessel located in the cell vessel area, a life support container located in a life support area.

[0056] Preferably, in such embodiment, the life support area overlaps or comprises the media supply area. According to a preferred embodiment, the bioprocessing system comprises a life support area. Preferably, the life support area comprises the media supply area and / or the waste area, preferably wherein the media supply area is the same area as or a different area than the waste area on the life support area, more preferably wherein the media supply area is the same area as the waste area.

[0057] According to a preferred embodiment, the life support area comprises the media supply area and / or the waste area such that the life support container contains a media container and / or a waste container.

[0058] According to a preferred embodiment, the support structure further comprises a rocking unit for rocking the cell vessel. The rocking unit is advantageous in order to perform a rocking motion or wave like cultivation of the cells in the cell vessel. This allows to provide adequate gas exchange through the gas-liquid interface in the cell vessel without the need for further oxygenation, e.g. via a sparger. However, an external additional gas supply may also be provided, e.g. in form of a sparger, if needed.

[0059] According to a preferred embodiment, the support structure further comprises a balance for weighing a life support tray. Weighing the support try has the advantage that the containers placed on the tray can be closely tracked, such that the incoming and exiting volume can be tracked. According to a preferred embodiment, the balance weighs the life support tray: before a transfer of a liquid medium from the media supply area to the cell vessel, after a transfer of a liquid medium from the media supply area to the cell vessel, during a transfer of a liquid medium from the media supply area to the cell vessel, before a transfer of a liquid from the cell vessel to the waste area, after a transfer of a liquid from the cell vessel to the waste area, and / or during a transfer of a liquid from the cell vessel to the waste area to determine and / or control an amount of transferred liquid medium. Liquid medium may encompass any liquid, including cell culture media, waste liquid but also wash liquid or liquid comprising a reagent.

[0060] In a further embodiment, the support structure further comprises a balance for weighing a media container. Hence, the balance may weigh the media container: before a transfer of a liquid medium from the media supply area to the cell vessel, after a transfer of a liquid medium from the media supply area to the cell vessel, and / or during a transfer of a liquid medium from the media supply area to the cell vessel to determine and / or control an amount of transferred liquid medium. Liquid may encompass cell culture media liquid.

[0061] In a further embodiment, the support structure further comprises a balance for weighing a waste container. Hence, the balance may weigh the waste container: before a transfer of a liquid from the cell vessel to the waste area, after a transfer of a liquid from the cell vessel to the waste area, and / or during a transfer of a liquid from the cell vessel to the waste area to determine and / or control an amount of transferred liquid medium. Liquid may encompass waste liquid.

[0062] In a further embodiment, the support structure further comprises a balance for weighing a cell vessel. For instance, the balance may be located at the cell vessel area, such that the cell vessel may be weighed during any liquid transfer to determine and / or control an amount of transferred liquid medium.

[0063] According to a preferred embodiment, the bioreactor module comprises a receiving interface with a connection for receiving electrical energy; a connection for receiving wire-bound signals; a connection for receiving gas; and / or a connection for a sensor, such as an optical sensor.

[0064] The term "gas" is well-known by the person skilled in the art and encompasses any type of gas, such as air, oxygen, carbon dioxide. "Gas" in scope of the present disclosure particularly refers to a gas required for cell cultivation.

[0065] According to a preferred embodiment, the framework comprises providing interfaces providing electrical energy; wire-bound signals;

[0066] - gas; a sensor connection, such as an optical sensor connection, preferably at different locations, in particular at the swapping location, at the expansion location, at the refill location, and / or at the emptying location. According to a preferred embodiment, the receiving interface is connectable to the providing interface of the framework.

[0067] Cell vessel

[0068] The bioreactor module according to the present disclosure comprises a cell vessel area, wherein in the cell vessel area a cell vessel can be located. Such cell vessel is well-known in the art and the skilled person understands the term "cell vessel". Herein, the term "cell vessel" may be exchangeable used with the term "vessel" or "bag". The cell vessel may be a flexible bag or a rigid vessel or container. The cell vessel preferably comprises a rigid part and a flexible part. Inside the cell vessel, steps of the bioprocess, in particular an expansion and / or an activation and / or a transduction step of the bioprocess can be performed.

[0069] According to a preferred embodiment, the cell vessel provides a volume for at least supporting cell cultures with volumes between 100 ml and 500 ml, preferably between 50 ml and 750 ml.

[0070] According to a preferred embodiment, the cell vessel has a volume of at most 6 I, preferably at most 3 I or 2 I.

[0071] According to further preferred embodiments, the cell vessel is suitable for cultivating cells in a liquid medium in a cultivation procedure is provided, wherein the vessel comprises a casing defining a main volume, and a reservoir defining a reservoir volume, wherein the reservoir volume and the main volume are adjacently arranged and are configured to be fluidically connected for fluidic exchange, characterized in that the reservoir is a pre-shaped reservoir.

[0072] The "cell vessel" may herein also be referred to as "vessel". The cell vessel can advantageously be used for cultivating cells from small to large scale. Specifically, the reservoir defines a reservoir volume, in which the cells can be initially cultivated. Such reservoir volume is generally lowerthan the main volume, allowing for small-scale culture. At the same time the reservoir volume by being adjacently arranged to the main volume and being fluidically connected for fluidic exchange provides access to the typically larger volume of the main volume defined by the casing. Therefore, the cells can be expanded with increasing volume in an adequate environment, i.e., initially in the reservoir volume, followed by culture in the main volume (and reservoir volume). Thereby, scale-up is achieved without the necessity to change the vessel (e.g., by transfer to a larger vessel). At the same time, the reservoir volume and main volume provide an adequate culture environment for the respective needs throughout culture. For instance, initially the cells may be present in a small volume, requiring small surface areas in order to minimize evaporation effects. This can be provided by the reservoir. Later in culture, more volume is needed for obtaining a suitably high cell number, such that the main volume provides an adequate extension of the reservoir volume. Such culture mode is particularly advantageous for manufacture of a cell therapy product, such as autologous immune cell therapy (e.g. CAR T-cells), since initially the cell number obtained from a patient sample is comparably low and requires expansion for manufacturing the cell therapy product. Thus, despite a low cell number and also a low culture volume, the cells can be cultured in the very same vessel during the complete expansion process. This not only simplifies the overall process but also makes it less prone to errors and reduces contamination risks. As is demonstrated in the Examples below, also higher daily expansion rates and cell viabilities can be achieved, such that cultivation duration can be shortened and product quality is improved (see e.g., Figs. 5 and 6).

[0073] By being "pre-shaped", the reservoir is dimensionally stable such that the reservoir volume is fully developed and does not require provision of a further device or system, e.g. rocker / rocking motion platform, in order to form the reservoir. "Pre-shaped" does not exclude that the reservoir can be generally deformed, however, it is to be understood that the reservoir has a certain defined shape independent of other (external) devices or system (such as a rocker platform). It is possible that the reservoir returns to its pre-shaped form when a deformation force decreases or disappears. By being pre-shaped, the reservoir can be reproducibly and stably provided enabling a more robust cultivation process. In particular, it can be achieved to provide the same volume (here reservoir volume) for each culture batch. Furthermore, by being pre-shaped, the reservoir is more resistant to deformation and material rupture compared to a reservoir or chamber that forms only when combined with a culture platform or system, such that failure or contamination risks are reduced.

[0074] The cell vessel is in particular suitable for cultivating cells in a liquid medium in a cultivation procedure. For cell cultivation, the cells are conventionally provided in a liquid medium, which allows for efficient expansion and manipulation of the cells. However, the present disclosure is not limited to cells being exclusively in liquid medium. For instance, the cells may be provided together with a carrier matrix or support matrix for cultivation, wherein these are dispersed in a liquid medium. In addition, the medium may comprise in part a dissolved or undissolved gaseous phase (e.g., culture gas as disclosed herein). A "cultivation procedure" in scope of the present disclosure shall not be limited in scope. Indeed, the skilled person is well-aware of various cultivation procedures, which are adequate in order to cultivate cells in a liquid medium. Cultivation procedures may include batch cultivation, fed- batch cultivation or perfusion culture of combinations thereof. In addition, a cultivation procedure may already be achieved if the cells are provided with an adequate environment, in which they may proliferate or at least not become completely apoptotic. In one embodiment, a cultivation procedure may also include adding a fluid, such as cell culture medium or reagent to the cells present in the cell vessel according to the present disclosure. According to a preferred embodiment, particularly suitable for manufacture of a cell therapy product, the cultivation procedure encompasses a preliminary cultivation phase, in which the cells are preliminarily cultivated, preferably wherein cells are predominantly cultivated in the reservoir; and a subsequent cultivation phase, in which the cells are subsequently cultivated preferably wherein cells are cultivated in the reservoir and the casing. Such culture allows for scaling up small cell number, such as typically only obtainable from a patient sample for autologous cell therapy, in the same vessel.

[0075] A "liquid medium" according to the present disclosure in particular relates to a composition in which the cells remain to the most extent viable. For instance, the cells may be combined with a cell culture medium for providing an environment in which the cells can proliferate. Also, the cells may be combined with a buffer or storage solution, in which the cells can be stored and / or kept essentially alive. In another embodiment, the cells may be combined with an agent (also referred to as "reagent") in order to manipulate the cells, e.g. an activation agent may be provided to activate the cells and / or a genetic modification agent may be provided to genetically modify the cells. The term "liquid medium" may herein be interchangeable used with the terms "medium", "media", "liquid media". Sometimes, also an activation agent, and / or genetic modification agent, in particular transduction and / or transfection agent, may be referred to as "liquid medium", such that the term shall encompass such compositions.

[0076] The vessel according to the present disclosure may comprise a casing defining a main volume, and a reservoir defining a reservoir volume, wherein the reservoir volume and the main volume are "adjacently arranged". The skilled person is well-aware about this terminology and understands it according to the common general knowledge. Following the teaching of the present disclosure it is clear that "adjacently arranged" is typically understood as two volumes (i.e., the main volume and the reservoir volume) being arranged next to each other. This does not exclude that a further volume may be in contact to the reservoir volume and / or the main volume. Rather, by being adjacently arranged, when the volume of the culture exceeds the reservoir volume it can move into the main volume, such that the culture can be continued without the need to stop the process and / or transfer the cell culture into another vessel. The arrangement of these volumes is important in order to efficiently enlarge the volume accessible for the cell culture over time, e.g., in an expansion process. While it is not excluded that between the reservoir volume and the main volume another volume is arranged, this is less preferred, as it allows less efficient enlargement of volume accessible to the cell culture. According to one embodiment, there is no volume defined by one or more tubes between the reservoir volume and the main volume. According to a preferred embodiment, the reservoir volume and the main volume are directly adjacent.

[0077] The reservoir volume and the main volume of the vessel are further configured to be fl uidica I ly connected for fluidical exchange. "Fluidic exchange" (which may be synonymously used herein with "fluidical exchange") in this context comprises that fluid in the reservoir and fluid located in the casing can be mixed such that an exchange between the fluids located in the different volumes occurs. It further may mean that liquid medium located in the reservoir and liquid medium located in the casing can be mixed such that an exchange between the liquids located in the different volumes happens. In one embodiment, the cells may undergo a preliminary cultivation phase, wherein the liquid medium might be contained solely in the reservoir. Fluidic exchange may occurthrough the gas liquid interface between the reservoir volume and the main volume, considering that gas it provided and present in the main volume. In case the culture comprises a subsequent cultivation phase (after the preliminary cultivation phase), fluidic exchange between liquid medium in the reservoir and liquid medium in the casing may happen mostly in such phase. The reservoir volume and the main volume develop the overall volume of the vessel. Also, in the preliminary cultivation phase liquid may enter the main volume, in particular during rocking. The transition between the preliminary cultivation phase and the subsequent cultivation phase may be a continuous transition if for example culture medium is added continuously and not in steps.

[0078] By being "configured to be fluidically connected for fluidic exchange", the vessel also encompasses embodiments, wherein the vessel is completely deflated (e.g. put under vacuum), which may happen when providing the vessel prior to any cultivation process in order to keep the volume of such vessel as small as possible. Nevertheless, when being inflated again with a fluid (e.g. gas and / or liquid), such vessel would be fluidically connected for fluidic exchange.

[0079] A "casing" is well-known to the person skilled in the art. Typically, a casing of a vessel refers to a bag or pouch, which is preferably flexible but may also be rigid or semi-rigid. Preferably, the casing in the present disclosure is at least partially flexible to adapt throughout culture and increasing culture volumes during expansion. The vessel according to the present invention further comprises a reservoir, which may be connected or form an integral part of the casing. Generally, the casing may be pre-shaped like the reservoir. However, it is also possible that the casing is flexible and particularly obtains its form during the cultivation procedure, for example because of rising pressure or weight inside the vessel.

[0080] The casing may preferably be a single-use bag which are widely used in the field of cell culture, for instance in single-use bioreactors or for storing or conveying cell fluids, such as cell medium, cell culture buffer or cell culture. Such bags may comprise at least one casing part, which may also be referred to as "wall''. Hence, according to a preferred embodiment, the casing comprises a casing part. Such casing part may be folded and sealed together in order to form a bag-like structure. Typically, a bag may comprise two (large) walls (here casing parts) sealed to one another. Once expanded, they have a limited volume and remain relatively thin, which justifies the fact that they are often called 2D bags (D meaning dimensions). 3D bags are also known and typically comprise two end walls and a side wall that can be folded flat or deployed unfolded, sealed to one another, with the volume able to reach up to 3,000 liters, and even more. Hence, according to a preferred embodiment, the casing comprises two or more casing parts, such as an upper casing part and a lower casing part. Such casing parts may be connected in order to form a bag-like structure (also referred to as 2D bags). It is also within the scope of the present disclosure that the casing comprises three casing parts, or four casing parts, or five casing parts or more than five casing parts. This may allow forming 3D casings (e.g., 3D bags).

[0081] The casing part may be composed of a multilayer film comprising a contact layer which is in contact with the medium that fills the casing, a barrier layer and an outer layer which is in contact with the external environment of the casing, the three layers being connected one to each other with a tie layer. In case the casing is to be filled with a biopharmaceutical product, the contact layer should be made from a material that can be in contact with this biopharmaceutical product without causing degradation of the film and of the biopharmaceutical product. Furthermore, it must be sealable on itself. For that purpose, the material is generally selected from polyolefins, such as polyethylene. The barrier layer provides a barrier to the passage of gases such as oxygen, carbon dioxide and is typically made from ethylene vinyl alcohol (EVOH). The outer layer contributes to the mechanical strength of the casing. For that purpose, it must be sufficiently flexible to withstand high mechanical stress but not be too much stretchable in order to prevent deformation of the casing when it is filled. According to further embodiments, the reservoir is attached to the casing. Such attachment advantageously allows for providing the casing and the reservoir as a single item or piece, avoiding manual assembly. Preferably the reservoir is attached to a casing part, more preferably a lower casing part. Such lower casing part may come into contact with a bioprocessing system or device, such as a rocker platform, during cultivation. Hence, such lowercasing part is preferably configured to be arranged at or on a bioprocessing system or device for cultivation, in particular a rocker platform. In the embodiment, wherein the reservoir is attached to a casing part, the casing part would have an opening allowing for the volume defined by the reservoir (i.e., the reservoir volume) to be adjacently arranged to the volume defined by the casing (i.e., main volume) and being configured for fluidic exchange. According to further embodiments, the reservoir is formed integrally with the casing, preferably with a casing part, more preferably with a lower casing part. By being integrally formed, robust connection between the casing and the reservoir can be achieved. The skilled person is aware of various methods and processes for attaching or integral formation of the casing and the reservoir, and the present disclosure shall not be limited in this respect. For instance, the reservoir is attached to the casing by welding or formed integrally with the casing, in particular by injection molding and / orthermoforming and / or gluing, for example UV cured gluing.

[0082] According to further embodiments, the vessel comprises at least one filter and / or is fluidically connected to at least one filter. The term "filter" is well-known by the person skilled in the art. A "filter" is typically used to remove particles from a fluid process stream and comprises a porous medium. A filtration process is a process by which particles are removed from a fluid by passing the fluid through a porous medium. Herein, the filter is particularly used in order to retain the cells within the vessel. The remaining filtered cells may be referred to as "retentate". The fluid passing the filter essentially does not comprise the cells. The passing fluid may be referred to as "permeate". The selection of a filter is within the skills of the person of ordinary skill in the art. In particular, the skilled person is well-aware of various filters for retaining cells but allowing liquid to pass. Selection of an adequate pore size or molecular cut-off is within the routine of the skilled person. Hence, the present disclosure shall not be limited to a particular filter material or pore size, insofar as the material and pore size should be suitable for cell culture.

[0083] Preferably, the filter is configured to allow liquid to flow through but essentially retain cells. This does not mean that all cells are completely retained but the majority of cells shall be retained. Also, this does not exclude that cell debris or apoptotic cells (which are oftentimes smaller in size than viable cells) pass the filter. According to further embodiments, the at least one filter comprises a filter medium selected from a surface filter and a depth filter.

[0084] According to further embodiments, the at least one filter is a membrane, such as a planar membrane, a hollow fiber membrane and / or floating membrane. A floating membrane may also be referred to as "pouch membrane", in particular being fl uidica I ly connected to the outside of the vessel, especially at least to the waste container (which may also be referred to as the "waste container").

[0085] The term "membrane" is known in the art. Various membrane materials can be used, including polyvinylidene difluoride (PVDF), polyethersulfone (PES), or polysulfone (PS). In one embodiment, the membrane is a PES membrane, optionally having a cutoff of 0.5 to 5 micrometer, such as 1.2 micrometer.

[0086] According to further embodiments, the at least one filter comprises a main membrane, and / or a reservoir membrane, preferably both of a main membrane and a reservoir membrane. A "main membrane" herein typically refers to a membrane that is arranged at the casing. A "reservoir membrane" herein typically refers to a membrane that is arranged at the reservoir. The reservoir membrane advantageously allows to perform a filtration process at larger scale, e.g. when the cell culture is present in the casing (and typically also the reservoir). The main membrane can therefore be advantageously used to perform medium to large volume liquid filtrations, e.g. as may be required throughout a perfusion culture.

[0087] According to further embodiments, the main membrane is arranged at the casing, preferably at a casing part, more preferably at the lower casing part. By being arranged at the casing, the membrane forms part of the casing and thus cell vessel, allowing for filtration through the membrane directly at the casing. Alternatively, or in addition, the main membrane is fluidically connected to the casing, preferably wherein fluidic connections between the casing and the main membrane are provided, in particular wherein the fluidic connections are provided by one or more tubes. Such fluid connection allows forflexibly arranging and exchanging the membrane independent of the casing and thus independent of the vessel. Nevertheless, such main membrane that is fluidically connected to the casing, preferably wherein fluidic connections between the casing and the main membrane are provided, may also encompass integral connection such as sealing or molding between the casing and the membrane. Different configurations are in general possible within the present disclosure as is recognized by the person skilled in the art. According to a preferred embodiment, the main membrane is configured for retaining cells in a perfusion culture.

[0088] When providing a main membrane that is arranged at the casing, preferably, the casing further comprises an outlet section, which is arranged outside the main volume. Specifically, such outlet section is preferably provided at the permeate side adjacent to the main membrane. Such outlet section is advantageously able to collect the permeate and guide the permeate to an outlet port. Hence, according to one embodiment, the casing comprises an outlet section, preferably, comprising an outlet port, wherein the outlet section is preferably arranged adjacent to the main membrane. An outlet port may also be referred to as "waste port" or "permeate port".

[0089] According to further embodiments, the vessel comprises a waste port for draining liquid medium, which was filtered by the main membrane.

[0090] According to further embodiments, the main membrane surrounds the reservoir, is adjacent to the reservoir and / or floats within the main volume, preferably wherein the main membrane is adjacent to the reservoir. Being adjacent to the reservoir does not mean that a part of the casing is between the reservoir and the main membrane. Typically, the main membrane is arranged at the same casing side or casing part, which may throughout culture be the lower casing part. This is due to the fact, that during culture the culture liquid would typically be located on the lower casing part (within the casing) due to gravity. Hence, a filtration process, such as a perfusion process, would be most efficient, when the main membrane is located where most of the culture liquid is located which is typically close to the reservoir, i.e. adjacent to the reservoir.

[0091] According to further embodiments, the main membrane is configured for removing and / or adding liquid through the main membrane but essentially retaining the cells within the main volume or preferably, within the main volume and the reservoir volume. Such configuration is particularly advantageous when performing a filtration process such as perfusion throughout culture, as it allows cells to be retained within the vessel but remove culture liquid. By adding liquid through the membrane, the membrane may be backflushed, e.g. in alternating flow. Additionally, or alternatively, liquid may be added through a supply port, arranged on the retentate side, e.g., in the casing or reservoir.

[0092] According to further embodiments, the main membrane is configured for cultivating the cells in the liquid medium via perfusion in the main volume or preferably, in the main volume and the reservoir volume. According to further embodiments, the casing comprises a main membrane, preferably, wherein the reservoir does not comprise the main membrane.

[0093] According to further embodiments, the reservoir membrane is arranged at the reservoir, preferably the reservoir comprises the reservoir membrane, and / or is fluidically connected to the reservoir, preferably wherein fluidic connections between the reservoir and the membrane are provided, more preferably wherein the fluidic connections are provided by one or more tubes. The reservoir membrane advantageously allows to perform a filtration process even at small scale, e.g. when the cell culture is only present in the reservoir. The reservoir membrane can therefore be advantageously used to perform low volume liquid filtrations. By being arranged at the reservoir, the reservoir membrane forms part of the reservoir and thus cell vessel, allowing for filtration through the reservoir membrane directly at the reservoir. Alternatively, or in addition, the reservoir membrane is fluidically connected to the reservoir, preferably wherein fluidic connections between the reservoir and the reservoir membrane are provided, in particular wherein the fluidic connections are provided by one or more tubes. Such fluid connection allows for flexibly arranging and exchanging the reservoir membrane independent of the reservoir and thus independent of the vessel. Nevertheless, such reservoir membrane that is fluidically connected to the reservoir, preferably wherein fluidic connections between the casing and the main membrane are provided, may also encompass integral connection such as sealing or molding between the reservoir and the membrane. Different configurations are in general possible within the present disclosure as is recognized by the person skilled in the art. According to a preferred embodiment, the reservoir membrane is configured for retaining cells in a filtration process.

[0094] According to further embodiments, the reservoir comprises a reservoir membrane forming a boundary of the reservoir volume, preferably, the reservoir membrane forms a bottom boundary and / or a side boundary of the reservoir volume, more preferably a bottom boundary. By forming a boundary to the reservoir volume, the reservoir membrane is preferably in direct contact with the cell culture liquid, when being inside the reservoir, such that the reservoir membrane can be used to perform a filtration process on the cell culture.

[0095] According to further embodiments, the reservoir membrane is configured for removing and / or adding liquid through the reservoir membrane but essentially retaining the cells within the reservoir volume and / or the reservoir volume and the main volume. Such configuration is particularly advantageous when performing a filtration process throughout culture, as it allows cells to be retained within the reservoir (and optionally casing) but remove liquid. By adding liquid through the membrane, the membrane may be backflushed, e.g. in alternating flow. Additionally, or alternatively, liquid may be added through a supply port, arranged on the retentate side, e.g., in the casing or reservoir.

[0096] According to further embodiments, the reservoir membrane is configured for cultivating the cells in the liquid medium via perfusion in the reservoir volume, and / or the reservoir volume and the main volume; and / or retaining the cells in the reservoir volume when removing a fluid from the reservoir volume and / or the main volume, such as when washing the cells in the reservoir volume, preferably configured for washing the cells in the reservoir volume.

[0097] Such embodiment is particularly advantageous, as the reservoir membrane allows for performing filtration processes at small scale, e.g. as may be required when low cell numbers are only present, such as for autologous cell therapy. In such an approach, the cells may need to undergo certain process steps, such as activation, transduction and / or transfection. Such process steps may advantageously be performed utilizing the reservoir membrane, wherein in a first step a certain agent may be provided to the reservoir comprising the cells, followed by incubation, followed by removal of liquid through the reservoir membrane. Thereby, the cells are retained, whereas the agent is removed. Afterwards washing steps may be performed and / or addition of cell culture medium for subsequent culture of the cells. Hence, the vessel allows for performing such complex processes inside the same vessel in which the expansion process is performed. Cells do not need to undergo transfer steps, as conventionally required for manufacture of a cell therapy product.

[0098] According to further embodiments, the reservoir comprises a plane bottom, in particular formed at least in part by the reservoir membrane. Adjacent to the membrane in such embodiment may be a support, that supports the membrane. Furthermore, a collection configuration may be provided that allowed for collecting the fluid passing through the membrane and advantageously allowing the fluid to exit, e.g. through a port.

[0099] According to further embodiments, the reservoir comprises a reservoir membrane, preferably, wherein the casing does not comprise the reservoir membrane.

[0100] According to further embodiments, the vessel is single-use and pre-sterilized such that the casing and the reservoir and the main volume and the reservoir volume are sterile. According to further embodiments, the casing comprises at least one sensor element for measuring a parameter or property of the cells and / or the fluid, such as the liquid medium, in the reservoir volume; and / or one or more sensor ports configured for allowing a sensor to be inserted.

[0101] According to further embodiments, the reservoir comprises at least one sensor element for measuring a parameter or property of the cells and / or the fluid, such as the liquid medium, in the reservoir volume; and / or one or more sensor ports configured for allowing a sensor to be inserted.

[0102] The term "sensor element" is known in the art and particularly refers to a transducer or probe, such as an electrode. The "sensor unit" is known in the art and particularly refers to a transmitter. The sensor element may be connected to the sensor either directly or as a separate unit connected to it. The connection can be also wireless. The sensor unit may be an external sensor unit, for example of the system.

[0103] The sensor(s) of the reservoir and / or casing can be either single-use or multiple use sensors and work as in-line or on-line measurement in direct fluidic connection to the fluid (such as liquid medium) and / or the cells. Further options are process near at-line or sample based off-line measurements without fluidic connection. The functionality differs with respect to the requested parameter and data between direct or soft-sensors measurement. Due to high sterility requirements single-use sensors are preferred and used in direct monitoring and control strategy of the respective bioprocess.

[0104] The term "sensor port" is known in the art and refers to the accessibility of the sensor to secure the contact of the sensor to the medium and / or cells within the vessel. The sensor port thereby forms a support structure for the one or more sensor elements and may be designed as separate part that can be integrated in the casing and / or reservoir of the vessel by molding, welding and / or as dip tube housing the sensor element.

[0105] According to another embodiment the "sensor port" supports spectroscopy measurements and therefore comprises a flow cell or is designed as spectroscopy port forming an integral part of the casing and / or the reservoir. The flow cell or spectroscopy port can be also located downstream of the cultivation vessel. According to further embodiments, the at least one sensor element is arranged upstream of the reservoir membrane, preferably above the reservoir membrane.

[0106] According to further embodiments, the at least one sensor element is arranged at a boundary of the reservoir volume, preferably arranged at a side boundary.

[0107] According to further embodiments, the at least one sensor element is arranged in or at a wall of the reservoir, preferably a side wall of the reservoir, preferably arranged at a side boundary of the reservoir volume.

[0108] According to further embodiments, the at least one sensor element is arranged at the retentate side of the reservoir volume.

[0109] According to further embodiments, the reservoir is a single molded piece; comprises a material that is optically transparent with a sensor element, in particular a dissolved oxygen sensor element and / or a pH sensor element mounted on the inside of the reservoir and readable through the reservoir; and / or comprises a reservoir wall that is thinned at a location of the sensor element.

[0110] An optical transparent material supports all opto-chemical measurements through the material ad is therefore suitable for pH and dissolved oxygen spots and / or other measurements with optical fibers involved. Sensor spots could be either pre-sterilized and already in place in in the casing or reservoir or protected by a coating that is harmless for the cells.

[0111] According to further embodiments, a further sensor element is arranged downstream of the reservoir membrane, preferably wherein such further sensor element is a flow sensor and / or pressure sensor.

[0112] According to another embodiment the at least one sensor element is based on the measurement principle of an opto-chemical sensor spot, preferably for pH and / or dissolved oxygen; electrochemical electrode, preferably for pH detection; a temperature sensor, preferably a Pt 1000 probe; impedance or capacitance measurement principles, preferably for biomass or viable cell density; and / or all type of spectroscopy principles like UV-Vis absorption, RAMAN, NIR / MIR and / or fluorescence preferably for metabolites or product titer. The sensor elements can be either single-use elements, e.g. sensor spots and / or a single use electrodes, or re-usable, e.g. temperature probes. In another embodiment the measurement principle is based on optical imaging preferably for cell counting, cell viability and / or detection of morphologic cell properties.

[0113] According to further embodiments, the vessel comprises a recirculation loop, preferably a tube loop leading from the vessel and to the vessel. According to a preferred embodiment, the recirculation loop is configured for analysis, including cell counting. For instance, the recirculation loop may comprise a sensor or system for counting cells. According to a preferred embodiment, the recirculation loop, preferably the tube loop, comprises at least one branch.

[0114] According to further embodiments, the vessel comprises one or more ports, preferably wherein the reservoir comprises at least one port. The one or more ports may be advantageously used to provide access points into and outside of the vessel. In one embodiment, the vessel comprises at least one supply port, at least one waste port, and at least one gas port. According to a particular embodiment, the vessel comprises one or two supply ports, two waste ports and one gas port.

[0115] According to further embodiments, the reservoir is configured to be heated.

[0116] According to further embodiments, the reservoir volume is at most 250 ml, preferably at most 150 ml or 120 ml; and / orthe main volume is at most 6 I, preferably at most 3 I or 2 I. Such volumes are particularly suitable for generating a cell therapy product, such as an autologous cell therapy product, wherein typically a low volume cell sample is expanded over time with increasing volume.

[0117] According to a further embodiment, the reservoir volume is at least 1 ml, preferably at least 5 ml, at least 10 ml, at least 15 ml, at least 20 ml, more preferably at least 25 ml or 30 ml. According to a further embodiment, the reservoir volume is selected from the range of 1 ml to 250 ml, preferably 5 ml to 225 ml, 10 ml to 200 ml, 15 ml to 175 ml, 20 ml to 150 ml, more preferably 25 ml to 150 ml or 25 ml to 120 ml.

[0118] According to a further embodiment, the main volume is at least 100 ml, preferably at least 200 ml, at least 300 ml, at least 400 ml, more preferably at least 500 ml. According to a further embodiment, the main volume is selected from the range of 100 ml to 6 I, preferably 200 ml to 5 I, 300 ml to 1, 400 ml to 3.5 I, more preferably 500 ml to 3 I or 500 ml to 2 I. According to a preferred embodiment, the vessel comprises a binding unit; and / or is fluidically connected to at least one a binding unit, wherein the binding unit comprises a binding matrix configured for allowing direct or indirect binding of a ligand expressed by at least a fraction of the cells. Such binding unit is particularly suitable for performing cell selection. In particular, by providing a binding unit, at least a fraction of the cells in the liquid medium may be sorted by expressing a ligand that binds to the binding matrix. Cells that do not express such ligand would not bind to the binding matrix. Such binding may be referred to as "direct" binding of the matrix to the ligand expressed in at least a fraction of the cells. Alternatively, one or more binding reagent(s) may be provided, which allows for "indirect" binding of the binding matrix to the ligand expressed in at least a fraction of the cells. In such case, the one or more binding reagent(s) usually bind to the ligand expressed by the cells, e.g. an antibody or antibody fragment capable of binding to the ligand expressed by the cells. The binding reagent then usually further comprises a moiety for binding to the binding matrix, e.g. biotin, avidin, streptavidin, such that the cells that express the ligand indirectly (i.e., via the binding reagent) bind to the binding matrix. When providing more than one binding reagent, a first binding reagent may bind to the ligand expressed by the cells, whereas the second binding reagent binds to the binding matrix and both, the first and second binding reagent bind to each other. Further configurations or chemistries may be applied, which achieve the desired outcome, i.e. direct or indirect binding of the cells expressing the ligand to the binding matrix. The skilled person is well-aware of suitable binding matrices and chemistries for allowing binding of a ligand expressed by at least a fraction of the cells.

[0119] The vessel may be fluidically connected to the vessel, wherein such fluidic connection may be provided in form of tubes. There may be more than one fluidic connection, such as preferably two fluidic connections, in particular at different sides or positions of the binding unit. For instance, there may be one fluidic connection from the vessel to the entrance of the binding unit and one fluidic connection from the exit of the binding unit to the vessel. Further fluidic connections may be present, which allow also fluid to be transferred through the binding unit into another container, e.g. waste container or storage container. The fluidic connect ion(s) between the vessel and the binding unit may be located at the casing and / or the reservoir of the vessel. Preferably, there is one fluidic connection between the reservoir and the binding unit and another fluidic connection between the casing and the binding unit. Other configurations are also possible, for instance, there may be two fluidic connections between the casing and the binding unit. Or, alternatively, two fluidic connections between the reservoir and the binding unit. After binding of the at least fraction of the cells, liquid medium present in the vessel can be removed, e.g. through the binding matrix or a fluidic line connected to vessel, and with the liquid the unbound cells (which then do not express the ligand). As a result, only cells expressing the ligand would remain in the vessel, i.e., a positive cell selection is performed. In orderto release the cells from the binding matrix, these may be eluted as commonly known in the art (e.g. by providing a release agent, such as salt, biotin, avidin or streptavidin). Eluted cells would then be released into the liquid medium present in the vessel. Preferably, the cells can be recirculated into the vessel, e.g. by pressing liquid through the binding unit which elutes the cells and then into a fluidic line connected to the vessel, such that the released cells recirculate into the cells. Afterwards, the binding unit may be closed or becomes inactive. The binding unit may also still be left "open", so in principle being accessible to the cells. However, no force or pressure is preferably applied towards the binding unit, such that the cells are not actively moved into the binding unit. The binding unit may also be closed, e.g., by closing a valve or a cover that closes the binding unit from the vessel.

[0120] Also, a negative cell selection step may be performed. For instance, after binding of the at least fraction of the cells, liquid medium present in the vessel can be removed, e.g. through the binding matrix or a fluidic line connected to vessel, and with the liquid the unbound cells (which then do not express the ligand). These unbound cells can then be collected, e.g. in a container. In order to release the cells from the binding matrix, these may be eluted as commonly known in the art. Eluted cells would then be released into the liquid medium present in the vessel and can then be removed through a waste port. Preferably, the cells can released from the binding unit, e.g. by pressing liquid through the binding unit which elutes the cells and then into a fluidic line connected to a waste container, such that the released cells are removed from the vessel. Afterwards, the collected cells may be recirculated back to the vessel.

[0121] According to some embodiments of the present disclosure more than one cell selection step is performed, such as at least two cell selection steps. These may comprise positive and / or negative cell selection, as disclosed herein.

[0122] According to a preferred embodiment, the binding matrix is provided as a resin or monolithic material. Various materials are known in the art for binding matrices. Particularly preferred may be a binding matrix which comprises resin beads. A binding matrix may be covered or enclosed by one or more membranes, which separates the cells from the binding matrix, as long as no force is applied that would drag the cells in contact with the binding matrix. According to a preferred embodiment, the binding unit is located within or adjacent to the reservoir of the vessel, preferably wherein the binding unit is arranged adjacent to the reservoir membrane. By providing the binding unit located within or adjacent to the reservoir, small volumes of cell culture or cell suspension can be handled. Specifically, the cells may be provided as a mixture of cells, which need to undergo a cell selection step utilizing the binding matrix. Since the cells are in such stage oftentimes present in low volume cell cultures, it is advantageous to provide the binding unit in the reservoir of the vessel, which can be advantageously used to handle and culture low volume cell cultures. In addition, the reservoir is pre-shaped, such that it is mechanically more stable than a reservoir that only shapes upon interaction with other devices throughout culture. Thus, the binding unit has then a fixed position, allowing for precise cell selection.

[0123] In the embodiments, wherein the binding unit is located within or adjacent to the reservoir of the vessel, the binding unit may be provided as a column, wherein the column is predominantly present internally, i.e., within the vessel, particularly within the reservoir, such that the column reaches into the reservoir volume. Such "internal column" configuration advantageously allows for the cells present in the cell vessel and reservoir, respectively, to be in direct connect with the column, such that no additional fluid transfer step is required. In such configuration, it may be advantageous to provide the binding matrix within the column covered by a membrane, such that the cells are not always in contact with the binding matrix in order to control the cell selection. As a result, the cells only interact with the binding matrix, once a force is put on the cells that drags them through the membrane into the column and thus in contact with the binding matrix. As a result, the cell selection is only occurring when such force is applied. According to one embodiment, an active element, e.g. a pump, is provided that manipulates the fluid in the vessel such that the fluid is dragged into the column. For instance, a pump may draw the fluid and with it the cells present in the fluid within the vessel into the column, such that the cells come in contact with the binding matrix, such that at least a fraction of the cells bind to the binding matrix. According to one embodiment, the binding unit further comprises a valve, which is configured for closing the fluid lines exiting the binding unit. This advantageously closes the binding matrix, such that cells are not dragged actively into the binding unit and this in contact with the binding matrix.

[0124] According to one preferred embodiment, the binding unit is provided as a column, preferably the opening of the column is arranged within an opening of the reservoir, more preferably an opening at the bottom of the reservoir. This has the advantage that the column can be used as known in the art for cell selection columns, however, as implementation of the cell vessel, such that cell selection can be performed with the same vessel, in which cell culture can take place, as well as preferably cell activation, cell transduction, cell transfection, media exchange, and / or volume reduction. Hence, relevant steps for manufacture of a cell therapy product can be performed within the same vessel, significantly simplifying the process.

[0125] Additionally or alternatively, the binding unit is provided as a column which is fluidically connected to the vessel, preferably the reservoir, wherein fluidic connections between the vessel and the column are provided, in particular wherein the fluidic connections are provided by one or more tubes, optionally further comprising a valve. Fluidically connecting the column and the reservoir has the advantage that the binding unit is separate from the vessel allowing for separate control. At the same time both are usually in close proximity, such that for instance a temperature control would effectively heat the vessel and the column, which is advantageous for maintaining high cell viability. Optionally, the fluidic connection, such as one or more tubes further comprise a valve. This has the advantage that the fluidic connection between the binding unit (in particular column) and the vessel (in particular reservoir) can be closed, which can be done subsequent to the cell selection.

[0126] Providing the binding unit as a column as disclosed herein the term "column'' shall not be limited in any specific geometry, as is known in the art. While typically columns may be provided in a pillar or column shape, also other shapes are known in the field. A column herein may also refer to a bag-like shape, wherein two or more walls are connected forming a casing. As typically casings who have a bag-like shape are flexible, such column configuration may also be referred to as "flexible column".

[0127] According to a preferred embodiment, the binding unit comprises a flexible column, comprising a casing, an entrance port and an exit port, wherein the casing comprises the binding matrix. The flexible column may further comprise two membranes, which confine the casing volume in which the binding matrix is present, e.g. one membrane at the entrance and one membrane at the exit of the flexible column. The flexible column may be fluidically connected to the vessel, wherein preferably such connection comprises valve to controlling the fluid flow between the vessel and the flexible column.

[0128] According to another preferred embodiment, the binding unit is provided as a floating unit configured for float within the reservoir volume and / or the main volume. When providing the binding unit as a floating unit, this may be provided in form of a pouch, which can float within a fluid of the vessel. Such floating unit is typically connected via fluidic line(s) going through the vessel to the outside. Hence, the floating unit can float but within a certain range limited to the length of the fluidic line(s). A floating unit has the advantage that it is present within the vessel, such that contact between the floating unit and the cells within the vessel is enabled. In order to achieve interaction between the cells and the binding matrix of the binding unit, the cells may be forced or pushed into the floating binding unit by overpressure within the vessel and / or under pressure within the binding unit, e.g. created by the fluidic line(s). Bound cells can then, as explained above, be retained within the binding matrix, whereas unbound cells exit the binding unit through the fluidic line(s).

[0129] According to a preferred embodiment, the binding unit is by an external loop fluidically connected to the vessel, particularly the reservoir, and / or a waste port, preferably both. By providing an external loop it is possible to recirculate the cells though the binding unit into the vessel, particularly the reservoir, and thus the vessel again. This has the advantage that cells can undergo multiple rounds of binding to achieve binding of as many cells as possible expressing the ligand that binds to the binding matrix. Furthermore, this has the advantage that cells that bind to the binding matrix and are subsequently eluted, can exit the binding unit and be recirculated into the cell vessel, in particular into the reservoir. Furthermore, by connecting the binding unit to a waste port, it is possible to transfer the unbound cells into a waste container.

[0130] According to a preferred embodiment, the external loop comprises at least one valve, preferably one valve for controlling the fluid flow between the binding unit and the waste port and another valve controlled the fluid flow between the vessel, e.g. reservoir, and the waste port, preferably wherein both valves are for controlling the fluid flow between the binding unit and the vessel, e.g. reservoir, via the external loop. By providing the valves, the fluid flow can be controlled, allowing for fluid flow into a waste container and / or recirculation into the vessel, particularly into the reservoir.

[0131] Swapping, refilling, and emptying

[0132] According to a preferred embodiment, the bioprocessing system is configured for allowing swapping of: the media container for a second media container, the waste container for a second waste container, and / or the life support container containing the media container and / or the waste container for a second life support container containing the second media container and / or a second waste container, preferably, wherein swapping is performed manually or automatically, more preferably wherein swapping is performed manually.

[0133] According to a preferred embodiment, the bioprocessing system is configured for allowing swapping during a cell culture cycle, in particular automatically in a swapping routine by the bioprocessing system.

[0134] According to a preferred embodiment, the bioprocessing system is configured for performing one or both of the following operations in an automated manner: a refill routine, preferably wherein the bioprocessing system automatically connects a refill container comprising a liquid medium to the media container and automatically refills the media container with the liquid medium and preferably automatically disconnects the refill container from the media container, optionally during a cell culture cycle; and an emptying routine, preferably wherein the bioprocessing system automatically connects a further waste container to the waste container and automatically empties the waste container from the waste and preferably automatically disconnects the further waste container from the waste container, optionally during a cell culture cycle.

[0135] According to a preferred embodiment, the bioprocessing system, preferably the framework of the bioprocessing system, comprises a refill location, at which a refill routine can be performed; an emptying location, at which an emptying routine can be performed; and / or a swapping location, at which a swapping operation can be performed, preferably wherein the bioprocessing system performs the swapping and / or at the swapping location the swapping is performed manually. optionally, wherein the bioprocessing system preferably the framework of the bioprocessing system, comprises the refill location and the emptying location, both of which have the same location.

[0136] Expansion locations

[0137] According to a preferred embodiment, the bioprocessing system, preferably the framework of the bioprocessing system, comprises at least one expansion location, preferably several expansion locations.

[0138] According to a preferred embodiment, the framework of the bioprocessing system comprises several expansion locations, wherein the expansion locations are placed vertically, more preferably, that the expansion locations are compartments in a shelf with one or more vertical columns.

[0139] According to a preferred embodiment, the bioprocess comprises expanding the cells or the cell culture, preferably wherein expanding the cells is performed predominantly at an expansion location of the bioprocessing system.

[0140] According to a preferred embodiment, the cell expansion location(s) is / are outside a swapping location, an emptying location and / or a swapping location.

[0141] Connection arrangement

[0142] According to a preferred embodiment, the bioprocessing system, preferably the framework of the bioprocessing system, comprises a connection arrangement configured for aseptically connecting and / or disconnecting one or more, preferably all, of the following the media container and the cell vessel, the media container and the refill container, and the waste container and the cell vessel, preferably, that the connection arrangement comprises a tube welding unit for welding together and / or cutting and closing off one or more tubes connected to the media container and the cell vessel, and preferably the waste container and the cell vessel.

[0143] According to a preferred embodiment, the connection arrangement is movable, preferably movable in an automated manner, wherein the connection arrangement can be moved to be located at the swapping location, at the refill location, and / or at the emptying location. By being movable, the connection arrangement, e.g. tube welder can advantageously move the respective positions in order to perform a connection and / or disconnection.

[0144] According to a preferred embodiment, the bioreactor module, in particular the life support tray, comprises at least one tube holder configured for holding at least one tube, preferably for holding at least one tube in a defined position relative to the support structure and / or the life support container.

[0145] According to a preferred embodiment, the tube holder comprises a tube mover mechanism for extending and / or retracting the at least one tube relative to the tube holder. According to a preferred embodiment, a connection arrangement, preferably a tube welding unit, interacts with the tube holder to weld and / or cut and seal the at least one tube.

[0146] Further features of the bioprocessing system

[0147] According to a preferred embodiment, the bioreactor module further comprises a lid for providing a controlled environment for the cell vessel; and / or a heating unit for the cell vessel.

[0148] According to a preferred embodiment, the framework comprises a unit operation location, in particular next to a swapping location or a refill location, preferably wherein at the unit operation location the cell culture is transferred from a cell container of a cartridge into the cell vessel.

[0149] According to a preferred embodiment, the cell culture is an immune or naive cell culture. The term "immune cells" is well known in the art and the skilled person is well-aware and understands the term "immune cells". Immune cells generally refer to types of white blood cells. Any type of white blood cells may be used here. Combinations of different types are also conceivable. According to a preferred embodiment, however, the term "immune cells" herein refers to a single type of cells, e.g. T-cells or subtypes thereof, or NK-cells or subtypes thereof. Hence, the term "immune cells" includes a variety of cells, for example, but not limited to dendritic cells, T lymphocytes, also referred to as T cells, B lymphocytes, natural killer cells, macrophages or the like. Immune cells may also include subtypes of immune cells, for example tumor-infiltrating lymphocytes or different types of T cells. Subtypes of a certain type of immune cells may be classified based on the type of antigen present at the cell surface. Hence, the term immune cells may for example refer to T cells comprising the surface antigen CD4 ("CD4+ T cells").

[0150] According to a preferred embodiment, the bioreactor module is adapted to be used for at least one cell culture cycle.

[0151] According to a preferred embodiment, in the cell vessel area a cell vessel comprising an individual cell culture can be located.

[0152] According to a preferred embodiment, during the cell culture cycle the cell vessel area is used for only a single individual cell culture. Bioreactor module according to a second aspect of the invention

[0153] According to a second aspect of the invention, a bioreactor module for performing a bioprocess on a cell culture is provided, comprising: a cell vessel area, wherein in the cell vessel area a cell vessel can be located, and a media supply area, wherein in the media supply area a media container can be located; wherein the bioreactor module including the cell vessel and the media container is adapted to be automatically transported by a transport mechanism.

[0154] The bioreactor module according to the second aspect advantageously allows for adding media to the cell vessel whenever necessary without having to move the cell vessel to a media station or the like and without having to be able to connect the cell vessel to a media container at an expansion location. To make the handling of the bioreactor module simpler, not all needed media are transported together with the cell vessel. Instead, the medium is replenished, either by refilling the media container or by adding a new media container. As such, the complexity and size of the bioreactor module are reduced. If the medium needs certain storage conditions, it may be possible to refill the media container often enough to eliminate the need for providing these storage conditions at the media supply area.

[0155] The individual features and preferred embodiments of the bioreactor according to the second aspect correspond to the individual features and embodiments of the bioprocessing system according to the first aspect insofar as these directly or indirectly relate to the (exchangeable) bioreactor module. Therefore, it is referred to the above disclosure which shall equally be applicable to the bioreactor module according to the second aspect. This particularly but not exclusively includes the bioprocessing system features, swapping, refilling, and emptying, the cell vessel, etc. Further features will now be described in detail.

[0156] According to one preferred embodiment, the bioreactor module further comprises a cell vessel located in the cell vessel area, a media container located in the media supply area, optionally a waste container located in a waste area.

[0157] Preferably in such embodiment, the bioreactor module may not comprise a life support area. Alternatively, the bioreactor module comprises a life support area, which comprises the media supply area and the waste area.

[0158] According to another preferred embodiment, the bioreactor module further comprises a cell vessel located in the cell vessel area, a life support container located in a life support area.

[0159] Preferably, in such embodiment, the life support area overlaps or comprises the media supply area.

[0160] According to a preferred embodiment, the cell vessel and the media container are fluidically connected, optionally, wherein the cell vessel and the waste container are fluidically connected.

[0161] According to a preferred embodiment, the bioreactor module further comprises a support structure, wherein due to the support structure the bioreactor module can be handled as a unit, in particular due to the support structure the bioreactor module can be automatically transported by a transport mechanism.

[0162] According to a preferred embodiment, due to the support structure the bioreactor module can be handled as a unit together with the cell vessel, the media container and, optionally, a waste container.

[0163] According to a preferred embodiment, the support structure of the bioreactor module comprises a life support area in which a life support container, in particular a life support tray, can be placed.

[0164] According to a preferred embodiment, the life support area comprises the media supply area and / or the waste area, preferably wherein the media supply area is the same area as or a different area than the waste area on the life support area, more preferably wherein the media supply area is the same area as the waste area.

[0165] According to a preferred embodiment, the life support area comprises the media supply area and / or the waste area such that the life support container contains a media container and / or a waste container.

[0166] According to a preferred embodiment, the support structure further comprises a rocking unit for rocking the cell vessel.

[0167] According to a preferred embodiment, the support structure further comprises a balance for weighing a life support tray.

[0168] According to a preferred embodiment, the balance weighs the life support tray: before a transfer of a liquid medium from the media supply area to the cell vessel, after a transfer of a liquid medium from the media supply area to the cell vessel, during a transfer of a liquid medium from the media supply area to the cell vessel, before a transfer of a liquid from the cell vessel to the waste area, after a transfer of a liquid from the cell vessel to the waste area, and / or during a transfer of a liquid from the cell vessel to the waste area, to determine and / or control an amount of transferred liquid medium.

[0169] In a further embodiment, the support structure further comprises a balance for weighing a media container. Hence, the balance may weigh the media container: before a transfer of a liquid medium from the media supply area to the cell vessel, after a transfer of a liquid medium from the media supply area to the cell vessel, and / or during a transfer of a liquid medium from the media supply area to the cell vessel to determine and / or control an amount of transferred liquid medium. Liquid may encompass cell culture media liquid.

[0170] In a further embodiment, the support structure further comprises a balance for weighing a waste container. Hence, the balance may weigh the waste container: before a transfer of a liquid from the cell vessel to the waste area, after a transfer of a liquid from the cell vessel to the waste area, and / or during a transfer of a liquid from the cell vessel to the waste area to determine and / or control an amount of transferred liquid medium. Liquid may encompass waste liquid.

[0171] In a further embodiment, the support structure further comprises a balance for weighing a cell vessel. For instance, the balance may be located at the cell vessel area, such that the cell vessel may be weighed during any liquid transfer to determine and / or control an amount of transferred liquid medium.

[0172] According to a preferred embodiment, the bioreactor module, in particular the life support tray, comprises at least one tube holder configured for holding at least one tube, preferably for holding at least one tube in a defined position relative to the support structure and / or the life support container.

[0173] According to a preferred embodiment, the tube holder comprises a tube mover mechanism for extending and / or retracting the at least one tube relative to the tube holder. According to a preferred embodiment, the bioreactor module further comprises a receiving interface with a connection for receiving electrical energy; a connection for receiving wire-bound signals; a connection for receiving gas; and / or a connection for a sensor, such as an optical sensor.

[0174] According to a preferred embodiment, the receiving interface is connectable to the providing interface of a framework, e.g. of a bioreactor system.

[0175] According to a preferred embodiment, the cell vessel provides a volume for at least supporting cell cultures with volumes between 100 ml and 500 ml, preferably between 50 ml and 750 ml.

[0176] According to a preferred embodiment, the cell vessel has a volume of at most 6 I, preferably at most 3 I or 2 I.

[0177] According to a preferred embodiment, the bioreactor module further comprises a lid for providing a controlled environment for the cell vessel; and / or a heating unit for the cell vessel.

[0178] According to a preferred embodiment, the cell culture is an immune or naive cell culture.

[0179] According to a preferred embodiment, the bioreactor module is adapted to be used for at least one cell culture cycle.

[0180] According to a preferred embodiment, wherein in the cell vessel area a cell vessel comprising an individual cell culture can be located.

[0181] According to a preferred embodiment, during the cell culture cycle the cell vessel area is used for only a single individual cell culture. Method for performing a bioprocess on a cell culture according to a third aspect of the invention

[0182] According to a third aspect of the invention, a method for performing a bioprocess on a cell culture is provided, wherein the method comprises: a) providing a. a cell culture, preferably an immune or naive cell culture; b. a bioreactor module (2) according to the present invention and / or a bioprocessing system according to the present invention; c. a cell vessel; d. a media container; and e. optionally, a waste container, preferably, wherein a life support container is provided comprising the media container and the waste container; b) optionally, transferring the cell culture into the cell vessel; and c) expanding the cell culture in the cell vessel, located in the cell vessel area, preferably wherein expanding involves transferring liquid medium of the media container into the cell vessel.

[0183] The method according to the third aspect advantageously allows for performing a bioprocess on a cell culture in a simplified and efficient manner. The individual steps and preferred embodiments of the method according to the third aspect correspond to the individual features and embodiments of the bioprocessing system according to the first aspect and the bioreactor module according to the second aspect insofa ras a ppi icable. Therefore, it is referred to the above disclosure which shall equally be applicable to the method according to the third aspect. This particularly but not exclusively includes the bioprocessing system features, swapping, refilling, and emptying, the cell vessel, etc. Further features will now be described in detail.

[0184] According to a preferred embodiment, the method further comprises removing liquid from the cell vessel into the waste container.

[0185] According to a preferred embodiment, the method comprises automatically transporting the bioreactor module between different positions, preferably between an expansion location and at least one further position, which can be the refill location, the emptying location, and / or the swapping location. According to a preferred embodiment, the method has one or more of the following characteristics: the cell vessel comprises an individual cell culture; the bioreactor module is used forat least one cell culture cycle in which a cell vessel is located at the cell vessel area and an individual cell culture is located in the cell vessel, wherein during the cell culture cycle the cell vessel area is used for only a single individual cell culture; during a cell culture cycle a first media container containing a first liquid medium is located in the media supply area and connected to the cell vessel and the first liquid medium is provided to the cell vessel; and / or during a cell culture cycle a first liquid medium is replenished by a second liquid medium and the second liquid medium is provided to the cell vessel.

[0186] According to a preferred embodiment, the bioreactor module including the cell vessel and the media container is automatically transported by a transport mechanism of the bioprocessing system.

[0187] According to a preferred embodiment, the cell culture is an immune or naive cell culture, preferably wherein the cell culture comprises T cells.

[0188] Method for manufacturing a cell therapy product according to a fourth aspect of the invention

[0189] According to a fourth aspect of the invention, a method for manufacturing a cell therapy product is provided, wherein the method comprises: a) providing a. a cell culture, preferably an immune or naive cell culture; b. a bioreactor module according to the present invention and / or a bioprocessing system according to the present invention; c. a cell vessel; d. a media container; and e. optionally, a waste container, preferably, wherein a life support container is provided comprising the media container and the waste container; b) transferring the cell culture into the cell vessel; and c) expanding the cell culture in the cell vessel, located in the cell vessel area, preferably wherein expanding involves transferring liquid medium of the media container into the cell vessel, for manufacturing a cell therapy product. The method according to the fourth aspect advantageously allows for manufacturing a cell therapy product in a simplified and efficient manner. The individual steps and preferred embodiments of the method according to the fourth aspect correspond to the individual features and embodiments of the other aspects of the invention insofar as applicable. Therefore, it is referred to the above disclosure which shall equally be applicable to the method according to the fourth aspect. This particularly but not exclusively includes the bioprocessing system features, swapping, refilling, and emptying, the cell vessel, etc. Further features will now be described in detail.

[0190] According to a preferred embodiment, the cell culture is an immune or naive cell culture, preferably wherein the cell culture comprises T cells.

[0191] According to a preferred embodiment, the method further comprises one or more of the following steps: activating cells, preferably activating T cells; transducing cells, preferably transducing T cells; transfecting cells, preferably transfecting T cells; and / or expanding cells, preferably T cells, more preferably genetically modified T cells; preferably, wherein the method comprises at least two or three of the above-mentioned steps.

[0192] According to a preferred embodiment, the method comprises after step b) but before step c): i. activating cells, preferably activating T cells; and ii. transducing cells, preferably transducing T cells, or transfecting cells, preferably transfecting T cells.

[0193] According to a preferred embodiment, the method further comprises after step c) formulating the expanded cell culture into a media suitable for being injected into a patient and / or transferring the expanded cell culture from the cell vessel into a harvesting vessel.

[0194] Uses according to a fifth and sixth aspect of the invention

[0195] According to a fifth aspect of the invention, a use of the bioreactor module disclosed herein and / or the bioprocessing system disclosed herein for manufacturing a cell therapy product is provided. Preferably wherein the manufacturing comprises at least one of the following: activating cells, preferably activating T cells; transducing cells, preferably transducing T cells; transfecting cells, preferably transfecting T cells; and / or expanding cells, preferably T cells, more preferably genetically modified T cells.

[0196] According to a sixth aspect of the invention, a use of the bioreactor module disclosed herein and / or the bioprocessing system disclosed herein in a method disclosed herein is provided.

[0197] The uses according to the fifth and sixth aspect advantageously allows for cell culture and manufacturing a cell therapy product in a simplified and efficient manner. The individual features and preferred embodiments of the uses correspond to the individual features and embodiments of the other aspects of the invention insofar as applicable. Therefore, it is referred to the above disclosure which shall equally be applicable to the uses. This particularly but not exclusively includes the bioprocessing system features, swapping, refilling, and emptying, the cell vessel, etc. Further features will now be described in detail.

[0198] Further aspects of the invention

[0199] According to a further aspect of the invention, an expanded cell culture is provided obtained by the method disclosed herein.

[0200] According to a further aspect of the invention, a cell therapy product is provided obtained by the method disclosed herein.

[0201] The expanded cell culture and the cell therapy product according to the further aspects advantageously utilize the methods to obtain a product accordingly. Hence, the individual features and preferred embodiments of these aspects correspond to the individual features and embodiments of the methods of the invention. Therefore, it is referred to the above disclosure which shall equally be applicable. This particularly but not exclusively includes the bioprocessing system features, swapping, refilling, and emptying, the cell vessel, etc. Further features will now be described in detail.

[0202] Further embodiments of the present disclosure

[0203] The following embodiments provide further advantages of the present disclosure: 1. A bioprocessing system for performing a bioprocess on a cell culture, wherein the bioprocessing system (1) comprises: i. at least one exchangeable bioreactor module (2) comprising a cell vessel area (4), wherein in the cell vessel area (4) a cell vessel (6) can be located, and a media supply area (5), wherein in the media supply area (5) a media container (7) can be located; ii. a framework (3), and iii. a transport mechanism (8) for automatically transporting the bioreactor module (2).

[0204] 2. The bioprocessing system according to embodiment 1, wherein the transport mechanism (8) is configured to automatically transfer the bioreactor module (2) between different positions, preferably between an expansion location (9) and at least one further position, which can be the refill location (16, 18), the emptying location (16, 18), and / or the swapping location (16, 18).

[0205] 3. The bioprocessing system according to embodiment 1 or 2, wherein the transport mechanism (8) comprises a transport element that is adapted to hold a bioreactor module (2) and movable in at least one direction, preferably at least one linear direction, such as vertically.

[0206] 4. The bioprocessing system according to embodiment 2 or 3, wherein the transport mechanism (8) further comprises a further transport element for pushing the bioreactor module (2) into the expansion location (9) and / or for retrieving the bioreactor module (2) from the expansion location (9).

[0207] 5. The bioprocessing system according to one or more of embodiments 1 to 4, wherein the bioreactor module (2) further comprises a support structure (10), wherein due to the support structure (10) the bioreactor module (2) can be handled as a unit, in particular due to the support structure (10) the bioreactor module (2) can be automatically transported by the transport mechanism (8).

[0208] 6. The bioprocessing system according to embodiment 5, wherein due to the support structure (10) the bioreactor module (2) can be handled as a unit together with the cell vessel (6), the media container (7) and, optionally, a waste container (12).

[0209] 7. The bioprocessing system according to embodiment 5 or 6, wherein the support structure (10) of the bioreactor module (2) comprises a life support area (13) in which a life support container (14), in particular a life support tray (15), can be placed.

[0210] 8. The bioprocessing system according to one or more of embodiments 1 to 7, wherein the bioprocessing system further comprises (I) a cell vessel (6) located in the cell vessel area (4), a media container (7) located in the media supply area (5), and optionally a waste container (12) located in a waste area (11); or

[0211] (II) a cell vessel (6) located in the cell vessel area (4), a life support container (14) located in a life support area (13).

[0212] 9. The bioprocessing system according to embodiment 7 or 8, wherein the life support area (13) comprises the media supply area (5) and / or the waste area (11), preferably wherein the media supply area (5) is the same area as or a different area than the waste area (11) on the life support area, more preferably wherein the media supply area (5) is the same area as the waste area (11).

[0213] 10. The bioprocessing system according to one or more of embodiments 7 to 9, wherein the life support area (13) comprises the media supply area (5) and / or the waste area (11) such that the life support container (14) contains a media container (7) and / or a waste container (12).

[0214] 11. The bioprocessing system according to one or more of embodiments 5 to 10, wherein the support structure (10) further comprises a rocking unit (26) for rocking the cell vessel (6).

[0215] 12. The bioprocessing system according to one or more of embodiments 5 to 11, wherein the support structure (10) further comprises a balance for weighing a life support tray (15).

[0216] 13. The bioprocessing system according to embodiment 12, wherein the balance weighs the life support tray (15): before a transfer of a liquid medium from the media supply area (5) to the cell vessel (6), after a transfer of a liquid medium from the media supply area (5) to the cell vessel (6), during a transfer of a liquid medium from the media supply area (5) to the cell vessel (6), before a transfer of a liquid from the cell vessel (6) to the waste area (11), after a transfer of a liquid from the cell vessel (6) to the waste area (11), and / or during a transfer of a liquid from the cell vessel (6) to the waste area (11), to determine and / or control an amount of transferred liquid medium.

[0217] 14. The bioprocessing system according to one or more of embodiments 1 to 13, wherein the bioprocessing system is configured for allowing swapping during a cell culture cycle, in particular automatically in a swapping routine by the bioprocessing system (1).

[0218] 15. The bioprocessing system according to one or more of embodiments 1 to 14, wherein the bioprocessing system is configured for allowing swapping of: the media container (7) for a second media container (7), the waste container (12) for a second waste container (12), and / or the life support container (14) containing the media container (7) and / or the waste container (12) for a second life support container (14) containing the second media container (7) and / or a second waste container (12), preferably, wherein swapping is performed manually or automatically, more preferably wherein swapping is performed manually.

[0219] 16. The bioprocessing system according to one or more of embodiments 1 to 15, wherein the bioprocessing system is configured for performing one or both of the following operations in an automated manner: a refill routine, preferably wherein the bioprocessing system (1) automatically connects a refill container (17) comprising a liquid medium to the media container (7) and automatically refills the media container (7) with the liquid medium and preferably automatically disconnects the refill container (17) from the media container (7), optionally during a cell culture cycle; and an emptying routine, preferably wherein the bioprocessing system (1) automatically connects a further waste container to the waste container (12) and automatically empties the waste container (12) from the waste and preferably automatically disconnects the further waste container from the waste container (12), optionally during a cell culture cycle.

[0220] 17. The bioprocessing system according to one or more of embodiments 1 to 16, wherein the bioprocessing system, preferably the framework (3) of the bioprocessing system, comprises a refill location (16, 18), at which a refill routine can be performed; an emptying location (16, 18), at which an emptying routine can be performed; and / or a swapping location (16, 18), at which a swapping operation can be performed, preferably wherein the bioprocessing system (1) performs the swapping and / or at the swapping location (16, 18) the swapping is performed manually; optionally, wherein the bioprocessing system preferably the framework (3) of the bioprocessing system, comprises the refill location (16, 18) and the emptying location (16, 18), both of which have the same location.

[0221] 18. The bioprocessing system according to one or more of embodiments 1 to 17, wherein the bioprocessing system, preferably the framework (3) of the bioprocessing system, comprises at least one expansion location, preferably several expansion locations.

[0222] 19. The bioprocessing system according to embodiment 18, wherein the framework (3) of the bioprocessing system comprises several expansion locations, wherein the expansion locations (9) are placed vertically, more preferably, the expansion locations (9) are compartments in a shelf with one or more vertical columns.

[0223] 20. The bioprocessing system according to one or more of embodiments 1 to 19, wherein the bioprocess com prises expanding the cells or the cell culture, preferably wherein expanding the cells is performed predominantly at an expansion location (9) of the bioprocessing system (1).

[0224] 21. The bioprocessing system according to one or more of embodiments 18 to 20, wherein the cell expansion location(s) (9) is / are outside a swapping location (16, 18), an emptying location (16, 18) and / or a swapping location (16, 18).

[0225] 22. The bioprocessing system according to one or more of embodiments 1 to 21, wherein the bioprocessing system, preferably the framework (3) of the bioprocessing system, comprises a connection arrangement (19) configured for aseptically connecting and / or disconnecting one or more, preferably all, of the following the media container (7) and the cell vessel (6), the media container (7) and the refill container (17), and the waste container (12) and the cell vessel (6), preferably, the connection arrangement (19) comprises a tube welding unit (20) for welding together and / or cutting and closing off one or more tubes connected to the media container (7) and the cell vessel (6), and preferably the waste container (12) and the cell vessel (6).

[0226] 23. The bioprocessing system according to embodiment 22, wherein the connection arrangement (19) is movable, preferably movable in an automated manner, wherein the connection arrangement can be moved to be located at the swapping location (16, 18), at the refill location (16, 18), and / or at the emptying location (16, 18).

[0227] 24. The bioprocessing system according to one or more of embodiments 1 to 23, wherein the bioreactor module (2), in particular the life support tray (15), comprises at least one tube holder (22) configured for holding at least one tube, preferably for holding at least one tube in a defined position relative to the support structure (10) and / or the life support container (14).

[0228] 25. The bioprocessing system according to embodiment 24, wherein the tube holder (22) comprises a tube mover mechanism for extending and / or retracting the at least one tube relative to the tube holder (22).

[0229] 26. The bioprocessing system according to embodiment 24 or 25, wherein a connection arrangement (19), preferably a tube welding unit (20), interacts with the tube holder (22) to weld and / or cut and seal the at least one tube. The bioprocessing system according to one or more of embodiments 1 to 26, wherein the bioreactor module (2) comprises a receiving interface (24) with a connection for receiving electrical energy; a connection for receiving wire-bound signals; a connection for receiving gas; and / or a connection for a sensor, such as an optical sensor. The bioprocessing system according to one to more of embodiments 1 to 27, wherein the framework (3) comprises providing interfaces (25) providing electrical energy; wire-bound signals; gas; a sensor connection, such as an optical sensor connection, preferably at different locations, in particular at the swapping location (16, 18), at the expansion location (9), at the refill location (16, 18), and / or at the emptying location (16, 18). The bioprocessing system according to embodiment 27 or 28, wherein the receiving interface (24) is connectable to the providing interface (25) of the framework (3). The bioprocessing system according to one or more of embodiments 1 to 29, wherein the cell vessel (6) provides a volume for at least supporting cell cultures with volumes between 100 ml and 500 ml, preferably between 50 ml and 750 ml. The bioprocessing system according to one or more of embodiments 1 to 30, wherein the cell vessel (6) has a volume of at most 6 I, preferably at most 3 I or 2 I. The bioprocessing system according to one or more of embodiments 1 to 31, wherein the bioreactor module (2) further comprises a lid (27) for providing a controlled environment for the cell vessel (6); and / or a heating unit for the cell vessel (6). The bioprocessing system according to one or more of embodiments 1 to 32, wherein the framework (3) comprises a unit operation location (28), in particular next to a swapping location (16, 18) or a refill location (16, 18), preferably wherein at the unit operation location (28) the cell culture is transferred from a cell container of a cartridge into the cell vessel (6). The bioprocessing system according to one or more of embodiments 1 to 33, wherein the cell culture is an immune or naive cell culture. The bioprocessing system according to one or more of embodiments 1 to 34, wherein the bioreactor module is adapted to be used for at least one cell culture cycle. The bioprocessing system according to one or more of embodiments 1 to 35, wherein in the cell vessel area (4) a cell vessel (6) comprising an individual cell culture can be located. The bioprocessing system according to one or more of embodiments 1 to 36, wherein during the cell culture cycle the cell vessel area (4) is used for only a single individual cell culture. The bioprocessing system according to one or more of embodiments 1 to 37, wherein the cell vessel comprises a casing defining a main volume, and a reservoir defining a reservoir volume, wherein the reservoir volume and the main volume are adjacently arranged and are configured to be fluidically connected for fluidic exchange, characterized in that the reservoir is a pre-shaped reservoir. The bioprocessing system according to embodiment 38, wherein the casing comprises a casing part, preferably two or more casing parts, such as an upper casing part and a lower casing part. The bioprocessing system according to embodiment 38 or 39, wherein the reservoir is attached to the casing, preferably to a casing part, more preferably a lower casing part, or the reservoir is formed integrally with the casing, preferably with a casing part, more preferably with a lower casing part. The bioprocessing system according to one or more of embodiments 38 to 40, wherein the cell vessel comprises at least one filter; and / or is fluidically connected to at least one filter, preferably, wherein the filter is configured to allow liquid to flow through but essentially retain cells. The bioprocessing system according to embodiment 41, wherein the at least one filter comprises a filter medium selected from a surface filter and a depth filter. The bioprocessing system according to embodiment 41 or 42, wherein the at least one filter is a membrane, such as a planar membrane, a hollow fiber membrane and / or floating membrane. The bioprocessing system according to one or more of embodiments 41 to 43, wherein the at least one filter comprises a main membrane, and / or a reservoir membrane; preferably both of a main membrane and a reservoir membrane. The bioprocessing system according to embodiment 44, wherein the main membrane is arranged at the casing, preferably at a casing part, more preferably at the lower casing part; and / or is fluidically connected to the casing, preferably wherein fluidic connections between the casing and the main membrane are provided, in particular wherein the fluidic connections are provided by one or more tubes. The bioprocessing system according to embodiment 44 or 45, wherein the main membrane surrounds the reservoir, is adjacent to the reservoir and / or floats within the main volume, preferably wherein the main membrane is adjacent to the reservoir. The bioprocessing system according to one or more of embodiments 44 to 46, wherein the main membrane is configured for removing and / or adding liquid through the main membrane but essentially retaining the cells within the main volume or preferably, within the main volume and the reservoir volume. The bioprocessing system according to one or more of embodiments 44 to 47, wherein the main membrane is configured for cultivating the cells in the liquid medium via perfusion in the main volume or preferably, in the main volume and the reservoir volume. The bioprocessing system according to one or more of embodiments 44 to 48, wherein the reservoir membrane is arranged at the reservoir, preferably the reservoir comprises the reservoir membrane, and / or is fluidically connected to the reservoir, preferably wherein fluidic connections between the reservoir and the membrane are provided, more preferably wherein the fluidic connections are provided by one or more tubes. The bioprocessing system according to one or more of embodiments 44 to 49, wherein the reservoir comprises a reservoir membrane forming a boundary of the reservoir volume, preferably, the reservoir membrane forms a bottom boundary and / or a side boundary of the reservoir volume, more preferably a bottom boundary. The bioprocessing system according to one or more of embodiments 44 to 50, wherein the reservoir membrane is configured for removing and / or adding liquid through the reservoir membrane but essentially retaining the cells within the reservoir volume and / or the reservoir volume and the main volume. The bioprocessing system according to embodiment 51, wherein the reservoir membrane is configured for cultivating the cells in the liquid medium via perfusion in the reservoir volume, and / or the reservoir volume and the main volume; and / or retaining the cells in the reservoir volume when removing a fluid from the reservoir volume and / or the main volume, such as when washing the cells in the reservoir volume, preferably configured for washing the cells in the reservoir volume.

[0230] 53. The bioprocessing system according to one or more of embodiments 38 to 52, wherein the reservoir comprises a plane bottom, in particular formed at least in part by the reservoir membrane.

[0231] 54. The bioprocessing system according to one or more of embodiments 38 to 53, wherein the cell vessel is single-use and pre-sterilized such that the casing and the reservoir and the main volume and the reservoir volume are sterile.

[0232] 55. The bioprocessing system according to one or more of embodiments 38 to 54, wherein the reservoir comprises at least one sensor element for measuring at least one parameter of the cells and / or the fluid, such as the liquid medium, in the reservoir volume; and / or one or more sensor ports configured for allowing a sensor to be inserted.

[0233] 56. The bioprocessing system according to embodiment 55, wherein the at least one sensor element is arranged upstream of the reservoir membrane, preferably above the reservoir membrane.

[0234] 57. The bioprocessing system according to embodiment 55 or 56, wherein the at least one sensor element is arranged at a boundary of the reservoir volume, preferably arranged at a side boundary.

[0235] 58. The bioprocessing system according to one or more of embodiments 55 to 57, wherein the at least one sensor element is arranged in or at a wall of the reservoir, preferably a side wall of the reservoir, preferably arranged at a side boundary of the reservoir volume.

[0236] 59. The bioprocessing system according to one or more of embodiments 55 to 58, wherein the at least one sensor element is arranged at the retentate side of the reservoir volume.

[0237] 60. The bioprocessing system according to one or more of embodiments 55 to 59, wherein the reservoir is a single molded piece; comprises a material that is optically transparent with a sensor element, in particular a dissolved oxygen sensor element and / or a pH sensor element mounted on the inside of the reservoir and readable through the reservoir; and / or comprises a reservoir wall that is thinned at a location of the sensor element.

[0238] 61. The bioprocessing system according to one or more of embodiments 55 to 60, wherein a further sensor element is arranged downstream of the reservoir membrane, preferably wherein such further sensor element is a flow sensor and / or pressure sensor. The bioprocessing system according to one or more of embodiments 38 to 61, wherein the cell vessel comprises a recirculation loop, preferably a tube loop leading from the cell vessel and to the cell vessel. The bioprocessing system according to embodiment 62, wherein the recirculation loop is configured for analysis, including cell counting. The bioprocessing system according to embodiment 62 or 63, wherein the recirculation loop, preferably the tube loop, comprises at least one branch. The bioprocessing system according to one or more of embodiments 1 to 64, wherein the cell vessel comprises one or more ports, preferably wherein the reservoir comprises at least one port. The bioprocessing system according to one or more of embodiments 38 to 65, wherein the reservoir is configured to be heated. The bioprocessing system according to one or more of embodiments 38 to 66, wherein the reservoir volume is at most 250 ml, preferably at most 150 ml or 120 ml; and / or the main volume is at most 6 I, preferably at most 3 I or 2 I. The bioprocessing system according to one or more of embodiments 38 to 67, wherein the cell vessel comprises a binding unit; and / or is fluidically connected to at least one a binding unit, wherein the binding unit comprises a binding matrix configured for allowing direct or indirect binding of a ligand expressed by at least a fraction of the cells. The bioprocessing system according to embodiment 68, wherein the binding matrix is provided as a resin or monolithic material. The bioprocessing system according to embodiment 68 or 69, wherein the binding unit is located within or adjacent to the reservoir of the cell vessel, preferably wherein the binding unit is arranged adjacent to the reservoir membrane. The bioprocessing system according to one or more of embodiments 68 to 70, wherein the binding unit is provided as a column, preferably wherein the opening of the column is arranged within an opening of the reservoir, more preferably an opening at the bottom of the reservoir, and / or the column is fluidically connected to the vessel (1), preferably the reservoir (5), wherein fluidic connections between the vessel (1) and the column are provided, in particular wherein the fluidic connections are provided by one or more tubes, optionally further comprising a valve. The bioprocessing system according to one or more of embodiments 68 to 71, wherein the binding unit is provided as a floating unit configured for float within the reservoir volume and / or the main volume. The bioprocessing system according to one or more of embodiments 68 to 72, wherein the binding unit is by an external loop fl uidica I ly connected to the vessel and / or a waste port, preferably both. The bioprocessing system according to embodiment 73, wherein the external loop comprises at least one valve, preferably one valve for controlling the fluid flow between the binding unit and the waste port and another valve controlled the fluid flow between the vessel and the waste port, preferably wherein both valves are for controlling the fluid flow between the binding unit and the vessel via the external loop. A bioreactor module for performing a bioprocess on a cell culture, comprising: a cell vessel area (4), wherein in the cell vessel area (4) a cell vessel (6) can be located, and a media supply area (5), wherein in the media supply area (5) a media container (7) can be located; wherein the bioreactor module (2) including the cell vessel (6) and the media container (7) is adapted to be automatically transported by a transport mechanism (8). The bioreactor module according to embodiment 75, wherein the bioreactor module (2) further comprises:

[0239] (1) a cell vessel (6) located in the cell vessel area (4), a media container (7) located in the media supply area (5), and optionally a waste container (12) located in a waste area (11); or

[0240] (II) a cell vessel (6) located in the cell vessel area (4), and a life support container (14) comprising the media container (7) and the waste container (12) located in a life support area (13). wherein the cell vessel (6) and the media container (7) are fluidically connected, optionally, wherein the cell vessel (6) and the waste container (12) are fluidically connected. The bioreactor module according to embodiment 75 or 76, wherein the bioreactor module

[0241] (2) further comprises a support structure (10), wherein due to the support structure (10) the bioreactor module (2) can be handled as a unit, in particular due to the support structure (10) the bioreactor module (2) can be automatically transported by a transport mechanism (8). 78. The bioreactor module according to embodiment 77, wherein due to the support structure (10) the bioreactor module (2) can be handled as a unit together with the cell vessel (6), the media container (7) and, optionally, a waste container (12).

[0242] 79. The bioreactor module according to embodiment 77 or 78, wherein the support structure (10) of the bioreactor module (2) comprises a life support area (13) in which a life support container (14), in particular a life support tray (15), can be placed.

[0243] 80. The bioreactor module according to embodiment 79, wherein the life support area (13) comprises the media supply area (5) and / or the waste area (11), preferably wherein the media supply area (5) is the same area as or a different area than the waste area (11) on the life support area, more preferably wherein the media supply area (5) is the same area as the waste area (11).

[0244] 81. The bioreactor module according embodiment 79 or 80, wherein the life support area (13) comprises the media supply area (5) and / or the waste area (11) such that the life support container (14) contains a media container (7) and / or a waste container (12).

[0245] 82. The bioreactor module according to one or more of embodiments 77 to 81, wherein the support structure (10) further comprises a rocking unit (26) for rocking the cell vessel (6).

[0246] 83. The bioreactor module according to one or more of embodiments 77 to 82, wherein the support structure (10) further comprises a balance for weighing a life support tray (15).

[0247] 84. The bioreactor module according to embodiment 83, wherein the balance weighs the life support tray (15): before a transfer of a liquid medium from the media supply area (5) to the cell vessel (6), after a transfer of a liquid medium from the media supply area (5) to the cell vessel (6), during a transfer of a liquid medium from the media supply area (5) to the cell vessel (6), before a transfer of a liquid from the cell vessel (6) to the waste area (11), after a transfer of a liquid from the cell vessel (6) to the waste area (11), and / or during a transfer of a liquid from the cell vessel (6) to the waste area (11), to determine and / or control an amount of transferred liquid medium.

[0248] 85. The bioreactor module according to one or more of embodiments 75 to 84, wherein the bioreactor module (2), in particular the life support tray (15), comprises at least one tube holder (22) configured for holding at least one tube, preferably for holding at least one tube in a defined position relative to the support structure (10) and / or the life support container (14). 86. The bioreactor module according to embodiment 85, wherein the tube holder (22) comprises a tube mover mechanism for extending and / or retracting the at least one tube relative to the tube holder (22).

[0249] 87. The bioreactor module according to one or more of embodiments 75 to 86, wherein the bioreactor module (2) further comprises a receiving interface (24) with a connection for receiving electrical energy; a connection for receiving wire-bound signals; a connection for receiving gas; and / or a connection for a sensor, such as an optical sensor.

[0250] 88. The bioreactor module according to embodiment 87, wherein the receiving interface (24) is connectable to the providing interface (25) of a framework (3).

[0251] 89. The bioreactor module according to one or more of embodiments 75 to 88, wherein the cell vessel (6) provides a volume for at least supporting cell cultures with volumes between 100 ml and 500 ml, preferably between 50 ml and 750 ml.

[0252] 90. The bioreactor module according to one or more of embodiments 75 to 89, wherein the cell vessel (6) has a volume of at most 6 I, preferably at most 3 I or 2 I.

[0253] 91. The bioreactor module according to one or more of embodiments 75 to 90, wherein the bioreactor module (2) further comprises a lid (27) for providing a controlled environment for the cell vessel (6); and / or a heating unit for the cell vessel (6).

[0254] 92. The bioreactor module according to one or more of embodiments 75 to 91, wherein the cell culture is an immune or naive cell culture.

[0255] 93. The bioreactor module according to one or more of embodiments 75 to 92, wherein the bioreactor module is adapted to be used for at least one cell culture cycle.

[0256] 94. The bioreactor module according to one or more of embodiments 75 to 93, wherein in the cell vessel area (4) a cell vessel (6) comprising an individual cell culture can be located.

[0257] 95. The bioreactor module according to one or more of embodiments 75 to 94, wherein during the cell culture cycle the cell vessel area (4) is used for only a single individual cell culture.

[0258] 96. A method for performing a bioprocess on a cell culture, wherein the method comprises: a) providing a. a cell culture, preferably an immune or naive cell culture; b. a bioreactor module (2) according to one or more of embodiments 75 to 95 and / or a bioprocessing system according to one or more of embodiments 1 to 74; c. a cell vessel (6); d. a media container (7); and e. optionally, a waste container (12), preferably, wherein a life support container (14) is provided comprising the media container (7) and the waste container (12); b) optionally, transferring the cell culture into the cell vessel (6); and c) expanding the cell culture in the cell vessel (6), located in the cell vessel area (4), preferably wherein expanding involves transferring liquid medium of the media container (7) into the cell vessel (6).

[0259] 97. The method according to embodiment 96, wherein the method further comprises removing liquid from the cell vessel (6) into the waste container (12).

[0260] 98. The method according to embodiment 96 or 97, wherein the method comprises automatically transporting the bioreactor module (2) between different positions, preferably between an expansion location (9) and at least one further position, which can be the refill location (16, 18), the emptying location (16, 18), and / or the swapping location (16, 18).

[0261] 99. The method according to one of more of embodiments 96 to 98, wherein the method has one or more of the following characteristics: the cell vessel (6) comprises an individual cell culture; the bioreactor module (2) is used for at least one cell culture cycle in which a cell vessel (6) is located at the cell vessel area (4) and an individual cell culture is located in the cell vessel (6), wherein during the cell culture cycle the cell vessel area (4) is used for only a single individual cell culture; during a cell culture cycle a first media container (7) containing a first liquid medium is located in the media supply area (5) and connected to the cell vessel (6) and the first liquid medium is provided to the cell vessel (6); and / or during a cell culture cycle a first liquid medium is replenished by a second liquid medium and the second liquid medium is provided to the cell vessel (6).

[0262] 100. The method according to one of more of embodiments 96 to 99, wherein the bioreactor module (2) including the cell vessel (6) and the media container (7) is automatically transported by a transport mechanism (8) of the bioprocessing system (1).

[0263] 101. The method according to one or more of embodiments 96 to 100, wherein the cell culture is an immune or naive cell culture, preferably wherein the cell culture comprises T cells.

[0264] 102. A method for manufacturing a cell therapy product, wherein the method comprises: a) providing a. a cell culture, preferably an immune or naive cell culture; b. a bioreactor module (2) according to one or more of embodiments 75 to 95 and / or a bioprocessing system according to one or more of embodiments 1 to 74; c. a cell vessel (6); d. a media container (7); and e. optionally, a waste container (12), preferably, wherein a life support container (14) is provided comprising the media container (7) and the waste container (12); b) transferring the cell culture into the cell vessel (6); and c) expanding the cell culture in the cell vessel (6), located in the cell vessel area (4), preferably wherein expanding involves transferring liquid medium of the media container (7) into the cell vessel (6), for manufacturing a cell therapy product.

[0265] 103. The method according to embodiment 102, wherein the cell culture is an immune or naive cell culture, preferably wherein the cell culture comprises T cells.

[0266] 104. The method according to embodiment 102 or 103, wherein the method further comprises one or more of the following steps: activating cells, preferably activating T cells; transducing cells, preferably transducing T cells; transfecting cells, preferably transfecting T cells; and / or expanding cells, preferably T cells, more preferably genetically modified T cells; preferably, wherein the method comprises at least two or three of the above-mentioned steps.

[0267] 105. The method according to one or more of embodiments 102 to 104, wherein the method comprises after step b) but before step c): i. activating cells, preferably activating T cells; and ii. transducing cells, preferably transducing T cells, or transfecting cells, preferably transfecting T cells.

[0268] 106. The method according to one or more of embodiments 102 to 105, wherein the method further comprises after step c) formulating the expanded cell culture into a media suitable for being injected into a patient and / or transferring the expanded cell culture from the cell vessel (6) into a harvesting vessel.

[0269] 107. Use of the bioreactor module (2) according to one or more of embodiments 75 to 95 and / or the bioprocessing system according to one or more of embodiments 1 to 74 for manufacturing a cell therapy product, preferably wherein manufacturing comprises at least one of the following: activating cells, preferably activating T cells; transducing cells, preferably transducing T cells; transfecting cells, preferably transfecting T cells; and / or expanding cells, preferably T cells, more preferably genetically modified T cells.

[0270] 108. Use of the bioreactor module (2) according to one or more of embodiments 75 to 95 and / or the bioprocessing system according to one or more of embodiments 1 to 74 in a method according to one or more of embodiments 96 to 106

[0271] 109. An expanded cell culture obtained by the method according to one or more of embodiments 96 to 101.

[0272] 110. A cell therapy product obtained by the method according to one or more of embodiments 102 to 106.

[0273] Further aspects and features of the present disclosure

[0274] A realization of the present disclosure is that a bioreactor module which comprises a cell vessel for the cells and a media supply area for a media container allows adding media to the cell vessel whenever necessary without having to move the cell vessel to a media station or the like and without having to be able to connect the cell vessel to a media container at an expansion location. To make the handling of the bioreactor module simpler, not all needed media are transported together with the cell vessel. Instead, the medium is replenished, either by refilling the media container or by adding a new media container. As such, the complexity and size of the bioreactor module are reduced. If the medium needs certain storage conditions, it may be possible to refill the media container often enough to eliminate the need for providing these storage conditions at the media supply area.

[0275] The combination of having a media container and replenishing the medium provides for a less complex transport mechanism and allows functional grouping in the bioprocessing system. For example, a connection system, in particular a tube welder, may be used at a central zone in the bioprocessing system and the bioreactor module can be transported there for replenishing without this transport having to happen too often, thereby reducing the complexity of the bioprocessing system. In addition, with transport less often required, it might be possible to run more bioprocesses in parallel on a single bioprocessing system.

[0276] In a further embodiment, the bioreactor module comprises a support structure which carries the cell vessel and the media container. The support structure can be designed for efficient automatic handling, and may make it unnecessary to handle flexible bags at any time other than at loading and unloading of the bags (if any), which may happen outside the bioprocessing system and without the cells being in the bags. Alternatively, the loading may happen in the bioprocessing system and monitored by the bioprocessing system. This may contribute to decreasing the risk of contamination or damage to the cell vessel or containers. The support structure may also act as a barrier for protecting the cells in particular and possibly contain leaks.

[0277] In a further embodiment, the media container is disconnected from the vessel and / or a second media container is placed in the media supply area and connected to the vessel. These embodiments relate to a replenishment of the liquid medium by addition of a new media container in particular by replacement of the old media container.

[0278] Similar to the media container a waste container may be included in the bioreactor module. For the waste container and the media container a life support tray may be present, which allows handling these two containers as a unit, too. That makes swapping the containers for new containers automatically easier than having to handle the containers directly. A tray may also be present for only the media container or only the waste container. The actual swapping is described herein elsewhere.

[0279] The swapping may be performed at a swapping location, increasing the functional grouping in the bioprocessing system thereby reducing its complexity.

[0280] Alternatively to the swapping, or even in addition thereto if the medium is replenished more than once, the media container may be refilled. For that, a connection between a refill container and the media container may be made. As for the swapping, the refill may be centralized at a refill location.

[0281] In a further embodiment, connecting and disconnecting the cell vessel and / or the different containers may be achieved via a connection arrangement, in particular a tube welding unit. Automatic tube welding, in particular at a central zone, allows making the necessary tube connections. Together with the proposed transport of the bioreactor module it becomes possible to replenish the medium and move the bioreactor module towards any desired location where the medium is used while keeping a low complexity.

[0282] Automatic tube welding provides unique challenges in localizing and grabbing the tubes for subsequent welding. In a further embodiment the bioreactor module comprises at least one tube holder which holds the tube in a defined position. This greatly reduces the complexity of automizing the tube welding as the location of the tube is already well known and the tube welding unit may interact with the rigid and well detectable tube holder instead of a flexible and transparent tube.

[0283] In a further embodiment, expansion locations which are preferably placed in a column in a shelflike framework. The advantage here is that the overall footprint is reduced.

[0284] Interfaces for interaction between the framework and the bioreactor module are also disclosed herein. These may be present at several locations and can be designed simpler due to the media container and therefore no necessity for a media connection for example.

[0285] In a further embodiment, the bioreactor module may be equipped with a rocking unit and / or a balance. The rocking unit allows rocking the cell vessel independently of where the bioreactor module is located. The balance allows detecting the amount of medium added to the vessel for example.

[0286] The transport mechanism is further described herein may relate to preferred volumes of the cell vessel. Other preferred features of the bioreactor module relating to the control of the environment of the cells are described herein.

[0287] Processing of the cells outside the bioreactor module is also possible and described herein.

[0288] Another teaching according, which is of equal importance, relates to a bioreactor module in particular for use in a bioprocess performed on immune or naive cell cultures, wherein the bioreactor module comprises a cell vessel area and a media supply area, wherein in the cell vessel area a cell vessel comprising an individual cell culture can be located, wherein in the media supply area a media container can be located, wherein the bioreactor module is adapted to be used for at least one cell culture cycle in which a cell vessel is located at the cell vessel area and an individual cell culture is located in the cell vessel, wherein during the cell culture cycle the cell vessel area is used for only a single individual cell culture, wherein during the cell culture cycle a first media container containing a first liquid medium is located in the media supply area and connected to the cell vessel and the first liquid medium is provided to the cell vessel, wherein during the cell culture cycle the first liquid medium is replenished by a second liquid medium and the second liquid medium is provided to the cell vessel, wherein the bioreactor module including the cell vessel and the media container are adapted to be automatically transported by the bioprocessing system.

[0289] All explanations given with regard to the proposed method are fully applicable.

[0290] In a further embodiment, a state in which the bioreactor module is loaded with the cell vessel and the media container at least is disclosed herein.

[0291] Another teaching herein, which is of equal importance, relates to a bioprocessing system for performing a bioprocess on immune or naive cell cultures, wherein the bioprocessing system comprises at least one exchangeable bioreactor module and a framework, wherein the bioreactor module comprises a cell vessel area and a media supply area, wherein in the cell vessel area a cell vessel comprising an individual cell culture can be located, wherein in the media supply area a media container can be located, wherein the bioreactor module is adapted to be used for at least one cell culture cycle in which a cell vessel is located at the cell vessel area and an individual cell culture is located in the cell vessel, wherein during the cell culture cycle the cell vessel area is used for only a single individual cell culture, wherein during the cell culture cycle a first media container containing a first liquid medium is located in the media supply area and connected to the cell vessel and the first liquid medium is provided to the cell vessel, wherein during the cell culture cycle the first liquid medium is replenished by a second liquid medium and the second liquid medium is provided to the cell vessel, wherein the bioprocessing system comprises a transport mechanism for automatically transporting the bioreactor module including the cell vessel and the media container.

[0292] All explanations given with regard to the proposed method and the proposed bioreactor module are fully applicable.

[0293] Description of Figures

[0294] Fig. 1 shows a bioprocessing system 1 adapted to perform the proposed method. The bioprocessing system 1 serves to perform several parallel bioprocesses on immune or naive cells. The cells are preferably dedicated for cell and / or gene therapy.

[0295] The term "immune cells" may generally refer to different types of white blood cells. Any type of white blood cells may be used here. Combinations of different types are also conceivable. Hence, the term "immune cells" includes a variety of cells, for example, but not limited to dendritic cells, T lymphocytes, also referred to as T cells, B lymphocytes, natural killer cells, macrophages or the like. Immune cells may also include subtypes of immune cells, for example tumor-infiltrating lymphocytes or different types of T cells. Subtypes of a certain type of immune cells may be classified based on the type of antigen present at the cell surface. Hence, the term immune cells may for example refer to T cells comprising the surface antigen CD4 ("CD4+ T cells").

[0296] Preferably, the cells are genetically modified T cells or are genetically modified to become genetically modified T cells. Preferably, the T cells are genetically modified to express a chimeric antigen receptor (CAR). Consequently, the term "CAR-T cells" describes T cells that have been genetically modified to express a CAR. Hence, preferably, the genetically modified T cells are genetically modified CAR-T cells.

[0297] Proposed is also a method for performing a bioprocess on immune or naive cell cultures by a bioprocessing system 1. The bioprocessing system 1 comprises at least one exchangeable bioreactor module 2, preferably a group of several exchangeable bioreactor modules 2, and a framework 3. Figures 2 and 3 show two embodiments of bioreactor modules 2 with several shared features and some differences. All features described for one embodiment may be present in the other embodiment, too. The bioreactor modules 2 are exchangeable as they are multi-use but may be exchanged after some time or with an updated version or the like. It is conceivable to also have bioreactor modules 2 which are not part of said group.

[0298] As may best be seen in Fig. 2 and Fig. 3, the bioreactor module 2 comprises a cell vessel area 4 and a media supply area 5. In the cell vessel area 4 a cell vessel 6 comprising an individual cell culture can be located and in the media supply area 5 a media container 7 can be located. The cell vessel 6 and / or the media container 7 may be a flexible bag or a rigid vessel or container. The cell vessel 6 here and preferably comprises a rigid part and a flexible part. Inside the cell vessel 6, steps of the bioprocess, in particular an expansion and / or an activation and / or a transduction step of the bioprocess are performed.

[0299] The bioreactor module 2 may be used for at least one cell culture cycle in which a cell vessel 6 is located at the cell vessel area 4 and an individual cell culture is located in the cell vessel 6. As explained, the bioreactor module 2 may be re-used with a different single-use cell vessel 6, however, presently only a single use is described. If the cell vessel 6 is replaced and cells of a new patient or cells either from one donor or pooled from several donors are introduced in a new cell vessel 6, that starts a new cell culture cycle. For present purposes, that new cell culture cycle may not be of interest. Therefore, during the cell culture cycle the cell vessel area 4 may be used for only a single individual cell culture. The cell vessel area 4 is defined such that it holds exactly one cell culture, it is not excluded that the bioreactor module 2 comprises a second cell vessel area 4 and possibly further cell vessel areas 4, in particular at least three, at least four, at least five or more.

[0300] The cells in the cell vessel 6 may be activated and / or transduced and / or expanded and / or otherwise processed, which here and preferably happens in the cell vessel 6. That would be possible by connecting external media supplies to the cell vessel 6, however, here it is proposed that during the cell culture cycle a first media container 7 containing a first liquid medium is located in the media supply area 5 and connected to the cell vessel 6 and the first liquid medium is provided to the cell vessel 6. Naturally, not all of the first liquid medium needs to be provided to the cell vessel 6. A part may stay in the first cell vessel 6 and may be discarded or used later. The bioreactor module 2 therefore comprises the cell vessel 6 and the media container 7.

[0301] It may however be the case that the media container 7 does not contain sufficient medium and / or not all needed media for the steps of the bioprocess performed inside the cell vessel 6. To overcome this shortage, during the cell culture cycle the first liquid medium is replenished by a second liquid medium and the second liquid medium is provided to the cell vessel 6. The second liquid medium may be of the same type as the first liquid medium or of a different type. It is therefore proposed to have a bioreactor module 2 with an included supply of media and a media replenishment step required at some point during the cell culture cycle. The bioprocessing system 1 may perform an action that leads to the replenishment.

[0302] With a view again to Fig. 1 it is further the case that the bioprocessing system 1 comprises a transport mechanism 8, for example a movable tray mounted on rails (located outside the visible area on the right side in Fig. 1) or a robotic arm, for automatically moving the bioreactor module 2. The transport mechanism 8 serves for automatically transporting the bioreactor module 2 including the cell vessel 6 and the media container 7 and automatically transports the bioreactor module 2, preferably several bioreactor modules 2. Here, the transport mechanism 8 is an elevator and / or loads bioreactor modules 2 from an expansion location 9 and / or into an expansion location 9. Several such expansion locations 9 may be placed in a column as shown. The transport mechanism 8 transports the cell vessel 6 and the media container 7 at the same time and together as both are connected fluidically.

[0303] As can be seen in Fig. 2 and Fig. 3, respectively, it is preferably the case that the bioreactor module 2 comprises a support structure 10 and that the support structure 10 comprises the cell vessel area 4 and the media supply area 5. It is therefore the case that the bioreactor module 2 can be handled as a unit together with the cell vessel 6 and the media container 7 due to the support structure 10. If handled manually the bioreactor module 2 could be lifted by its support structure 10 which then carries the cell vessel 6 and the media container 7.

[0304] According to one embodiment it is proposed that during the cell culture cycle the media container 7 is disconnected from the cell vessel 6 and preferably removed from the media supply area 5. Two ways of replenishing the first liquid medium will be described. One way preferably includes removing the media container 7 and, during the cell culture cycle, placing a second media container 7 in the media supply area 5, wherein the second media container 7 containing a second liquid medium is connected to the cell vessel 6 to provide the second liquid medium to the cell vessel 6.

[0305] It is preferably the case that during the cell culture cycle the bioreactor module 2 performs a cell expansion operation as part of the bioprocess on the individual cell culture held by the bioreactor module 2, and, that the first liquid medium is used for the cell expansion operation, and / or, that the second liquid medium is used for the cell expansion operation. Preferably, the volume of the cell culture is increased during the cell expansion operation. However, it may not be required that the different bioreactor modules 2 perform the cell culture cycle and thereby the expansion operation, at the same time.

[0306] It is preferably the case that the volume of the cell culture is actively changed by more than just an addition of an agent. Preferably, a volume of the cell culture is increased in the cell vessel 6 by at least 10 %, preferably at least 50 %, more preferably at least 100 %, more preferably at least 200 %, more preferably at least 300 %, more preferably at least 400 %, more preferably at least 500 %, more preferably at least 600 %, more preferably at least 700 %, more preferably at least 800 %, more preferably at least 900 %. Additionally or alternatively, the volume of the cell culture inside the cell vessel 6 may be at most 100 ml, preferably at most 80 ml, more preferably at most 50 ml, more preferably at most 25 ml, more preferably at most 15 ml, and / or at least 5 ml, when first introduced into the cell vessel 6 and / or at least 100 ml, preferably at least 300 ml, more preferably at least 500 ml, more preferably at least 1 1, at the end of the expansion operation. It is also possible that the bioprocessing system 1 performs a volume decrease of at least 10 %, preferably at least 30 %, more preferably at least 50 %, on the cell culture in the cell vessel 6.

[0307] In addition to the media supply, the cells produce waste, which may need to be removed from the cell vessel 6. In particular, it is preferably the case that perfusion is used to cultivate the cells in a generally known manner with a permeate for example being a type of waste. It is therefore preferably the case that the support structure 10 of the bioreactor module 2 comprises a waste area 11, that in the waste area 11 a waste container 12 can be located, and, that the bioreactor module 2 can be handled as a unit together with the cell vessel 6 and the media container 7 and the waste container 12 due to the support structure 10. The waste area 11 is therefore comparable to the media supply area 5. The waste container 12 may be a flexible bag or a rigid vessel or container. The waste area 11 and the media supply area 5 may overlap or be above each other or, as shown, next to each other.

[0308] To make it easier to load or swap out the media container 7 and the waste container 12 it is preferably the case that the support structure 10 of the bioreactor module 2 comprises a life support area 13 in which a life support container 14, in particular life support tray 15, can be placed and that the life support area 13 comprises the media supply area 5 and / or the waste area

[0309] 11 such that the life support container 14 contains the media container 7 and / or the waste container 12 (shown in Fig. 3, may also be present in the embodiment of fig Fig. 2 but is not shown there). The life support container 14 can be handled as a unit together with the media container 7 and / or the waste container 12. This embodiment is shown in Fig. 3. The life support tray 15 preferably provides a leakage protection in the way that liquid leaking from the media container 7 and / or the waste container 12 is caught by the life support tray 15.

[0310] Consequently it may be the case that during the cell culture cycle a first waste container 12 is placed in the waste area 11, wherein the first waste container 12 is connected to the cell vessel 6 and receives waste from the cell vessel 6 during the cell expansion operation, preferably, that during the cell culture cycle the first waste container 12 is disconnected from the cell vessel 6 and removed from the waste area 11, that during the cell culture cycle a second waste container

[0311] 12 is placed in the waste area 11, that the second waste container 12 is connected to the cell vessel 6 and receives waste from the cell vessel 6 during the cell expansion operation.

[0312] Regarding the swapping it is preferably the case that the second media container 7 uses at least partially physically the same space as the first media container 7 before. The second media container 7 may be connected to the same tube as the first media container 7 was. The same may be true forthe waste containers 12.

[0313] According to one embodiment it is proposed, that during the cell culture cycle a first life support container 14 containing the media container 7 and / or the waste container 12 is swapped out for a second life support container 14 containing the second media container 7 and / or the second waste container 12, in particular automatically in a swapping routine by the bioprocessing system

[0314] 1.

[0315] It may then be the case that disconnecting the first media container 7 from the cell vessel 6 and / or removing the first media container 7 and / or placing the second media container 7 in the media supply area 5 and / or connecting the second media container 7 to the cell vessel 6 and / or disconnecting the first waste container 12 from the cell vessel 6 and / or removing the first waste container 12 and / or placing the second waste container 12 in the waste supply area and / or connecting the second waste container 12 to the cell vessel 6 is done automatically in the swapping routine by the bioprocessing system 1.

[0316] According to one embodiment it is proposed, that the framework 3 comprises a swapping location 16, 18, that at the swapping location 16, 18, the bioprocessing system 1 performs the swapping routine for the bioreactor module 2, and, that for the bioreactor module 2 a cell expansion operation is performed outside the swapping location 16, 18, in particular in one of several expansion locations 9 of the bioprocessing system 1. The expansion will be explained more in detail later.

[0317] In a different embodiment or conceivably even in addition to the swapping it may be the case that in a refill routine the bioprocessing system 1 automatically connects a refill container 17 with the second liquid medium to the media container 7 and automatically refills the media container 7 with the second liquid medium and preferably automatically disconnects the refill container 17 from the media container 7 during the cell culture cycle. Preferably, the framework 3 comprises a refill location 16, 18 and the bioprocessing system 1 performs the refill routine at the refill location 16, 18 for the bioreactor module 2. It may also be the case that the waste container 12 is emptied. That may happen substantially in the same manner.

[0318] For performing the refilling for example, it may be the case that the framework 3 comprises a connection arrangement 19 for aseptically connecting and / or disconnecting the media container 7 and the cell vessel 6 and / or the media container 7 and the refill container 17 and / or the waste container 12 and the cell vessel 6, for the bioreactor module 2. Details of a preferred connection arrangement 19 are described in EP 4342 975 Al.

[0319] Here and preferably, the connection arrangement 19 comprises a tube welding unit 20 for welding together and / or cutting and closing off tubes connected to the media container 7 and the cell vessel 6, and preferably the waste container 12 and the cell vessel 6. The connection arrangement 19 may be located at the swapping location 16, 18 and / orthe refill location 16, 18. It is shown here that a central connecting zone 21 exists in which the connection arrangement 19 can be moved by the bioprocessing system 1, in particular move itself. The transport mechanism 8 here and preferably transports the bioreactor module 2 into the central connecting zone 21 for the replenishing. It may be the case that exactly one connection arrangement 19 is present.

[0320] The tube welding unit 20 here and preferably automatically grabs the tubes. It is preferably the case that the bioreactor module 2, in particular the life support tray 15, comprises at least one tube holder 22 holding at least one tube in a defined position relative to the support structure 10 and / or the life support container 14 and that the tube welding unit 20 interacts with the tube holder 22 to weld and / or cut and seal the tube. Fig. 1 shows a close-up onto one embodiment of such tube holders 22. Preferably, the tube holder 22 comprises a tube mover mechanism for extending and / or retracting the tube relative to the tube holder 22. Anyhow, the tube holders 22 enable a precise handling of the tubes without making it necessary for the tube welding unit 20 to somehow locate the tube itself. It is sufficient to locate the tube holder 22 which has a better defined position and orientation. It is further preferred that the tube welding unit 20 performs an integrity test on the newly established weld to determine that the weld has been correctly established. In case the weld fails the integrity test, it is further preferred that the tube welding unit 20 may cut the tubes and establish a new weld.

[0321] It is preferred that the tubes are cut by a blade. For this, the bioprocessing system 1 may provide a blade supply, particularly a blade box, as well as a blade removal, in particular a waste bin, for supply and discard of the blades. The blade supply and the blade removal may be provided as a combined unit within the bioprocessing system 1 (not shown in detail). The tube welding unit 20 may automatically move to the blade supply / removal unit for blade supply and / or removal.

[0322] It is preferably the case that the bioreactor module 2 comprises a drive unit for moving the tube holder 22, in particular linearly along a holder rail 23 of the bioreactor module 2. The rails can be seen in Fig. 1, too.

[0323] As already mentioned, according to one embodiment it is proposed, that the framework 3 comprises several expansion locations 9 at which cell expansion operations are at least partially performed, preferably, that the expansion locations 9 are placed vertically, more preferably, that the expansion locations 9 are compartments in a shelf with one or more vertical columns. It is preferably also the case that the bioreactor module 2 comprises a receiving interface 24 with a connection for receiving electrical energy and / or a connection for receiving wire-bound signals and / or a connection for receiving gas and / or a connection for an optical sensor, and, that the receiving interface 24 is connectable to a providing interface 25 of the framework 3.

[0324] Preferably, the framework 3 comprises providing interfaces 25 providing electrical energy and / or wire-bound signals and / or gas and / or an optical sensor connection at different locations, in particular at the swapping location 16, 18 and / or the expansion location 9 and / or the refill location 16, 18. The bioreactor module 2 may be self-sufficient to some extent and may comprise a battery. With the media container 7 and preferably waste container 12, the bioreactor module 2 may be self-sufficient for at least 12 hours, preferably at least 24 hours. That protects the cells even during a power outage or the like.

[0325] Different providing interfaces 25 may provide a different subset of connections for the receiving interface 24. For example, gas may be provided only at the expansion locations 9 while energy may be provided by each providing interface 25.

[0326] It is further preferred that the support structure 10 comprises a rocking unit 26 for rocking the cell vessel 6, and / or, that the support structure 10 comprises a balance for weighing the life support tray 15. The rocking unit 26 preferably allows rocking at any location and may have the advantage that only the cell vessel 6 and not the media container 7 and / or waste container 12 are rocked.

[0327] Preferably, the balance weighs the life support tray 15 before and / or after and / or during a transfer of a liquid medium from the media supply area 5 to the cell vessel 6 to determine an amount of transferred liquid medium and / or before and / or after and / or during a transfer of a liquid from the cell vessel 6 to the waste area 11 to determine an amount of transferred liquid.

[0328] Additionally or alternatively, the support structure 10 may comprise a balance for weighing the cell vessel 6, wherein it is preferably the case that the bioreactor module 2 weighs the cell vessel 6 while the rocking unit 26 is not rocking the cell vessel 6.

[0329] It is generally preferred that the transport mechanism 8 automatically transfers the bioreactor module 2 away from the expansion locations 9 and / or to the swapping location 16, 18 and / or to the refill location 16, 18. The transport mechanism 8 may comprise a transport element that is adapted to hold a bioreactor module 2 and movable in at least one linear direction. The transport element may be movable in exactly one linear direction, in particular vertically, as explained with regard to the elevator embodiment above. A control strategy regarding the control of the cell vessel 6, for example rocking or media supply, of the bioreactor module 2, in particular executed by a control unit comprised by the bioreactor module 2, may depend on a location of the bioreactor module 2. Location information may be provided by the providing interface 25. The transport element may comprise a mechanism for pushing the bioreactor module 2 into the expansion location 9 and / or for retrieving the bioreactor module 2 from the expansion location 9.

[0330] Here and preferably the cell vessel 6 provides a volume for at least supporting cell cultures with volumes between 100 ml and 500 ml, preferably between 50 ml and 750 ml. Here and preferably the cell vessel 6 supports volumes between 10 ml and 2 I.

[0331] According to one embodiment it is proposed, that the bioreactor module 2 comprises a lid 27 for providing a controlled environment for the cell vessel 6, and / or, that the bioreactor module 2 comprises a heating unit for the cell vessel 6.

[0332] It is also conceivable that the framework 3 comprises a unit operation location 28, in particular next to the swapping location 16, 18 or the refill location 16, 18, that at the unit operation location 28 the cell culture is pumped from a cell container of a cartridge into the cell vessel 6, and, that the framework 3 performs the unit operation by using the cartridge. A cartridge may be a container that houses elements required to perform a unit operation. For example, the cartridge may contain a centrifugation unit and / or a magnetic separation unit and / or an electroporation unit for performing the unit operations of concentration, separation and / or genetic modification, respectively.

[0333] With a view to Fig. 4, the cell vessel 6 may comprise a tube loop 29 leading from the vessel to the vessel, in particular for analysis like cell counting. The loop 29 may connect supply ports 30 of the cell vessel 6 which are also connected to the media container 7 and / or the waste container 12. Preferably, the loop 29 comprises at least one branch 31. In Fig. 4 the schematic loop 29 comprises the same tubes as shown at the cell vessel 6 in the same order. For exam pie, the shown tube leading away from the supply port 30 may comprise a branch 31, preferably towards a pump and / or a sensor and from there return to another branch 31 of a tube connected to the other supply port 30 for example (not shown). The loop 29 in a preferred and shown embodiment is a two-way loop 29. Then the loop 29 goes from one port, in particular through a branch 31, to a loop destination 32, e.g. a sensor. From there, the loop 29 goes on to an air source, in particular a further gas port 33 of the cell vessel 6. A sample drawn through the loop 29 is however not routed through the whole loop 29 but instead to the loop destination 32 and back. The part of the loop 29 not used for the liquid is then used for air to push the liquid back and allow for the liquid to flow forward.

[0334] The cell vessel 6 may further comprise a gas inlet port 34, a gas outlet port 35 and / or a waste port 36, as shown.

[0335] Another teaching which is of equal importance relates to a bioreactor module 2 in particular for use in a bioprocess performed on immune or naive cell cultures, wherein the bioreactor module 2 comprises a cell vessel area 4 and a media supply area 5, wherein in the cell vessel area 4 a cell vessel 6 comprising an individual cell culture can be located, wherein in the media supply area 5 a media container 7 can be located, wherein the bioreactor module 2 is adapted to be used for at least one cell culture cycle in which a cell vessel 6 is located at the cell vessel area 4 and an individual cell culture is located in the cell vessel 6, wherein during the cell culture cycle the cell vessel area 4 is used for only a single individual cell culture, wherein during the cell culture cycle a first media container 7 containing a first liquid medium is located in the media supply area 5 and connected to the cell vessel 6 and the first liquid medium is provided to the cell vessel 6, wherein during the cell culture cycle the first liquid medium is replenished by a second liquid medium and the second liquid medium is provided to the cell vessel 6, wherein the bioreactor module 2 including the cell vessel 6 and the media container 7 are adapted to be automatically transported by the bioprocessing system 1.

[0336] The bioreactor module 2 may comprise a control unit adapted to communicate with the bioprocessing system 1 during the automatic transport, wherein the control unit sends and / or receives and processes and preferably acts upon data containing information about the transport.

[0337] The media supply area 5 may be oriented such that the media container 7 when placed in the media supply area 5 is placed above, in particular on top of, the support structure 10. Additionally or alternatively, the waste area 11 may be oriented such that the waste container 12 when placed in the waste area 11 is placed above, in particular on top of, the support structure 10. According to one embodiment it is proposed that the bioreactor module 2 comprises the cell vessel 6, the media container 7 and preferably the waste container 12 which are fluidically connected.

[0338] Another teaching which is of equal importance relates to a bioprocessing system 1 for performing a bioprocess on immune or naive cell cultures, wherein the bioprocessing system 1 comprises at least one exchangeable bioreactor module 2 and a framework 3, wherein the bioreactor module 2 comprises a cell vessel area 4 and a media supply area 5, wherein in the cell vessel area 4 a cell vessel 6 comprising an individual cell culture can be located, wherein in the media supply area 5 a media container 7 can be located, wherein the bioreactor module 2 is adapted to be used for at least one cell culture cycle in which a cell vessel 6 is located at the cell vessel area 4 and an individual cell culture is located in the cell vessel 6, wherein during the cell culture cycle the cell vessel area 4 is used for only a single individual cell culture, wherein during the cell culture cycle a first media container 7 containing a first liquid medium is located in the media supply area 5 and connected to the cell vessel 6 and the first liquid medium is provided to the cell vessel 6, wherein during the cell culture cycle the first liquid medium is replenished by a second liquid medium and the second liquid medium is provided to the cell vessel 6, wherein the bioprocessing system 1 comprises a transport mechanism 8 for automatically transporting the bioreactor module 2 including the cell vessel 6 and the media container 7.

[0339] Items according to the present disclosure

[0340] The following items provide further advantageous embodiments of the present disclosure:

[0341] 1. Method for performing a bioprocess on immune or naive cell cultures by a bioprocessing system (1), wherein the bioprocessing system (1) comprises at least one exchangeable bioreactor module (2) and a framework (3), wherein the bioreactor module (2) comprises a cell vessel area (4) and a media supply area (5), wherein in the cell vessel area (4) a cell vessel (6) comprising an individual cell culture can be located, wherein in the media supply area (5) a media container (7) can be located, wherein the bioreactor module (2) is used for at least one cell culture cycle in which a cell vessel (6) is located at the cell vessel area (4) and an individual cell culture is located in the cell vessel (6), wherein during the cell culture cycle the cell vessel area (4) is used for only a single individual cell culture, wherein during the cell culture cycle a first media container (7) containing a first liquid medium is located in the media supply area (5) and connected to the cell vessel (6) and the first liquid medium is provided to the cell vessel (6), wherein during the cell culture cycle the first liquid medium is replenished by a second liquid medium and the second liquid medium is provided to the cell vessel (6), wherein the bioprocessing system (1) comprises a transport mechanism (8) for automatically transporting the bioreactor module (2) including the cell vessel (6) and the media container (7) and automatically transports the bioreactor module (2).

[0342] 2. Method according to claim 1, characterized in that the bioreactor module (2) comprises a support structure (10), that the support structure (10) comprises the cell vessel area (4) and the media supply area (5), and, that the bioreactor module (2) can be handled as a unit together with the cell vessel (6) and the media container (7) due to the support structure (10).

[0343] 3. Method according to claim 1 or 2, characterized in that during the cell culture cycle the media container (7) is disconnected from the cell vessel (6) and preferably removed from the media supply area (5), and / or, that during the cell culture cycle a second media container (7) is placed in the media supply area (5), wherein the second media container (7) containing a second liquid medium is connected to the cell vessel (6) to provide the second liquid medium to the cell vessel (6).

[0344] 4. Method according to claim 2 or 3, characterized in that the support structure (10) of the bioreactor module (2) comprises a waste area (11), that in the waste area (11) a waste container (12) can be located, that the bioreactor module (2) can be handled as a unit together with the cell vessel (6) and the media container (7) and the waste container (12) due to the support structure (10), preferably, that the support structure (10) of the bioreactor module (2) comprises a life support area (13) in which a life support container (14), in particular life support tray (15), can be placed, that the life support area (13) comprises the media supply area (5) and / or the waste area (11) such that the life support container (14) contains the media container (7) and / or the waste container (12), that the life support container (14) can be handled as a unit together with the media container (7) and / or the waste container (12).

[0345] 5. Method according to claim 4, characterized in that during the cell culture cycle a first life support container (14) containing the media container (7) and / or the waste container (12) is swapped out for a second life support container (14) containing the second media container (7) and / or a second waste container (12), in particular automatically in a swapping routine by the bioprocessing system (1).

[0346] 6. Method according to claim 5, characterized in that the framework (3) comprises a swapping location (16, 18), that at the swapping location (16, 18), the bioprocessing system (1) performs the swapping routine for the bioreactor module (2), and, that for the bioreactor module (2) a cell expansion operation is performed outside the swapping location (16, 18), in particular in one of several expansion locations (9) of the bioprocessing system (1).

[0347] 7. Method according to one of the preceding claims, characterized in that in a refill routine the bioprocessing system (1) automatically connects a refill container (17) with the second liquid medium to the media container (7) and automatically refills the media container (7) with the second liquid medium and preferably automatically disconnects the refill container (17) from the media container (7) during the cell culture cycle, preferably, that the framework (3) comprises a refill location (16, 18) and that the bioprocessing system (1) performs the refill routine at the refill location (16, 18) for the bioreactor module (2).

[0348] 8. Method according to one of the preceding claims, characterized in that the framework (3) comprises a connection arrangement (19) for aseptically connecting and / or disconnecting the media container (7) and the cell vessel (6) and / or the media container (7) and the refill container (17) and / or the waste container (12) and the cell vessel (6), for the bioreactor module (2), preferably, that the connection arrangement (19) comprises a tube welding unit (20) for welding together and / or cutting and closing off tubes connected to the media container (7) and the cell vessel (6), and preferably the waste container (12) and the cell vessel (6), and / or, that the connection arrangement (19) is located at the swapping location (16, 18) and / or the refill location (16, 18).

[0349] 9. Method according to claim 8, characterized in that the bioreactor module (2), in particular the life support tray (15), comprises at least one tube holder (22) holding at least one tube in a defined position relative to the support structure (10) and / or the life support container (14) and that the tube welding unit (20) interacts with the tube holder (22) to weld and / or cut and seal the tube, preferably, that the tube holder (22) comprises a tube mover mechanism for extending and / or retracting the tube relative to the tube holder (22).

[0350] 10. Method according to one of the preceding claims, characterized in that the framework (3) comprises several expansion locations (9) at which cell expansion operations are at least partially performed, preferably, that the expansion locations (9) are placed vertically, more preferably, that the expansion locations (9) are compartments in a shelf with one or more vertical columns.

[0351] 11. Method according to one of the preceding claims, characterized in that the bioreactor module (2) comprises a receiving interface (24) with a connection for receiving electrical energy and / or a connection for receiving wire-bound signals and / or a connection for receiving gas and / or a connection for an optical sensor, that the receiving interface (24) is connectable to a providing interface (25) of the framework (3), preferably, that the framework (3) comprises providing interfaces (25) providing electrical energy and / or wire-bound signals and / or gas and / or an optical sensor connection at different locations, in particular at the swapping location (16, 18) and / or the expansion location (9) and / or the refill location (16, 18).

[0352] 12. Method according to one of the preceding claims, characterized in that the support structure (10) comprises a rocking unit (26) for rocking the cell vessel (6), and / or, that the support structure (10) comprises a balance for weighing the life support tray (15), preferably, that the balance weighs the life support tray (15) before and / or after and / or during a transfer of a liquid medium from the media supply area (5) to the cell vessel (6) to determine an amount of transferred liquid medium and / or before and / or after and / or during a transfer of a liquid from the cell vessel (6) to the waste area (11) to determine an amount of transferred liquid.

[0353] 13. Method according to one of the preceding claims, characterized in that the transport mechanism (8) automatically transfers the bioreactor module (2) away from the expansion locations (9) and / or to the refill location (16, 18), preferably, that the transport mechanism (8) comprises a transport element that is adapted to hold a bioreactor module (2) and movable in at least one linear direction, more preferably, that the transport element is movable in exactly one linear direction, in particular vertically.

[0354] 14. Method according to one of the preceding claims, characterized in that the cell vessel (6) provides a volume for at least supporting cell cultures with volumes between 100 ml and 500 ml, preferably between 50 ml and 750 ml.

[0355] 15. Method according to one of the preceding claims, characterized in that the bioreactor module (2) comprises a lid (27) for providing a controlled environment for the cell vessel (6), and / or, that the bioreactor module (2) comprises a heating unit for the cell vessel (6). 16. Method according to one of the preceding claims, characterized in that the framework (3) comprises a unit operation location (28), in particular next to the swapping location (16, 18) or the refill location (16, 18), that at the unit operation location (28) the cell culture is pumped from a cell container of a cartridge into the cell vessel (6), and, that the framework (3) performs the unit operation by using the cartridge.

[0356] 17. Bioreactor module in particular for use in a bioprocess performed on immune or naive cell cultures, wherein the bioreactor module (2) comprises a cell vessel area (4) and a media supply area (5), wherein in the cell vessel area (4) a cell vessel (6) comprising an individual cell culture can be located, wherein in the media supply area (5) a media container (7) can be located, wherein the bioreactor module (2) is adapted to be used for at least one cell culture cycle in which a cell vessel (6) is located at the cell vessel area (4) and an individual cell culture is located in the cell vessel (6), wherein during the cell culture cycle the cell vessel area (4) is used for only a single individual cell culture, wherein during the cell culture cycle a first media container (7) containing a first liquid medium is located in the media supply area (5) and connected to the cell vessel (6) and the first liquid medium is provided to the cell vessel (6), wherein during the cell culture cycle the first liquid medium is replenished by a second liquid medium and the second liquid medium is provided to the cell vessel (6), wherein the bioreactor module (2) including the cell vessel (6) and the media container (7) are adapted to be automatically transported by the bioprocessing system (1).

[0357] 18. Bioreactor module according to claim 17, characterized in that the bioreactor module (2) comprises the cell vessel (6), the media container (7) and preferably the waste container (12) which are fluidically connected.

[0358] 19. Bioprocessing system for performing a bioprocess on immune or naive cell cultures, wherein the bioprocessing system (1) comprises at least one exchangeable bioreactor module (2) and a framework (3), wherein the bioreactor module (2) comprises a cell vessel area (4) and a media supply area (5), wherein in the cell vessel area (4) a cell vessel (6) comprising an individual cell culture can be located, wherein in the media supply area (5) a media container (7) can be located, wherein the bioreactor module (2) is adapted to be used for at least one cell culture cycle in which a cell vessel (6) is located at the cell vessel area (4) and an individual cell culture is located in the cell vessel (6), wherein during the cell culture cycle the cell vessel area (4) is used for only a single individual cell culture, wherein during the cell culture cycle a first media container (7) containing a first liquid medium is located in the media supply area (5) and connected to the cell vessel (6) and the first liquid medium is provided to the cell vessel (6), wherein during the cell culture cycle the first liquid medium is replenished by a second liquid medium and the second liquid medium is provided to the cell vessel (6), wherein the bioprocessing system (1) comprises a transport mechanism (8) for automatically transporting the bioreactor module (2) including the cell vessel (6) and the media container (7). Throughout the description, where methods, compositions or uses are described as having, including, or comprising specific components or steps, it is contemplated that, additionally, there are methods, compositions or uses of the present invention that consist essentially of, or consist of, the recited components or steps.

[0359] In the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.

[0360] Terms "a" and ''an'' and ''the'' and similar reference used in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0361] The use of the term "include," "includes," "including," "have," "has," "having," "contain," "contains," or "containing," including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[0362] Where the use of the term "about" or ''approximately'' is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term "about" refers to a ±10% variation from the nominal value unless otherwise indicated or inferred.

[0363] Also as used herein, ''and / or'' refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or"). The use of the alternative (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives.

[0364] All citations are hereby incorporated by reference.

[0365] All individual embodiments and aspects as disclosed herein can be combined with each other within the framework and context of the present disclosure. It will be understood that the embodiments disclosed herein are only exemplary, and that any feature presented for a particular exemplary embodiment may be used with the present disclosure on its own or in combination with any feature presented for the same or another particular exemplary embodiment and / or in combination with any other feature not mentioned. It will further be understood that any feature presented for an example embodiment in a particular category may also be used in a corresponding manner in an example embodiment of any other category.

[0366] EXAMPLES

[0367] It should be understood that the following example is for illustrative purpose only and not to be construed as limiting this invention in any manner. The following example demonstrates that the bioprocessing system and the bioreactor module according to the present disclosure can be advantageously used for performing certain bioprocesses on the cell culture, specifically on an immune cell culture comprising T cells. In particular, it is shown that T cells can be transferred into the cell vessel placed on the cell vessel area of the bioreactor module. Afterwards, the cells are activated and expanded in the very same cell vessel, allowing for simple, precise and robust production of a cell therapy product.

[0368] Peripheral blood mononuclear cells (PBMCs) were thawed and isolated using CD3+ StemCell Technologies Kit according to the manufacturer's instructions. Part of the cells were activated in flask for reference (herein referred to as "BRO2") according to the manufacturer's protocols and part were used for performing the methods according to the present disclosure (herein referred to as "BRO3").

[0369] In BRO3, cells were inoculated and activated in the cell vessel mounted on the bioreactor module (50mL at a cell density of 1.43xlO6 / mL). In BRO2, cells were activated in T-flask at 1.43xl06(in 20mL). For culture according to the present disclosure (BRO3), cells were shaken for 1 h to ensure the activation reagent and cell culture were evenly uniform (rate 16 rpm angle-4 / +4). The fluidic lines were primed with media 6 mL media to ensure volume was representative. After 24 h, cell activation was completed and the cells were rocked for 30 min to ensure homogenous distribution (rate: 16 rpm angle-4 / +4), then returned to static position. After 48h, cells were rocked at a rate of 16 rpm angle-4 / +4.

[0370] Post 65 h of activation the cells went through three cycles of perfusion to wash off the activation reagent (0.34mL / min). For this purpose, the culture liquid comprising left over activation reagent was retrieved as permeate through the reservoir membrane. Afterwards, fresh cell culture medium was added through the fluidic lines. This process was accordingly repeated until the activation reagent has been essentially completely removed. From day 3 on, cell density was set to lxlO6 / mL by dilution and the cells were cultured in the cell vessel up to day 7.

[0371] On day 7, cell density was set to lxlO6 / mL again by dilution with fresh cell culture medium and the cells were cultured in the cell vessel for another 2 h interval. Then, perfusion started and carried on until day 13. This was advantageously done using the reservoir membrane and / or the main membrane disclosed herein. At the end of day 13, the cells were harvested.

[0372] As shown in Fig. 5, BRO3 led not only to a larger total number of cells compared to BRO2 (p=0.0002, graph 1) - which would be expected due to the different starting volumes - but also to a higher daily fold expansion. Hence, by cultivating the cells in the bioprocessing system according to the present disclosure, greater cell numbers were achieved in shorter time, allowing for more efficient production of activated T cells, and thus better manufacturing of a cell therapy product.

[0373] In addition, as shown in Fig. 6, the expansion of BRO3 had higher a viable cell density (VCD) compared to BRO2 (p=0.01 graph 1). No significant difference was seen in the VCD during-the batch culture (p=0.84), but a significant difference was observed the moment perfusion culture was initiated. Hence, by using the bioprocessing system according to the present disclosure, not only higher cell density but also more viable cells were obtained. Thus, not only was production more efficient with higher yields but also of higher quality, which is an important parameter in the manufacture of a cell therapy product.

[0374] While the Example is representative for one bioreactor run, the used bioprocessing system comprises the transport mechanism by which the bioreactor module can be transported to different positions, such as to an expansion position in an automated manner. Hence, multiple bioreactor runs can be performed in parallel in a simplified and efficient way utilizing the bioprocessing system (and bioreactor module) according to the present disclosure.

Claims

CLAIMS1. A bioprocessing system for performing a bioprocess on a cell culture, wherein the bioprocessing system (1) comprises: i. at least one exchangeable bioreactor module (2) comprising a cell vessel area (4), wherein in the cell vessel area (4) a cell vessel (6) can be located, and a media supply area (5), wherein in the media supply area (5) a media container (7) can be located; ii. a framework (3), and iii. a transport mechanism (8) for automatically transporting the bioreactor module (2).

2. The bioprocessing system according to claim 1, wherein the transport mechanism (8) is configured to automatically transfer the bioreactor module (2) between different positions, preferably between an expansion location (9) and at least one further position, which can be the refill location (16, 18), the emptying location (16, 18), and / or the swapping location (16, 18).

3. The bioprocessing system according to claim 1 or 2, wherein the transport mechanism (8) comprises a transport element that is• adapted to hold a bioreactor module (2) and• movable in at least one direction, preferably at least one linear direction, such as vertically; and / or a further transport element for pushing the bioreactor module (2) into the expansion location (9) and / or for retrieving the bioreactor module (2) from the expansion location (9).

4. The bioprocessing system according to one or more of claims 1 to 3, wherein the bioreactor module (2) further comprises a support structure (10), preferably having one or more of the following characteristics: due to the support structure (10) the bioreactor module (2) can be handled as a unit, in particular due to the support structure (10) the bioreactor module (2) can be automatically transported by the transport mechanism (8); due to the support structure (10) the bioreactor module (2) can be handled as a unit together with the cell vessel (6), the media container (7) and, optionally, a waste container (12);the support structure (10) of the bioreactor module (2) comprises a life support area (13) in which a life support container (14), in particular a life support tray (15), can be placed; the support structure (10) further comprises a rocking unit (26) for rocking the cell vessel (6); and / or the support structure (10) further comprises a balance for weighing a life support tray (15).

5. The bioprocessing system according to one or more of claims 1 to 4, wherein the bioprocessing system further comprises(I) a cell vessel (6) located in the cell vessel area (4), a media container (7) located in the media supply area (5), and optionally a waste container (12) located in a waste area (11); or(II) a cell vessel (6) located in the cell vessel area (4), a life support container (14) located in a life support area (13).

6. The bioprocessing system according to one or more of claims 1 to 5, wherein the bioprocessing system further comprises a life support area (13) comprising the media supply area (5) and / or the waste area (11), preferably wherein the media supply area (5) is the same area as or a different area than the waste area (11) on the life support area, more preferably wherein the media supply area (5) is the same area as the waste area (11).

7. The bioprocessing system according to one or more of claims 1 to 6, wherein the bioprocessing system is configured for performing one or both of the following operations in an automated manner: a refill routine, preferably wherein the bioprocessing system (1) automatically connects a refill container (17) comprising a liquid medium to the media container (7) and automatically refills the media container (7) with the liquid medium and preferably automatically disconnects the refill container (17) from the media container (7), optionally during a cell culture cycle; and an emptying routine, preferably wherein the bioprocessing system (1) automatically connects a further waste container to the waste container (12) and automatically empties the waste container (12) from the waste and preferably automatically disconnects the further waste container from the waste container (12), optionally during a cell culture cycle.

8. The bioprocessing system according to one or more of claims 1 to 7, wherein the bioprocessing system, preferably the framework (3) of the bioprocessing system, has one or more of the following characteristics:it comprises: i. a refill location (16, 18), at which a refill routine can be performed; ii. an emptying location (16, 18), at which an emptying routine can be performed; and / or iii. a swapping location (16, 18), at which a swapping operation can be performed, preferably wherein the bioprocessing system (1) performs the swapping and / or at the swapping location (16, 18) the swapping is performed manually; optionally, wherein the bioprocessing system preferably the framework (3) of the bioprocessing system, comprises the refill location (16, 18) and the emptying location (16, 18), both of which have the same location; it comprises at least one expansion location, preferably several expansion locations, more preferably the expansion locations (9) are placed vertically.

9. The bioprocessing system according to one or more of claims 1 to 8, wherein the bioprocessing system, preferably the framework (3) of the bioprocessing system, comprises a connection arrangement (19) configured for aseptically connecting and / or disconnecting one or more, preferably all, of the following the media container (7) and the cell vessel (6), the media container (7) and the refill container (17), and the waste container (12) and the cell vessel (6), preferably, the connection arrangement (19) comprises a tube welding unit (20) for welding together and / or cutting and closing off one or more tubes connected to the media container (7) and the cell vessel (6), and preferably the waste container (12) and the cell vessel (6); and / or is movable, preferably movable in an automated manner, wherein the connection arrangement can be moved to be located at the swapping location (16, 18), at the refill location (16, 18), and / or at the emptying location (16, 18).

10. A bioreactor module for performing a bioprocess on a cell culture, comprising: a cell vessel area (4), wherein in the cell vessel area (4) a cell vessel (6) can be located, and a media supply area (5), wherein in the media supply area (5) a media container (7) can be located; wherein the bioreactor module (2) including the cell vessel (6) and the media container (7) is adapted to be automatically transported by a transport mechanism (8).

11. The bioreactor module according to claim 10, wherein the bioreactor module (2) further comprises a support structure (10), preferably having one or more of the following characteristics: due to the support structure (10) the bioreactor module (2) can be handled as a unit, in particular due to the support structure (10) the bioreactor module (2) can be automatically transported by the transport mechanism (8); due to the support structure (10) the bioreactor module (2) can be handled as a unit together with the cell vessel (6), the media container (7) and, optionally, a waste container (12); the support structure (10) of the bioreactor module (2) comprises a life support area (13) in which a life support container (14), in particular a life support tray (15), can be placed; the support structure (10) further comprises a rocking unit (26) for rocking the cell vessel (6); and / or the support structure (10) further comprises a balance for weighing a life support tray (15).

12. A method for performing a bioprocess on a cell culture, wherein the method comprises: a) providing a. a cell culture, preferably an immune or naive cell culture; b. a bioreactor module (2) according to claim 10 or 11 and / or a bioprocessing system according to one or more of claims 1 to 9; c. a cell vessel (6); d. a media container (7); and e. optionally, a waste container (12), preferably, wherein a life support container (14) is provided comprising the media container (7) and the waste container (12); b) optionally, transferring the cell culture into the cell vessel (6); and c) expanding the cell culture in the cell vessel (6), located in the cell vessel area (4), preferably wherein expanding involves transferring liquid medium of the media container (7) into the cell vessel (6).

13. The method according to claim 12, wherein the method comprises automatically transporting the bioreactor module (2) between different positions, preferably between an expansion location (9) and at least one further position, which can be the refill location (16, 18), the emptying location (16, 18), and / or the swapping location (16, 18).

14. A method for manufacturing a cell therapy product, wherein the method comprises: a) providing a. a cell culture, preferably an immune or naive cell culture;b. a bioreactor module (2) according to claim 10 or 11 and / or a bioprocessing system according to one or more of claims 1 to 9; c. a cell vessel (6); d. a media container (7); and e. optionally, a waste container (12), preferably, wherein a life support container (14) is provided comprising the media container (7) and the waste container (12); b) transferring the cell culture into the cell vessel (6); and c) expanding the cell culture in the cell vessel (6), located in the cell vessel area (4), preferably wherein expanding involves transferring liquid medium of the media container (7) into the cell vessel (6), for manufacturing a cell therapy product.

15. Use of the bioreactor module (2) according to claim 10 or 11 and / or the bioprocessing system according to one or more of claims 1 to 9 for manufacturing a cell therapy product, preferably wherein manufacturing comprises at least one of the following: activating cells, preferably activating T cells; transducing cells, preferably transducing T cells; transfecting cells, preferably transfecting T cells; and / or expanding cells, preferably T cells, more preferably genetically modified T cells.

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