CELL PROCESSING UNIT, CELL PROCESSING SYSTEM AND METHOD OF USING SAME - Patent application

Abstract

The present invention relates to a cell processing unit for the manufacture of cell and gene therapies, the cell processing unit comprising: a housing defining an enclosure, wherein a cell processing platform can be mounted into the enclosure; a platform mounting bracket within the housing, wherein the platform mounting bracket is configured and arranged to receive and hold the cell processing platform; a drive device configured and arranged to operably engage and act on the cell processing platform, thereby moving the cell processing platform relative to the platform mounting bracket; and an actuator configured and arranged to exert a force on a container mounted in the cell processing platform, thereby ejecting contents from the container.

Description

[Technical field]

[0001] The present invention relates to a cell processing unit for the production of cell and gene therapies, including a system using such an apparatus and a method using same. The present invention relates to a method for the production of cells and / or the production of gene therapies using such a processing unit. [Background technology]

[0002] Cell and gene therapy manufacturing processes are often complex and include manual or semi-automated steps across several devices. Equipment systems used in various steps (i.e., unit operations) in cell-based therapeutics (CTP) manufacturing can include devices for cell collection, cell isolation / selection, cell expansion, cell washing and volume reduction, cell storage and transport. Unit operations can vary greatly based on the manufacturing model (i.e., autologous vs. allogeneic), cell type, intended purpose, among other factors. In addition, cells are "living" entities that are sensitive to even the simplest manipulations (e.g., differences in cell transplantation procedures). The role of cell manufacturing equipment in ensuring scalability and reproducibility is a critical factor for cell and gene therapy manufacturing.

[0003] In addition, cell-based therapeutics (CTPs) have made significant advances and thus there is a need for improved cell manufacturing equipment for various cell manufacturing procedures (e.g., but not limited to, stem cell enrichment, generation of chimeric antigen receptor (CAR) T cells) and various cell manufacturing processes (e.g., collection, purification, genetic modification, culture / harvesting, washing, infusion into patients, and / or freezing, etc.).

[0004] Cultivating or processing cells typically requires the use of a device to hold the cells, for example in a suitable culture medium, as they are cultured. Known devices include shaker flasks, roller bottles, T-flasks, and bags. Although such bottles or flasks are widely used, they suffer from several drawbacks. Chief among the problems is the requirement for contamination-free transfer of cells when subsequently passaging or processing, as well as the sterile addition of supplements and factors. Existing cell culture devices require resupply of culture medium and oxygen for continued cell growth. A gas-permeable cell culture device is described in US Pat. No. 5,399,433. However, such devices require transfer of medium and / or cells into or out of the device.

[0005] Foldable cell processing devices for use in the medical field are known, see, for example, U.S. Patent No. 5,399,433 for a blood collector or U.S. Patent No. 5,399,433 for a canister liner for fluid collection, but such devices have not been fabricated or constructed for use in manufacturing unit operations (i.e., steps) of cell and / or gene therapy.

[0006] A key limiting factor in the production of cell or gene therapies for use in the field of medicine is the lack of a compact, automated, closed system to perform unit operations without contamination. For example, there is a risk of contamination during cell culture, during upstream or downstream processing of the cells, when adding to the culture vessel, or when removing cells or removing liquid samples. The operating systems are largely manual and therefore expensive to operate. Multiple pieces of equipment are typically required to cover all of the non-cell culture steps, which involve many transfers, each of which can lead to operator error and contamination. Moreover, as manual operations increase, the risk of manual error increases, and therefore current labor-intensive processes lack the robustness required for the production of clinical-grade therapies.

[0007] There is therefore a need for cell processing devices (e.g., multi-step cell processors) that enable such processing that avoids the need for constant transfer of cells into fresh devices. For example, it would be advantageous if scale-up of cells in culture could be achieved without transfer of cells into larger devices as the cell population for any given culture increases.

[0008] Previous cell manufacturing devices have used complex instruments that are large and difficult to assemble, using complex networks of tubing, valves and pumps to link the instrument elements together.

[0009] Here, the applicant provides an improved cell therapy and / or gene therapy processing equipment, which combines the advantages of the cell culture container of the applicant's previous applications (US Pat. No. 5,399,623 and US Pat. No. 5,499,633) (i.e., avoiding the need for pumps and the requirement for constant passaging of cells into fresh culture devices, holding vessels, tubing, etc.) with the advantages afforded by having an individually configurable cell therapy and / or gene therapy processing device. The improved devices and containers described herein, together with the improved closed cell processing units, allow various unit processes to be carried out in a single device or container, which has a smaller footprint and is less complex than existing equipment, as will be described in more detail herein. Moreover, the cell processing containers described herein are capable of maintaining sterile connections without prerequisites such as laminar flow cabinets or glove boxes.

[0010] The applicant's previous application (US Pat. No. 5,399,433) describes a cell culture container in which wall elements constructed from a flexible material are compressible relative to its top and base sections. The cell culture container described therein is compatible with the cell processing units and devices described herein.

[0011] In a further previous application (US Pat. No. 5,399,633), the applicant describes an improved version of a cell culture container, which further includes one or more auxiliary containers having at least one inlet and in fluid communication with the primary container. The cell culture container described therein is improved to be compatible with the cell processing units and devices described herein. Moreover, the connections between the cell culture container described therein and other components are improved, thereby maintaining a sterile environment throughout the connections. In the previous application (US Pat. No. 5,399,633), a laminar flow cabinet was required to ensure a sterile environment during the manufacturing and / or processing of cell and / or gene therapy. However, this can increase costs and become a more labor-intensive process. Therefore, the present application also aims to provide a sterile connection between components, regardless of the surrounding environment or atmosphere. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] U.S. Patent No. 8,415,144 [Patent Document 2] U.S. Patent No. 4,867,172 [Patent Document 3] WO2008 / 030597 [Patent Document 4] PCT / GB2016 / 051451 [Patent Document 5] PCT / GB2017 / 053389 [Patent Document 6] WO2018 / 087558 [Patent Document 7] WO2003 / 046141 Summary of the Invention [Problem to be solved by the invention]

[0013] It is an object of some aspects of the present invention to provide improvements over the techniques described above and known technologies, in particular to provide cell processing units, cell processing platforms, cell processing devices, and cell processing containers and systems that facilitate flexible, compact and low-cost multi-step cell processing while reducing the risk of contamination. [Means for solving the problem]

[0014] According to the present invention there is provided a cell processing unit, a cell processing system and a method for the production of cell and / or gene therapy according to the appended claims.

[0015] Also described are cell processing platforms, and cell processing systems and methods for use in one or more unit operations in the manufacture of cell and / or gene therapies.

[0016] Also described are cell processing devices for use in one or more unit operations in the manufacture of cell and / or gene therapies, as well as cell processing systems and methods.

[0017] Also described are cell processing containers for use in one or more unit operations in the manufacture of cell and / or gene therapies, cell processing systems including the cell processing containers, and multi-step methods of performing one or more unit operations in the manufacture of cell and / or gene therapies.

[0018] Cell Processing Unit According to one aspect of the invention, there is provided a cell processing unit for the manufacture of cell and gene therapies, the cell processing unit comprising: a housing defining an enclosure, into which a cell processing platform can be mounted; a platform mounting bracket within the housing, the platform mounting bracket configured and arranged to receive and hold the cell processing platform; a drive device configured and arranged to operatively engage and act on the cell processing platform, such as to move the cell processing platform relative to the platform mounting bracket; and an actuator configured and arranged to exert a force on a container mounted into the cell processing platform, such as to eject contents from the container.

[0019] The term "cell processing unit" is used to define a unit in which one or more unit operations in the manufacture or processing of cell and / or gene therapies may be performed. The cell processing unit may serve as a housing for components used in such manufacture and processing. The cell processing unit may take any suitable shape or size. The cell processing unit may take the form of an apparatus or the like. That is, the terms "cell processing unit", "cell processing apparatus", and "apparatus for the manufacture or processing of cell and / or gene therapies" may be used interchangeably.

[0020] The term "enclosure" is used to define an area or space within which another component may be received, housed, or enclosed, either partially or completely. An enclosure may take the form of a chamber, receptacle, volume of space, etc.

[0021] The term "cell processing platform" is used to define a platform or interface on which one or more unit operations in the manufacture or processing of cell and / or gene therapies may be performed. The terms "cell processing platform", "liquid handling platform", "platform", "cell processing interface", and "interface" may be used synonymously. In some examples, the cell processing platform serves as an interface between components (e.g., containers or bioreactors, etc.) such that a user can manipulate the cell processing platform and thereby control one or more unit operations in the manufacture or processing of cell and / or gene therapies. The cell processing platform may provide a fluid pathway, such as through conduits, seals, valves, or septa, to provide an interface between components (e.g., containers or bioreactors, etc.).

[0022] The term "platform mounting bracket" is used to define a mounting bracket for a cell processing platform as described herein. The platform mounting bracket can take the form of one or more components constructed and arranged such that the cell processing platform can be mounted thereto.

[0023] The term "actuator" is used to define an operable mechanism that can cause the actuation (or operation) of one or more components of a cell processing unit or cell processing platform. In some examples, an actuator can cause the actuation (or operation) of one or more containers. In some examples, an actuator can cause the actuation (or operation or compression) of one or more compressible containers. In some examples, an actuator can cause the activation (or operation) of one or more valves.

[0024] In some embodiments, the housing is accessible through a door in a wall of the housing. More specifically, the door may be hingedly connected to the wall of the housing. Even more specifically, the door is positioned in a front wall of the housing. In this manner, front loading of the cell processing unit is possible.

[0025] In some embodiments, the housing has a rectangular or square footprint.

[0026] In some embodiments, the platform mounting bracket includes a mounting plate. More specifically, the mounting plate is configured to receive a portion of the cell processing platform such that the cell processing platform is retained on the mounting plate during use.

[0027] In some embodiments, the platform mounting bracket includes a retention flange that is spaced apart from the mounting plate such that the cell processing platform can be received and held in place in the housing between the mounting plate and the retention flange. More specifically, the retention flange and the mounting plate together provide a recess (slot) into which a portion of the cell processing platform can be positioned and held.

[0028] In some embodiments, the mounting plate is substantially C-shaped, so that the cell processing platform can be moved from a sideways (i.e., front) loading position to a location above the mounting plate.

[0029] In some embodiments, the mounting plate is attached to the housing.

[0030] In some embodiments, the mounting plate is adjustable. More specifically, the distance between the base of the housing and the mounting plate is adjustable. In this manner, different cell processing devices can be positioned within the housing.

[0031] In some embodiments, the mounting plate is positioned within the housing and allows the cell treatment device to be supported by the plate without contacting the walls, top, or base of the housing. In this manner, the mounting plate suspends the cell treatment device within the housing. Thus, the cell treatment device can rotate within the housing.

[0032] In some embodiments, the drive device is a rotational drive device that is configured and arranged to operably engage and act on the cell processing platform to rotate the cell processing platform relative to the platform mounting bracket. Thus, when the cell processing platform is positioned in the cell processing unit and engaged with the rotational drive device, it can be indexed in its position relative to the platform mounting bracket by operation of the rotational drive device. Thus, in some embodiments, the cell processing unit is operable to move the cell processing platform therein in an automatic process.

[0033] In some embodiments, the rotational drive device includes a drive wheel mounted on the platform mounting bracket, the drive wheel configured to engage a surface of the cell processing platform and impart rotational movement to the cell processing platform.

[0034] In some embodiments, the rotational drive device includes a spring loaded wheel biased toward and spaced apart from the drive wheel and mounted on the platform mounting bracket.

[0035] In some embodiments, the rotational drive device includes a hinged wheel biased toward and spaced apart from the drive wheel and mounted on the platform mounting bracket.

[0036] The term "hinged wheel" is used to define a wheel that is hinged (i.e., mounted on a hinge) such that it may be moveable between at least a first and a second configuration. The wheel may be hinged in any suitable manner and may be moveable between any number of suitable configurations.

[0037] In some embodiments, the hinged wheels are movable into an open position and a closed position, in which the cell processing platform can be inserted into and engaged with the platform mounting bracket, and in which the hinged wheels engage with a surface of the cell processing platform to retain the cell processing platform within the cell processing platform mounting bracket.

[0038] In some embodiments, the hinged wheels are manually movable.

[0039] In some embodiments, the hinged wheels are automatically movable. More specifically, the hinged wheels may be operatively coupled to an actuator operable to move the hinged wheels between the open and closed positions.

[0040] In some embodiments, the hinged wheel is mounted to a door of the housing.

[0041] In some embodiments, the door of the housing includes a platform engagement means. More specifically, the platform engagement means is one of a flange, protrusion, or lug that is positioned on the inside of the door (facing the inside of the housing) and is operable to engage a surface of the cell processing platform when the door is closed. In this manner, the platform engagement means is operable to retain the cell processing platform within the mounting bracket. The platform engagement means may be operable to maintain the cell processing platform in engagement with a drive wheel of the rotational drive device.

[0042] In some embodiments, the drive device comprises a three-point contact arrangement, thus the cell processing platform within the cell processing unit is held within the drive mechanism around its entire periphery.

[0043] In some embodiments, the three elements of the drive device (e.g., the drive wheel, the spring-loaded wheel, and the hinged wheel) are equally spaced from one another within the housing, such an arrangement facilitating rotational movement of the cell processing platform with a minimum number of drive wheels.

[0044] In some embodiments, the actuator is a linear actuator.

[0045] The term "linear actuator" is used to define an actuator that moves in a linear manner (i.e., along an axis). In some examples, a linear actuator may be operable along a longitudinal axis.

[0046] In some embodiments, the actuator comprises a lever, plunger, or a series of levers, plungers, or bellows configured to compress a container mounted into the cell processing platform, hi some embodiments, the actuator is configured to compress a primary container and / or one or more auxiliary containers mounted to the cell processing platform and positioned within a housing.

[0047] In some embodiments, the linear actuator includes a plunger operably coupled to a drive motor, the plunger configured to engage a container in the cell processing platform and exert a compressive force on the container.

[0048] In some embodiments, the cell processing unit includes a plurality of actuators, hi some embodiments, the apparatus includes a primary actuator, the primary actuator constructed and arranged to exert a force on a primary container mounted on the cell processing platform to eject contents (e.g., fluid or cells) from the container.

[0049] In some embodiments, the primary actuator is a linear actuator.

[0050] In some embodiments, the linear primary actuator includes a lever, plunger, or a series of levers, plungers, or bellows configured to compress the primary container.

[0051] In some embodiments, the primary actuator includes a plunger operably coupled to a drive motor, the plunger configured to engage a primary container mounted to the cell processing platform and exert a compressive force on the primary container.

[0052] It will be appreciated that any actuator should preferably not only be able to compress or collapse a container attached to the cell processing platform, but also be able to reopen it if this is required. In this way, the contents of the container can be agitated by repeated compression / expansion of the container.

[0053] In some embodiments, the apparatus includes a valve actuator operable to act on a valve in the cell processing platform to open or close the valve when a force is applied to the container, hi some embodiments, the valve is a pinch valve.

[0054] In some embodiments, the valve actuator is a linear actuator.

[0055] In some embodiments, the valve actuator includes a valve solenoid.

[0056] In some embodiments, the apparatus includes a position detection sensor, the position detection sensor operable to detect the position of the cell processing platform relative to the platform mounting bracket.

[0057] In some embodiments, the position detection sensor is operable to detect the rotational position of the cell processing platform relative to the platform mounting bracket. In this manner, the location of the container port, and thus the location of the container mounted in the cell processing platform, can be detected as the cell processing platform moves relative to the housing.

[0058] In some embodiments, the position detection sensor includes one or more of a Hall effect sensor, an RFID sensor, an optical sensor, or a cog operable to engage an additional cog.

[0059] In some embodiments, the apparatus includes a home position detection sensor, the home position detection sensor operable to detect a home position of the cell processing platform relative to the platform mounting bracket.

[0060] The term "home position" is used to define the first, default, or original position of a configuration of a cell processing platform. The home position may be so referred to in reference to a predetermined position relative to the platform mounting bracket.

[0061] In some embodiments, the home position detection sensor is operable to detect a single rotational position of the cell processing platform relative to the platform mounting bracket.

[0062] The term "single rotational position" is used to define a position in the path of rotation of the cell processing platform. The single rotational position may be so referred to with respect to a position (e.g., a predetermined position) on the platform mounting bracket.

[0063] In some embodiments, the home position detection sensor includes one or more of a Hall effect sensor, an RFID sensor, a light sensor, or a cog operable to engage an additional cog.

[0064] In some embodiments, the voltage detected by the Hall effect sensor is greater at the home position of the cell processing platform relative to the platform mounting bracket than at any other position during the rotation of the cell processing platform relative to the platform mounting bracket.

[0065] In some embodiments, the container is mounted on a cell processing platform to form a cell processing device as described herein. More specifically, the container is compressible. In this manner, the container configuration is based on a concertina (which can act as a pump), and therefore there is no need for a separate pump and a complex set of tubing / pipes to transfer the contents of the container to another container in the system. And this configuration reduces the space required for the cell and / or gene therapy manufacturing process.

[0066] In some embodiments, the container is the container described in Applicant's earlier US Pat. No. 6,399,633.

[0067] In some embodiments, the container is the container described in Applicant's earlier US Pat. No. 6,399,633.

[0068] In some embodiments, the container includes a base section, a top section disposed substantially parallel to the base section, and a wall element disposed between the top section and the base section and defining an internal lumen of the container, the wall element of the container being preferably compressible relative to the top section and the base section, the wall element of the container being constructed from a flexible material. Alternatively, the container can include a syringe arrangement that allows it to be refilled or emptied. In such a syringe arrangement, the container has an arrangement similar to a syringe with a movable element to either expel fluid from the container or draw fluid back into the container.

[0069] In some embodiments, the container can include any shape container with a moving seal that allows for variable volume operation.

[0070] In some embodiments, the primary container is compressible.

[0071] In some embodiments, the primary container includes a base section, a top section disposed substantially parallel to the base section, and a wall element disposed between the top section and the base section and defining an interior lumen of the container, the wall element of the container preferably being compressible relative to the top section and the base section, and the wall element of the container being constructed from a flexible material.

[0072] In some embodiments, the container is one of a reagent container, a bioreactor, a cell culture container, a waste container, a filter, an electroporator, a purifier, a waste container, a filter, an electroporator, a purifier, a holding container, an apheresis / leukapheresis, a differentiation chamber, a chromatography column, a sedimentation chamber, a sieve, a shaking / mixer, a centrifuge, and a magnetic bead separator, etc.

[0073] In some embodiments, the primary container is a cell culture container.

[0074] In some embodiments, the control of the cell processing unit is automated.

[0075] The term "automated" is used to refer to operation of a component without, or substantially without, user intervention.

[0076] In some embodiments, the cell processing unit includes a control system operable to activate the actuator and / or drive means such that a cell processing device loaded into the unit can be selectively moved to position a container in relation to the actuator and / or the actuator can be activated to act on a container within the housing to expel its contents.

[0077] In some embodiments, the control system is manual or automatic. More specifically, an automatic control system can be programmed to operate the actuators and / or drive means in a pre-determined sequence.

[0078] In some embodiments, the control system includes a user interface on the housing.

[0079] In some embodiments, the control system includes a user interface, the user interface being operably linked to and remote from the housing.

[0080] In some embodiments, the user interface is operable to allow a user to program instructions into the control system.

[0081] In some embodiments, the cell treatment unit includes a temperature control means, in this way the temperature within the housing can be controlled and selected.

[0082] According to another aspect, the present invention provides a cell processing system comprising a cell processing unit according to the present invention.

[0083] According to a further aspect of the invention there is provided a method for the production of cell and / or gene therapy utilising a cell processing unit according to the invention.

[0084] Cell Processing Platform According to a further aspect of the present invention, there is provided a cell processing platform for use in performing one or more unit operations in the manufacture of cell and / or gene therapy, the platform including a body portion including at least one fluid inlet fluidly connected to a fluid outlet and an auxiliary container port fluidly coupled to the at least one fluid inlet of the body portion, the auxiliary container port configured and arranged to receive an auxiliary container and sealingly engage the auxiliary container and fluidly connect the auxiliary container lumen with the at least one fluid inlet of the body portion, and the primary container port configured and arranged to sealingly engage a primary container and fluidly connect the primary container lumen with the fluid outlet of the body portion.

[0085] The term "cell processing platform" is used to define a platform or interface on which one or more unit operations in the manufacture or processing of cell and / or gene therapies may be performed. The terms "cell processing platform", "liquid handling platform", "platform", "cell processing interface", and "interface" may be used synonymously. In some examples, the cell processing platform serves as an interface between components (e.g., containers or bioreactors, etc.) to allow a user to manipulate the cell processing platform and thereby control one or more unit operations in the manufacture or processing of cell and / or gene therapies. The cell processing platform may provide a fluid pathway, such as through conduits, seals, valves, or septa, and provide an interface between components (e.g., containers or bioreactors, etc.). The cell processing platform may provide a sterile fluid pathway, such as through conduits, seals, valves, or septa, and provide an interface between components (e.g., containers or bioreactors, etc.).

[0086] The primary container may be considered a first container. The auxiliary container may be considered a second (or secondary) container. Any number of containers may be used.

[0087] The term "primary container" is used to define that a container is connected to a first side (or surface) of a cell processing platform. For example, the term "primary container" may be used to define that a container is attached to a lower side (or surface) of a cell processing platform. There can be any number of primary containers.

[0088] The primary container can be a bellows-based container, e.g., a bellows-based bioreactor. That is, the container or bioreactor can be based on a bellows, i.e., the container or bioreactor comprises a wall element comprising a series of Z-folds or a wall element comprising (or forming) a concertina. The bellows-based container or bioreactor can comprise a base section, an upper section disposed substantially parallel to the base section, and a wall element disposed between the upper section and the base section and defining the internal lumen of the container or bioreactor. The wall element of the container or bioreactor is preferably compressible relative to the upper section and the base section. The wall element of the container or bioreactor can be constructed of a flexible material. The wall element can comprise a series of Z-folds. The wall element can comprise (or form) a bellows. The container can take the form of a concertina.

[0089] The term "auxiliary container" or "secondary container" is used to define that a container is connected to a second side (or surface) of the cell processing platform. For example, the term "auxiliary container" or "secondary container" may be used to define that a container is attached to the upper side (or surface) of the cell processing platform. There can be any number of auxiliary containers.

[0090] The auxiliary container can be a bellows-based container, e.g., a bellows-based bioreactor. That is, the container or bioreactor can be based on a bellows, i.e., the container or bioreactor comprises a wall element comprising a series of Z-folds or a wall element comprising (or forming) a concertina. The bellows-based container or bioreactor can comprise a base section, an upper section disposed substantially parallel to the base section, and a wall element disposed between the upper section and the base section and defining the internal lumen of the container or bioreactor. The wall element of the container or bioreactor is preferably compressible relative to the upper section and the base section. The wall element of the container or bioreactor can be constructed of a flexible material. The wall element can comprise a series of Z-folds. The wall element can comprise (or form) a bellows. The container can take the form of a concertina.

[0091] In general, the terms "container" or "cell processing container" are used to define a container, receptacle, volume, or bioreactor, etc., in which one or more unit operations of cell and / or gene therapy manufacturing or processing may be completed.

[0092] In some embodiments, the body portion includes one (i.e., a single) fluid inlet and one (i.e., a single) fluid outlet. In some embodiments, the body portion includes one or more fluid inlets and one or more fluid outlets. In some embodiments, the body portion includes one (i.e., a single) fluid inlet and multiple fluid outlets. In some embodiments, the body portion includes multiple fluid inlets and one (i.e., a single) fluid outlet. In some embodiments, the body portion includes multiple fluid inlets and multiple fluid outlets.

[0093] In some embodiments, the auxiliary container port includes a sealable fluid inlet and / or a sealable fluid outlet.

[0094] In some embodiments, the auxiliary container port is configured for sealing engagement with a fluid outlet of the auxiliary container.

[0095] In some embodiments, the primary container port is configured for sealing engagement with a fluid inlet of a primary container.

[0096] In some embodiments, the auxiliary container port includes a container receiving sleeve connected to the body portion and configured to surround at least a portion of the auxiliary container, the portion including a fluid outlet portion of the container.

[0097] In some embodiments, the container receiving sleeve includes an insulating means configured to maintain the contents of the auxiliary container received therein at a particular temperature. More specifically, the insulating means is a thermal sleeve. Thus, the auxiliary container receiving port can be configured to maintain the contents of the container received therein at an optimal temperature. For example, the optimal temperature can be cell culture temperature (37 degrees Celsius), room temperature (22 degrees Celsius), refrigeration (e.g., approximately 4 degrees Celsius), or freezing (e.g., approximately minus 4 degrees Celsius or below, e.g., minus 20 degrees Celsius or minus 80 degrees Celsius, etc.).

[0098] In some embodiments, the cell processing platform can have one or more auxiliary container ports configured to maintain different temperatures.

[0099] In some embodiments, the auxiliary container port includes a mating element that is configured to fluidly connect to a corresponding mating element on the auxiliary container.

[0100] In some embodiments, the mating element is one of a sterile connector end or a Luer Lok™. When the mating element of the auxiliary container port is a Luer Lok™, the port can have a male Luer Lok™ connector that will engage and mate with a corresponding female Luer Lok™ connector on the container, or vice versa.

[0101] In some embodiments, the primary container port includes a mating element that is configured to fluidly connect to a corresponding mating element on the primary container.

[0102] In some embodiments, the mating element includes one of a sterile connector end or a Luer Lok™. When the mating element of the primary container port is a Luer Lok™, the port can have a male Luer Lok™ connector that will engage and interlock with a corresponding female Luer Lok™ connector on the container, or vice versa.

[0103] In some embodiments, the auxiliary container port includes a Luer Lok™ connector at the fluid inlet and / or fluid outlet of the auxiliary container port, each Luer Lok™ connector configured to mate with an additional Luer Lok™ connector on the container and / or on the body portion, respectively. More specifically, a male Luer Lok™ connector is configured to mate with a female Luer Lok™ connector.

[0104] In some embodiments, the fluid outlet of the body portion includes a Luer Lok™ connector configured to engage with an additional Luer Lok™ connector on a primary container attachable to the body portion.

[0105] In some embodiments, the auxiliary container port includes a sterile connector end at the fluid inlet and / or fluid outlet of the auxiliary container port, each sterile connector end configured to engage with a further sterile connector end on the container and / or on the body portion, respectively.

[0106] In some embodiments, the fluid outlet portion of the body portion includes a sterile connector end configured to engage with a further sterile connector end on a primary container attachable to the body portion.

[0107] In some embodiments, the body portion is substantially hollow.

[0108] In some embodiments, at least one fluid inlet and fluid outlet of the body portion are fluidly connected to one another by a fluid conduit.

[0109] In some embodiments, the fluid conduit includes a valve operable to open and close the fluid conduit.

[0110] In some embodiments, the valve is one of a pinch valve, a pressure sensitive valve, a clamp valve, a membrane valve, a rupture disk, a venous valve, and an aperture valve.

[0111] In some embodiments, the auxiliary container port includes a container fill port.

[0112] In some embodiments, the container fill port is fluidly connected to a fluid inlet of the auxiliary container port.

[0113] In some embodiments, the container fill port includes a valve that is operably coupled to the fluid inlet and fluid outlet of the auxiliary container port and is operable to control the fluid flow direction through the auxiliary container port.

[0114] In some embodiments, the container fill port includes a valve that, in an open position, is operable to allow fluid to flow to the fluid inlet of the auxiliary container port and not to the fluid outlet of the auxiliary container port, and, in a closed position, to close the container fill port and allow fluid to flow from the fluid inlet of the auxiliary container port to the fluid outlet of the auxiliary container port.

[0115] In some embodiments, the platform includes a plurality of auxiliary container ports each fluidly connected to the fluid inlet of the body portion, such that each of the plurality of auxiliary container ports is configured and arranged to receive an auxiliary container and sealingly engage the auxiliary container to fluidly connect the container lumen with the fluid inlet of the body portion.

[0116] In some embodiments, each auxiliary container port is coupled to a separate fluid inlet portion of the body portion.

[0117] In some embodiments, each separate fluid inlet of the body portion is fluidly connected to a fluid outlet of the body portion.

[0118] In some embodiments, the platform includes at least one position tracking device operable to indicate a set location on the platform, thus allowing the position of the platform to be tracked, for example, when the platform is mounted into a cell processing unit according to the invention.

[0119] In some embodiments, the at least one position tracking device is a mechanical device.

[0120] In some embodiments, at least one position tracking device includes a cog. In such embodiments, the mounting plate of the cell processing unit can include additional cogs operable to engage protrusions of cogs on the cell processing platform. In this way, the cell processing platform will need to be physically inserted into the mounting plate of the cell processing unit in the correct orientation. This ensures that the operator knows the position of the platform (and thus the position of the containers attached to the platform within the cell processing unit).

[0121] In some embodiments, the position tracking device is an encoder. More specifically, the position tracking device is one or more of a magnet, an RFID sensor, or an optical sensor, etc.

[0122] In some embodiments, the platform includes multiple position tracking devices.

[0123] In some embodiments, at least one position tracking device is positioned relative to the auxiliary container port (or relative to each auxiliary container port) such that the location of the position tracking device is related to the location of the auxiliary container port.

[0124] In some embodiments, the at least one position tracking device is positioned on the body portion relative to the auxiliary container port.

[0125] In some embodiments, the platform includes a sampling port in the body portion.

[0126] In some embodiments, the platform includes a gas transfer port in the body portion.

[0127] In some embodiments, the auxiliary container port is configured to receive a container having a base section, a top section disposed substantially parallel to the base section, and a wall element disposed between the top section and the base section and defining an interior lumen of the container, the wall element of the container preferably being compressible relative to the top section and the base section, and the wall element of the container being constructed from a flexible material.

[0128] In some embodiments, the auxiliary container port is configured to receive the containers described in US Pat. No. 6,399,362.

[0129] In some embodiments, the auxiliary container is removably attached to the auxiliary container port.

[0130] In some embodiments, the primary container port is configured to receive a primary container having a base section, a top section disposed substantially parallel to the base section, and a wall element disposed between the top section and the base section and defining an interior lumen of the container, the wall element of the container preferably being compressible relative to the top section and the base section, and the wall element of the container being constructed from a flexible material.

[0131] In some embodiments, the auxiliary container port is configured to accept a primary container as described in US Pat. No. 6,399,623 or US Pat. No. 6,399,623.

[0132] In some embodiments, the primary container further includes a mounting flange attached to the top section of the primary container and configured to sealingly engage and mount to the primary container port.

[0133] In some embodiments, the primary container is removably attached to the primary container port.

[0134] Cell Processing Device According to a further aspect of the present invention, there is provided a cell processing device for use in performing one or more unit operations in the manufacture of cell and / or gene therapy comprising a cell processing platform according to the present invention fluidly connected to at least one container.

[0135] The term "cell treatment device" is used to define a cell treatment platform having at least one container coupled thereto. The at least one container may be fluidly coupled thereto.

[0136] The term "cell processing platform" is used to define a platform or interface on which one or more unit operations in the manufacture or processing of cell and / or gene therapies may be performed. The terms "cell processing platform", "liquid handling platform", "platform", "cell processing interface", and "interface" may be used synonymously. In some examples, the cell processing platform serves as an interface between components (e.g., containers or bioreactors, etc.) to allow a user to manipulate the cell processing platform and thereby control one or more unit operations in the manufacture or processing of cell and / or gene therapies. The cell processing platform may provide a pathway (e.g., a fluid pathway), such as through conduits, seals, valves, or septa, to provide an interface between components (e.g., containers or bioreactors, etc.).

[0137] In some instances, the cell processing platform may be fluidly coupled to at least one container, thereby allowing fluid communication therebetween, i.e., in some instances, the cell processing platform allows for the introduction of one or more fluids into the at least one container, or the extraction of one or more fluids from the at least one container.

[0138] In some embodiments, the cell processing platform is fluidly connected to at least one auxiliary container.

[0139] In some embodiments, the cell processing platform is fluidly connected to at least one primary container.

[0140] Thus, in some embodiments, a cell processing device is provided for use in performing one or more unit operations in the manufacture of cell and / or gene therapy, comprising a cell processing platform fluidly connected to at least one auxiliary container and fluidly connected to at least one primary container.

[0141] In some embodiments, the cell processing platform includes a body portion including at least one fluid inlet fluidly connected to the fluid outlet, and an auxiliary container port fluidly connected to the at least one fluid inlet of the body portion, wherein the at least one auxiliary container is received in sealing engagement with the auxiliary container port such that the auxiliary container lumen is fluidly connected to the at least one fluid inlet of the body portion, and wherein the primary container is received in sealing engagement with the primary container port such that the primary container lumen is fluidly connected to the fluid outlet of the body portion.

[0142] The primary container may be considered a first container. The auxiliary container may be considered a second (or secondary) container. Any number of containers may be used.

[0143] The term "primary container" is used to define that a container is connected to a first side (or surface) of a cell processing platform. For example, the term "primary container" may be used to define that a container is attached to a lower side (or surface) of a cell processing platform. There can be any number of primary containers.

[0144] The primary container can be a bellows-based container, e.g. a bellows-based bioreactor. That is, the container or bioreactor can be based on a bellows, i.e. the container or bioreactor comprises a wall element comprising a series of Z-folds or a wall element comprising (or forming) a concertina. The bellows-based container or bioreactor can comprise a base section, an upper section arranged substantially parallel to the base section, and a wall element arranged between the upper section and the base section and defining the internal lumen of the container or bioreactor. The wall element of the container or bioreactor is preferably compressible relative to the upper section and the base section. The wall element of the container or bioreactor can be made of a flexible material. The wall element can comprise a series of Z-folds, i.e. the wall element can comprise (or form) a bellows. The container can take the form of a concertina.

[0145] The term "auxiliary container" or "secondary container" is used to define that a container is connected to a second side (or surface) of the cell processing platform. For example, the term "auxiliary container" or "secondary container" may be used to define that a container is attached to the upper side (or surface) of the cell processing platform. There can be any number of auxiliary containers.

[0146] The auxiliary container can be a bellows-based container, e.g., a bellows-based bioreactor. That is, the container or bioreactor can be based on a bellows, i.e., the container or bioreactor comprises a wall element comprising a series of Z-folds or a wall element comprising (or forming) a concertina. The bellows-based container or bioreactor can comprise a base section, an upper section disposed substantially parallel to the base section, and a wall element disposed between the upper section and the base section and defining the internal lumen of the container or bioreactor. The wall element of the container or bioreactor is preferably compressible relative to the upper section and the base section. The wall element of the container or bioreactor can be constructed of a flexible material. The wall element can comprise a series of Z-folds. The wall element can comprise (or form) a bellows. The container can take the form of a concertina.

[0147] In general, the terms "container" or "cell processing container" are used to define a container, receptacle, volume, or bioreactor, etc., in which one or more unit operations of cell and / or gene therapy manufacturing or processing may be completed.

[0148] In some embodiments, the body portion includes one (i.e., a single) fluid inlet and one (i.e., a single) fluid outlet. In some embodiments, the body portion includes one or more fluid inlets and one or more fluid outlets. In some embodiments, the body portion includes one (i.e., a single) fluid inlet and multiple fluid outlets. In some embodiments, the body portion includes multiple fluid inlets and one (i.e., a single) fluid outlet. In some embodiments, the body portion includes multiple fluid inlets and multiple fluid outlets.

[0149] In some embodiments, at least one auxiliary container is removably connected to the auxiliary container port.

[0150] In some embodiments, the primary container is removably connected to the primary container port.

[0151] In some embodiments, one or more auxiliary containers are indirectly fluidly coupled to the auxiliary container port. More specifically, one or more auxiliary containers may be connected to each other in series. Thus, the auxiliary containers can be in fluid communication with additional auxiliary containers that are not in direct fluid communication with the auxiliary container port of the cell processing platform. Additionally or alternatively, the cell processing device can further include one or more additional containers (e.g., bioreactors, etc.) that are in direct fluid communication with the primary container, but not necessarily in direct fluid communication with the cell processing platform. In this manner, the cell processing device can provide a multi-stage bioreactor operable to perform one or more unit processes in a cell and / or gene therapy manufacturing process.

[0152] In some embodiments, the auxiliary container port includes a container receiving sleeve connected to the body portion and configured to surround at least a portion of the auxiliary container, the portion including a fluid outlet portion of the container.

[0153] In some embodiments, the container receiving sleeve includes an insulating means configured to maintain the contents of the auxiliary container received therein at a particular temperature. More specifically, the insulating means is a thermal sleeve. Thus, the auxiliary container port can be configured to maintain the contents of the auxiliary container at an optimal temperature. For example, the optimal temperature can be cell culture temperature (37 degrees Celsius), room temperature (22 degrees Celsius), refrigeration (e.g., approximately 4 degrees Celsius), or freezing (e.g., approximately minus 4 degrees Celsius or below, e.g., minus 20 degrees Celsius or minus 80 degrees Celsius, etc.).

[0154] In some embodiments, the cell processing device includes one or more auxiliary container ports configured to maintain different temperatures.

[0155] In some embodiments, the cell processing platform includes a plurality of auxiliary container ports, each of the plurality of auxiliary containers being received in sealing engagement with one of the plurality of auxiliary container ports such that the lumen of each auxiliary container is fluidly connected to the fluid inlet portion of the body portion.

[0156] In some embodiments, the auxiliary container is removably attached to the auxiliary container port.

[0157] In some embodiments, each auxiliary container port is coupled to a separate fluid inlet portion of the body portion.

[0158] In some embodiments, each separate fluid inlet of the body portion is fluidly connected to a fluid outlet of the body portion.

[0159] In some embodiments, at least one fluid inlet and fluid outlet of the body portion are fluidly connected to one another by a fluid conduit.

[0160] In some embodiments, the fluid conduit includes a valve operable to open and close the fluid conduit.

[0161] In some embodiments, the valve is one of a pinch valve, a pressure sensitive valve, a clamp valve, a membrane valve, a rupture disk, a venous valve, and an aperture valve.

[0162] In some embodiments, each auxiliary container port includes a container fill port.

[0163] In some embodiments, the container fill port is fluidly connected to a fluid inlet of the auxiliary container port.

[0164] In some embodiments, each container fill port includes a valve that is operably coupled to the fluid inlet and fluid outlet of the auxiliary container port and is operable to control the fluid flow direction through the auxiliary container port.

[0165] In some embodiments, the container fill port includes a valve that, in an open position, is operable to allow fluid to flow to the fluid inlet of the auxiliary container port and not to the fluid outlet of the auxiliary container port, and, in a closed position, to close the container fill port and allow fluid to flow from the fluid inlet of the auxiliary container port to the fluid outlet of the auxiliary container port.

[0166] In some embodiments, at least one auxiliary container includes a mating element configured to fluidly connect to a corresponding mating element on the auxiliary container port.

[0167] In some embodiments, the mating element is one of a sterile connector end or a Luer Lok™.

[0168] In some embodiments, the primary container port includes a mating element that is configured to fluidly connect to a corresponding mating element on the primary container.

[0169] In some embodiments, the mating element includes one of a sterile connector end or a Luer Lok™.

[0170] In some embodiments, the auxiliary container port includes a Luer Lok™ connector at the fluid inlet and / or fluid outlet of the auxiliary container port, each Luer Lok™ connector configured to mate with an additional Luer Lok™ connector on the container and / or on the body portion, respectively. More specifically, a male Luer Lok™ connector is configured to mate with a female Luer Lok™ connector.

[0171] In some embodiments, the fluid outlet of the body portion includes a Luer Lok™ connector configured to engage with an additional Luer Lok™ connector on a primary container attachable to the body portion.

[0172] In some embodiments, the auxiliary container port includes a sterile connector end at the fluid inlet and / or fluid outlet of the auxiliary container port, each sterile connector end configured to engage with a further sterile connector end on the container and / or on the body portion, respectively.

[0173] In some embodiments, the fluid outlet portion of the body portion includes a sterile connector end configured to engage with a further sterile connector end on a primary container attachable to the body portion.

[0174] In some embodiments, the cell treatment device comprises at least one position tracking device operable to indicate a set location on the cell treatment platform, in this way, for example, when the cell treatment device is mounted into a cell treatment unit according to the invention, the position of the platform can be tracked.

[0175] In some embodiments, the at least one position tracking device is a mechanical device.

[0176] In some embodiments, at least one position tracking device includes a cog. In such embodiments, the mounting plate of the cell processing unit can include additional cogs operable to engage with protrusions of cogs on the cell processing platform. In this manner, the cell processing device will need to be physically inserted into the mounting plate of the cell processing unit in the correct orientation. This ensures that the operator knows the location of the device (and thus the location of the containers mounted on the platform in the cell processing unit).

[0177] In some embodiments, the position tracking device is an encoder. More specifically, the position tracking device is one or more of a magnet, an RFID sensor, or an optical sensor, etc.

[0178] In some embodiments, the cell processing device includes multiple position tracking devices.

[0179] In some embodiments, at least one position tracking device is positioned on the cell processing platform relative to the auxiliary container port such that the location of the position tracking device is related to the location of the auxiliary container port.

[0180] In some embodiments, at least one position tracking device is positioned on the body portion of the cell processing platform relative to the auxiliary container port.

[0181] In some embodiments, the system includes a plurality of position tracking devices each positioned on the body portion of the cell processing platform relative to the auxiliary container ports.

[0182] In some embodiments, the cell processing device includes a sampling port in the body portion of the cell processing platform. Alternatively, the sampling port may be located in the base section of the primary container.

[0183] In some embodiments, the cell treatment device includes a gas transfer port in a body portion of the cell treatment platform. Alternatively, the gas transfer port may be located in a wall of the primary container.

[0184] In some embodiments, the auxiliary container port is configured to receive a container having a base section, a top section disposed substantially parallel to the base section, and a wall element disposed between the top section and the base section and defining an interior lumen of the container, the wall element of the container preferably being compressible relative to the top section and the base section, and the wall element of the container being constructed from a flexible material.

[0185] In some embodiments, the primary container port is configured to receive a primary container having a base section, a top section disposed substantially parallel to the base section, and a wall element disposed between the top section and the base section and defining an interior lumen of the container, the wall element of the container preferably being compressible relative to the top section and the base section, and the wall element of the container being constructed from a flexible material.

[0186] In some embodiments, the primary container further includes a mounting flange attached to the top section of the primary container and configured to sealingly engage and removably mount to the primary container port.

[0187] In some embodiments, at least one auxiliary container is compressible. Thus, the container configuration is based on a concertina (which can act as a pump), and therefore there is no need for a separate pump and a complex set of tubing / pipes to transfer the contents of a container to another container in the system. And, this configuration reduces the space required for the cell and / or gene therapy manufacturing process.

[0188] In some embodiments, the container is the container described in Applicant's earlier US Pat. No. 6,399,633.

[0189] In some embodiments, the container is the container described in Applicant's earlier US Pat. No. 6,399,633.

[0190] Alternatively, the container may include a syringe arrangement that allows it to be refilled or emptied.

[0191] In some embodiments, the at least one auxiliary container is a syringe. In such a syringe configuration, the container has an arrangement similar to a syringe with a movable element to either expel fluid from the container or draw fluid back into the container.

[0192] In some embodiments, the container can include any shape container with a moving seal that allows for variable volume operation.

[0193] In some embodiments, at least one auxiliary container is a bag, which is held in the frame and is movable relative to the frame. More specifically, the top section, base section, and wall elements of at least one auxiliary container can form a bag, which can be held in an external adjustable frame, or which includes an internal adjustable frame in the material of the bag. Thus, one or more of the auxiliary containers in fluid communication with the cell processing platform of the present invention can form a bag, which can be held in an external adjustable frame, or which includes an internal adjustable frame in the material of the bag. Such a bag can be configured to act as, for example, an intravenous drip bag. Thus, it will be understood that the products of any reaction carried out in the primary or further container of the cell processing device can be collected into the bag, which can then be removed and transferred to the intravenous drip. Alternatively, the products of any reaction can be delivered directly to the patient from the lumen of the container.

[0194] In some embodiments, the cell processing device includes one or more auxiliary containers that are connected to an auxiliary container port of the cell processing platform. More specifically, the one or more auxiliary containers are removably connected to the auxiliary container port of the cell processing platform.

[0195] In some embodiments, one or more of the auxiliary containers are connected to their respective auxiliary container ports by a sterile connector.

[0196] In some embodiments, one or more of the auxiliary containers are connected to their respective auxiliary container ports by a Luer Lok™ style connector.

[0197] In some embodiments, the at least one auxiliary container is located above the cell processing platform.

[0198] In some embodiments, the primary container is located at the bottom of the cell processing platform.

[0199] According to a further aspect, the present invention provides a multi-step method of performing one or more unit operations in the manufacture of cell and / or gene therapies using a cell processing device according to the present invention.

[0200] In some embodiments, the method includes introducing a cell population (e.g., a cell population of interest) into a primary container and sequentially adding one or more reagents from one or more auxiliary containers into the primary container via a cell processing platform to achieve growth, culture, and / or recombination of the cells, e.g., to achieve a desired growth, culture, and / or recombination of the cells.

[0201] In some embodiments, the auxiliary container is one of a reagent container, a cell culture container, a waste container, an empty container, or a bioreactor.

[0202] In some embodiments, the primary container is one of a cell culture container or bioreactor, a reagent container, a waste container, a filter, an electroporator, a purifier, a waste container, a filter, an electroporator, a purifier, a holding container, an apheresis / leukapheresis, a differentiation chamber, a chromatography column, a sedimentation chamber, a sieve, a shaking / mixer, a centrifuge, and a magnetic bead separator, etc.

[0203] Containers of the present invention can be of circular, square, rectangular, oval, or triangular cross-section. Alternatively, containers of the present invention can include a number of different sections or regions of varying cross-sections (such as, for example, a series of circular cross-sections having variable (increasing and / or decreasing) diameters).

[0204] Advanced blow molding techniques can be used to deposit a second (or even third) exterior coating or layer of oxygen impermeable plastic onto the walls, top, and base of the secondary container. In this way, the shelf life of the container during storage can be extended.

[0205] According to a further aspect, the present invention provides a cell treatment system comprising a cell treatment device according to an aspect of the present invention and a cell treatment unit according to the present invention.

[0206] Cell Processing Container A critical step and risk in performing unit operations in the manufacture of cell and / or gene therapies is the sterile connection of equipment components to form a usable cell processing device or the like.

[0207] At least this object and advantage, which will be apparent from the description, is realized by a cell processing container for use in one or more unit operations in the manufacture of cell and / or gene therapy, the container comprising a base section, an upper section disposed substantially parallel to the base section, and a wall element disposed between the upper section and the base section and defining an internal lumen of the container, the wall element of the cell culture container preferably being compressible relative to the upper section and the base section, the wall element of the cell culture container being constructed from a flexible material, and the cell processing container comprising at least one sterile connector end, the at least one sterile connector end configured to operably couple with a further sterile connector end to form a sterile connector between the cell processing container and a further component with which the cell processing container is to be fluidly connected.

[0208] As referred to herein, a sterile connector shall include at least a sterile connection device, which is configured to create a sterile connection or weld between two elements (e.g., two containers or two pieces of compatible tubing). This procedure allows for the sterile connection of various containers and tubes of various diameters by maintaining a closed system as the two parts of the sterile connection device are mated together. In this way, a sterile fluid path is maintained between the two elements (e.g., containers or tubes, etc.). Each tube / container can have a sterile connector end embedded therein and can also have a removable membrane (e.g., paper) or valve barrier for mating with another connector end embedded in an additional tube / container. Sterile connectors are designed to connect one process stream to another process stream (e.g., connecting a container to a sampling line, connecting a medium to a product vessel, or connecting a filtration assembly to a filling line, etc.). They are useful when a biological containment hood is not available to make the sterile connection. This is because, due to the sterile pathway that is created, a sterile connection can be achieved regardless of the environment or surroundings in which the connection is being made.

[0209] The lines at the juncture of the connection cannot be disconnected without force because there are safety mechanisms in place to prevent this. Disconnection between connected sterile connector ends may require, for example, a disconnect device, tube sealer, or tube crimper.

[0210] The term "fluidly connected" is used to refer to a connection between components to allow the passage of a fluid. The term "fluid" is used to refer to gases and liquids, as well as solutions, suspensions, pastes, and gels. Moreover, fluids can also refer to granular particulates or solids (e.g., powders, etc.). Such particulates, solids, or powders may or may not be suspended in a liquid (e.g., a solution), etc.

[0211] In some instances, the wall elements of the cell processing container are preferably (i.e., optionally) compressible relative to the top section and the base section, i.e., the top section can be compressed relative to the base section, or the base section can be compressed relative to the top section, or the top section and the base section can be compressed relative to the base section and top section, respectively.

[0212] In other examples, the wall elements of the cell processing container are not compressible relative to the top and base sections. In some examples, the wall elements of the cell processing container can be flexible such that compressing (or squeezing) the wall elements inwardly toward the central longitudinal axis can be achieved.

[0213] In general, the terms "container" or "cell processing container" are used to define a container, receptacle, volume, or bioreactor, etc., in which one or more unit operations of cell and / or gene therapy manufacturing or processing may be completed.

[0214] In some embodiments, at least one sterile connector end is a genderless sterile connector end, and the genderless sterile connector end is configured to operably couple with an additional genderless sterile connector end.

[0215] That is, at least one sterile connector end can be genderless in the sense that it does not include a male or female portion. In some examples, a genderless sterile connector end can include one or more portions that cooperate with a portion of an additional genderless sterile connector end.

[0216] In some embodiments, at least one sterile connector end is a male sterile connector end, the male sterile connector end being configured to operably couple with a female sterile connector end.

[0217] In some embodiments, at least one sterile connector end is a female sterile connector end, the female sterile connector end being configured to operably couple with a male sterile connector end.

[0218] In some embodiments, the cell processing container includes a plurality of sterile connector ends, each configured to operably couple with a separate additional sterile connector end, forming a plurality of sterile connectors between the cell processing container and at least one additional component with which the cell processing container is to be fluidly connected.

[0219] In some embodiments, the at least one further component is one of a further cell processing container, a cell processing platform according to the invention, or a tube, or the like.

[0220] In some embodiments, the sterile connector end is embedded within the cell processing container.

[0221] In some instances, the sterile connector end can form part of the cell processing container, hi some instances, the sterile connector end can form an integral part or can be formed integrally with or as part of the cell processing container.

[0222] In some embodiments, the sterile connector end is operably connected to a pinch valve that is embedded within the cell processing container.

[0223] In some embodiments, the cell processing container has a circular, square, rectangular, oval, or triangular cross-section.

[0224] In some embodiments, when the cell processing container has a circular shape, the sterile connector ends are connected to the top section and / or base section of the cell processing container in an essentially circular pattern.

[0225] According to one aspect of the present invention, there is provided a cell processing system comprising a cell processing container as described above, the cell processing system further comprising one or more auxiliary containers removably connected to the cell processing container.

[0226] In some embodiments, one or more of the auxiliary containers includes an additional sterile connector end and is connected to the cell processing container via said additional sterile connector end.

[0227] In some embodiments, one or more of the auxiliary containers are located at or near the upper section of the cell processing container.

[0228] In some embodiments, one or more of the auxiliary containers are positioned above the upper section of the cell processing container.

[0229] In some embodiments, one or more of the auxiliary containers are positioned above the upper section of the cell culture container.

[0230] In some embodiments, one or more of the auxiliary containers are positioned at or near the base section of the cell processing container.

[0231] In some embodiments, the one or more auxiliary containers are positioned above the upper section of the cell processing container.

[0232] In some embodiments, one or more of the auxiliary containers are positioned above the base section of the cell culture container.

[0233] In some embodiments, one or more containers may be connected in series. For example, a cell processing system of the invention can include an auxiliary container that is in fluid communication with an additional auxiliary container that is not in direct fluid communication with the cell processing container of the system.

[0234] In some embodiments, each container in the series of containers includes a sterile connector end in the top section and in the base section. In this way, it is possible to perform one or more processing steps in the auxiliary container before making a sterile connection via the sterile connector end in the connected container to perform one or more further processing steps in the combined container. In some embodiments, the one or more processing steps and the one or more further processing steps may require different cell processing units.

[0235] In some embodiments, the one or more auxiliary containers have a base section, a top section disposed substantially parallel to the base section, and a wall element disposed between the top section and the base section and defining an interior lumen of the container, wherein the wall element of the auxiliary container is preferably compressible relative to the top section and the base section, and wherein the wall element of the auxiliary container is constructed from a flexible material.

[0236] Advanced blow molding techniques can be used to deposit a second (or even third) exterior coating or layer of oxygen impermeable plastic onto the walls, top, and base of the secondary container. In this way, the shelf life of the container during storage can be extended.

[0237] According to a further aspect of the invention there is provided a cell processing system operable to perform one or more unit operations in the manufacture of cell and / or gene therapies, the cell processing system comprising a cell processing unit according to an aspect of the invention, a cell processing device according to an aspect of the invention comprising a cell processing platform according to an aspect of the invention.

[0238] In some embodiments, the cell processing system comprises at least one cell processing container according to an aspect of the present invention.

[0239] According to a further aspect of the invention, there is provided a multi-step method of one or more unit operations in the manufacture of cell and / or gene therapies using a cell culture system according to the invention.

[0240] In some embodiments, the method includes introducing a cell population (e.g., a cell population of interest) into a cell processing container and sequentially adding one or more reagents from one or more auxiliary containers into the cell processing container to achieve one or more unit operations in the manufacture of a cell and / or gene therapy, e.g., a desired one or more unit operations in the manufacture of a cell and / or gene therapy.

[0241] As will be apparent to one of ordinary skill in the art, the elements, components, features, and advantages of the cell processing units, cell processing platforms, cell processing devices, cell processing containers, sterile connector ends, and methods of manufacture, use, and components thereof may be equally applicable to the various embodiments described herein, i.e., when a feature is described in the context of one embodiment, aspect, or example, this is not intended to exclude the inclusion of such feature with respect to another embodiment, aspect, or example, as will be recognized by one of ordinary skill in the art.

[0242] These and other aspects, features and advantages, by which embodiments of the present invention may be realized, will become apparent and elucidated from the following description of embodiments and aspects of the invention, which refers to the accompanying drawings. [Brief description of the drawings]

[0243] [Figure 1] FIG. 2 is a perspective view of a cell treatment unit according to an embodiment of the present invention, with a cell treatment device partially loaded into the device. [Diagram 2] FIG. 2 is a side view of a cell treatment device according to an embodiment of the present invention. [Diagram 3] FIG. 3 is a cross-sectional view of a portion of the cell treatment device of FIG. 2. [Figure 4a] FIG. 3 is a perspective view of a valve means of the cell treatment platform of the cell treatment device of FIG. 2. [Figure 4b]FIG. 3 is a perspective view of a valve means of the cell treatment platform of the cell treatment device of FIG. 2. [Diagram 5] FIG. 3 is an isolated side view of one auxiliary container port and auxiliary container of the cell processing device of FIG. 2. [Figure 6] FIG. 2 is a perspective view of the mounting bracket, actuator, and friction drive mechanism of the cell processing unit of FIG. 1. [Figure 7] FIG. 7 is a top view of the mounting plate and friction drive mechanism of the partial cell processing unit of FIG. 6. [Figure 8] FIG. 3 is a perspective view of the underside of the cell treatment device of FIG. 2. [Figure 9] FIG. 9 is a close-up view of the cell processing device and sensor arrangement of FIG. 8. [Figure 10] FIG. 9 is a top view of the cell processing device and sensor arrangement of FIG. 8. [Figure 11] FIG. 1 illustrates a Hall effect sensor of a cell processing unit and a cell processing platform including at least one magnet. [Figure 12] FIG. 2 is a side perspective view of a representation of one embodiment of a cell processing container including multiple sterile connectors according to embodiments of the present invention. [Figure 13] FIG. 1 is a side perspective view of a representation of one embodiment of a cell processing system of the present invention. [Figure 14A] FIG. 1 is a side perspective view of a representation of one embodiment of a cell processing system of the present invention, showing an auxiliary container connected to a cell processing container, leaving an empty auxiliary container port for an additional auxiliary container to be connected. [Figure 14B] FIG. 2 is a side perspective view of a representation of one embodiment of a cell processing system of the present invention, in which an auxiliary container is connected to an empty auxiliary container port of the cell processing container. [Figure 15A] FIG. 1 shows a known sterile connector arrangement formed from two sterile connector ends. [Figure 15B]FIG. 1 shows a known sterile connector arrangement formed from two sterile connector ends. [Figure 15C] FIG. 1 shows a known sterile connector arrangement formed from two sterile connector ends. [Figure 15D] FIG. 1 shows a known sterile connector arrangement formed from two sterile connector ends. [Figure 16A] FIG. 1 illustrates the formation of a sterile connector from two known sterile connector ends. [Figure 16B] FIG. 1 illustrates the formation of a sterile connector from two known sterile connector ends. [Figure 16C] FIG. 1 illustrates the formation of a sterile connector from two known sterile connector ends. [Figure 16D] FIG. 1 illustrates the formation of a sterile connector from two known sterile connector ends. [Figure 17A] FIG. 2 is a side perspective view of a representation of one embodiment of a cell processing container including a sterile connector end embedded therein. [Figure 17B] FIG. 15B is a close-up view of the sterile connector end of the cell processing container of FIG. 15A. [Figure 17C] FIG. 2 is a side perspective view of a representation of an auxiliary container for a cell processing device and / or cell processing system according to the present invention, including sterile connector ends and ready to be filled with reagents. [Figure 17D] FIG. 2 is a side perspective view of a representation of an auxiliary container for a cell processing device and / or cell processing system according to the present invention, including sterile connector ends and ready to be filled with reagents. [Figure 17E] FIG. 2 is a side perspective view of a representation of an auxiliary container for a cell processing device and / or cell processing system according to the present invention, including sterile connector ends and ready to be filled with reagents. [Figure 18A]FIG. 13 is a side perspective view of a representation of one embodiment of a supplemental container including a sterile connector end recessed in the base section and a screw-top cap in the top section. [Figure 18B] FIG. 2 is a side perspective view of a representation of one embodiment of a cell processing container including multiple sterile connector ends embedded within the top and bottom sections. [Figure 18C] FIG. 1 shows a schematic representation of multiple pre-filled auxiliary containers connected to a cell processing container to produce a cell processing system according to the present invention, the auxiliary container having a sterile connector end in an auxiliary container port for receiving further auxiliary containers containing patient cells. [Figure 18D] FIG. 1 shows a schematic representation of multiple pre-filled auxiliary containers connected to a disposable wave container to produce a cell processing system according to the present invention, having a sterile connector end in an auxiliary container port for receiving further auxiliary containers containing patient cells. [Figure 18E] FIG. 1 shows a schematic representation of multiple pre-filled auxiliary containers having sterile connector ends in the auxiliary container ports for receiving further auxiliary containers containing patient cells, connected to a CSTR bioreactor to generate a cell processing system according to the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0244] Specific embodiments of the present invention will now be described with reference to the accompanying drawings. However, the present invention may be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. The terminology used in the detailed description of the embodiments illustrated in the accompanying drawings is not intended to be limiting of the present invention. In the drawings, like numbers refer to like elements.

[0245] The terminology used herein is for the purpose of describing particular aspects of the present disclosure only and is not intended to be limiting of the present disclosure. As used herein, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise.

[0246] In the drawings and specification, exemplary embodiments of the present disclosure are disclosed. However, many variations and modifications can be made to these embodiments without substantially departing from the principles of the present disclosure. Therefore, the present disclosure should be regarded as illustrative rather than restrictive, and should not be regarded as being limited to the specific embodiments discussed above. Thus, although specific terms are used, they are used in a generic and descriptive sense only, and not for purposes of limitation, and the definition of dimensions such as width, breadth, height, length, or diameter depends on what exemplary embodiment is shown, and therefore, when shown differently, a width or diameter shown in one depiction is a length or thickness in another depiction.

[0247] It should be noted that the word "comprising" does not necessarily exclude the presence of other elements or steps than those listed, and the word "a" or "an" preceding an element does not exclude the presence of a plurality of such elements. It should be further noted that any reference signs are not intended to limit the scope of the claims, that exemplary aspects may be implemented at least in part by both hardware and software, and that several "means," "units," or "devices" may be represented by the same item of hardware.

[0248] It should be understood that any feature, integer, attribute, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the invention is applicable to any other aspect, embodiment, or example described herein, except where incompatible therewith. All of the features disclosed herein (including any accompanying claims, abstract, and drawings) and / or all of the steps of any method or process so disclosed may be combined in any combination (except combinations in which at least some of such features and / or steps are mutually exclusive). The invention is not limited to the details of any of the preceding embodiments. The invention extends to any novel one or any novel combination of the features disclosed herein (including any accompanying claims, abstract, and drawings) or to any novel one or any novel combination of the steps of any method or process so disclosed.

[0249] In the drawings, like reference numbers refer to like parts.

[0250] Cell Processing Unit FIG. 1 illustrates a cell processing unit 1 according to the present invention. The cell processing unit includes a housing 2 formed of four walls upstanding from a base wall and a top wall, the top wall being parallel to the base wall and spaced apart from it by the length of the wall. The housing 2 forms a chamber 3 with a hinged door 7 in one wall for receiving a cell processing device 901 including a cell processing platform (CPP) 9. A control panel 5 is located on the front panel of the cell processing unit 1 and allows a user to program and control various features located in the chamber 3 and their interaction with the cell processing device 901. Details of these features and the cell processing device 901 are described in more detail below.

[0251] The cell processing unit 1 has a housing 2 defining an enclosed space, which is a chamber 3 within which one or more unit operations (i.e., steps) of a cell and / or gene therapy manufacturing process can be carried out.

[0252] An automated cell processing system according to an embodiment of the present invention includes a cell processing unit 1 and a cell processing device 901 as shown in FIG. 2. The cell processing device 901 includes a cell processing platform 9 and one or more auxiliary containers 11 coupled to the platform 9. The platform 9 is operated by the cell processing unit 1 and is capable of transferring liquid between the auxiliary containers 11 (e.g., feed bellows) located at the top of the cell processing platform 9 and a primary container 13 (e.g., reactor bellows) located at the bottom of the cell processing platform 9. FIG. 1 shows an embodiment in which the cell processing system has a cell processing unit 1 and a cell processing device 901, which includes five auxiliary containers 11 fluidly connected to the cell processing platform 9. The cell processing unit 1 rotates the platform 9 using a friction drive system. The cell processing unit 1 includes a valve solenoid micro-linear actuator (38, FIG. 6) that, when activated, opens a pinch valve 27 in the cell processing platform 9 and pushes the auxiliary container 11 using a linear actuator (106, FIG. 6). The cell processing platform 9 includes a body portion including a base plate 15 on which a primary container 13 (e.g., reactor bellows) is mounted down into a primary container port (FIG. 2, reference number 14) and five auxiliary containers 11 (e.g., feed bellows) are mounted on the base plate 15 in an auxiliary container port 19. The auxiliary containers 11 (e.g., feed bellows) are mounted on a sleeve that forms the auxiliary container port 19, which contains a Luer Lok™ fitting to connect the auxiliary containers 11 to tubing in the auxiliary container port 19. The tubing is fluidly connected through base plate 15 to tubing within base plate 15 above the fluid outlet at primary container port 14 .Each auxiliary container port 19 includes a fill valve 31 that allows for filling of the auxiliary container 11 that is fluidly connected to the port 19. The base plate 15 of the cell processing platform 9 contains a normally closed pinch valve 27 that acts on the tubing 29 between the auxiliary container 11 and the primary container 13. In this embodiment, the cell processing system includes a cell processing device with five auxiliary containers. However, it should be recognized that the cell processing device can have a different number of auxiliary containers in accordance with the present disclosure. It is further envisioned that the containers can have different volumes in accordance with the present disclosure.

[0253] The chamber 3 is not sterile, but the containers are completely closed when loaded into the cell processing platform. The parallel and / or serial containers in the cell processing platform provide a single closed consumable unit (cell processing device) for the entire manufacturing process. Filling the containers is done aseptically (e.g., in a laminar flow hood) or using sterile connections (e.g., tube welds or sterile connections).

[0254] The housing 2 of the cell processing unit 1 allows easy insertion and removal of the cell processing device 901 through the front opening door 7. With the door 7 open, the cell processing device 901, including the cell processing platform 9 and attached auxiliary containers 11 each containing various cell processing reagents, can be lowered and slid into its final position. The control panel 5 is located at the front of the housing 2, meaning that all interactions with the device 1 are from the front. In this way, multiple cell processing units 1 can be installed near each other, side by side, or on top of each other. Having a row of units or a stack of units respectively facilitates the capacity for advanced manufacturing and processing. The embodiment shown is shown with five buttons, one for each feed actuation in the test protocol for the system. The door 7 is transparent, allowing the operation to be seen when demonstrating the functionality of the device. In an alternative embodiment, an opaque door can be provided. In this way, the cells can be shielded from UV light during processing.

[0255] Cell Processing Unit Figure 6 shows a portion 101 of the cell processing unit 1 with the housing 2 removed for ease of depiction. Inside the housing, the cell processing unit portion 101 includes a linear actuator 103 for compression of the auxiliary container 11 feed bellows, a linear actuator 106 for compression of the primary container 13 reactor bellows, a friction drive mechanism (107, 109, 111) mounted on a mounting plate 104 and operable to rotate the cell processing platform 9, and a micro linear actuator 38 for opening pinch valves operable to open and close tubing within the platform. The internal structure of the device is machined from aluminum and the linear actuators 106, 103 are of aluminum and steel construction with lead screws that are hard coated with TFE dry lubricant.

[0256] In addition to the mounting plate 104, the mounting bracket includes a mounting flange (not shown) that is positioned above the mounting plate to hold the cell processing platform by a friction fit between the mounting plate 104 and the mounting flange.

[0257] The layout of the actuators 38, 103, 106 allows them to be hidden at the rear of the device by a cover (not shown), with only the plungers 103a, 106a protruding through the cover to compress the bellows of the auxiliary and primary containers, respectively, helping to give a clean, uncomplicated appearance and providing a device that is easier to clean and wipe down. Power and electronics for the actuators and friction drive mechanisms are mounted below the mounting plate 104 on a plate 112. Four risers 114 are adjustable in height and operable to vary the distance between the mounting plate 104 and the plate 112 which houses the power and electronics. In this manner, the device is capable of accommodating primary containers of different sizes.

[0258] The housing 2 contains all of the actuators and electronics necessary to operate the cell processing device. The feed bellows plunger 103a and reactor plunger 106a, operable to exert a compressive force on the auxiliary container and primary container, respectively, are mounted on linear rails, each with a maximum force of 100N. The motor that drives the linear rail is a bipolar stepper motor. The valve actuator 38 is a linear actuator with a maximum force of 45N.

[0259] The friction drive mechanism (107, 109, 111) includes a drive wheel 107 that is positioned on the mounting plate 104 and is operable to impart rotation to the cell processing device. The drive wheel 107 is a bipolar stepper motor. The actuator stepper motor on the linear rail and the stepper motor within the friction drive mechanism are driven by a control system and associated power supply (not shown).

[0260] FIG. 7 shows elements of the friction drive mechanism (107, 109, 111) mounted on the mounting plate 104 of the mounting bracket. To allow the cell processing platform 9 and the cell processing device 901, including the auxiliary containers, to be inserted only from the front, a drive method was developed in which the cell processing platform 9 is held between three friction wheels, one of which is driven (107), another is spring-loaded (109), and the third is a hinged wheel 111 in a door that opens to allow the insertion of the platform 9 and closes to lock it in place. The cell processing device 901 rotates on low friction PTFE pads 116 on the mounting plate 104. The spring force of the spring-loaded friction wheel 109 ensures that there is no slip between the drive wheel 107 and the outer surface of the base plate 15 of the platform 9. The drive wheel 107 is directly connected to a stepper motor. The base plate 15 of the cell processing platform 9 is fitted with a series of magnets 118 around its periphery so that its position can be read by a Hall effect sensor 120 mounted on the mounting plate 104. The cell processing platform 9 thus acts like an encoder, giving closed loop position feedback independent of any motor slip.

[0261] A Hall effect sensor 120 mounted on the mounting plate 104 attached to the housing 2 is operable to detect a magnetic field from a magnet 118 on the cell processing platform 9 mounted in the housing 2. The Hall effect sensor 120 is operable to detect the position of the cell processing platform 9 relative to the mounting plate 104. As best seen in FIG. 8, each auxiliary container port 19 mounted on the base plate 15 of the cell processing platform 9 has a magnet 118 positioned in the base plate 15 adjacent to the port 19. In this manner, the Hall effect sensor 120 will detect the magnet 118 when the auxiliary container port 19 and its associated magnet 118 are aligned with the sensor. Thus, each auxiliary container port 19 is at a known position in the housing relative to the mounting plate 104.

[0262] 8, 9, 10 and 11 show a position sensor array operable to detect the position of the cell processing platform 9 of the cell processing device in the cell processing unit 1. FIG.

[0263] The sensor array includes a Hall effect sensor 120 and a series of magnets 118 on the base plate 15. The sensor array tracks the position of the cell processing platform 9 using the Hall effect sensor 120. The Hall effect sensor 120 produces a voltage in response to the magnetic field produced by the magnet 118. There are two Hall effect sensors 120 mounted on the mounting plate 104 in the housing 2 and a series of magnets 118 embedded in the cell processing platform 9. One of the Hall effect sensors 120 is for tracking the rotation of the cell processing platform 9 relative to the mounting plate 104, and the other Hall effect sensor 120 is dedicated to tracking the so-called home position of the cell processing platform 9 relative to the mounting plate 104. The home position is determined by having one magnet 118 on a different pitch circle diameter than the other magnets 118 on the cell processing platform 9, and serves as an index or marker for counting the full rotation of the cell processing platform 9 in the housing 2. Using the cell handling device as the encoder, rather than having an encoder on the motor, means that there is closed loop position feedback on the cell handling device itself.

[0264] To ensure that there will be no slip between the drive mechanism and platform 9, the friction between the elastomeric drive (friction) wheels 107 and the base plate 15 must be greater than the friction between the PTFE pads 116 and the base plate 15. Using the maximum force that will be transmitted between the drive wheels 107 and the base plate 15 of the platform 9, the typical force required to ensure a consistent drive can be calculated.

[0265] Cell Processing Device As shown in Figures 2-5, the cell processing device 9 includes a cell processing platform having an annular base plate 15 with a number of auxiliary container ports 19 (in this case, five) located on its upper surface, and a single primary or reaction container 13 mounted thereon at a primary container port 14. Each auxiliary container port 19 is adapted to receive an auxiliary container 11 (such as, for example, the type described herein or in Applicant's earlier US Patent No. 5,999,333). Each of the auxiliary containers 11 in the example has a maximum capacity of 45 ml, such that the total feed capacity of the five auxiliary containers 11 is 225 ml. The primary container 13 has a maximum capacity of 150 ml.

[0266] 3, the auxiliary container 11 includes a top section 21 and a base section 23 with the collapsible bellows portion 17 positioned therebetween to define a storage volume 20. The base section 23 includes a fluid outlet 25 through which the contents of the storage volume 20 may be transferred. With the auxiliary container 11 positioned into the auxiliary container port 19, the outlet 25 is in fluid communication with a connector 26 positioned therein. In the example shown, the connector 26 includes a four-way stopcock, which is described in more detail below.

[0267] The secondary container 11 is made from blow molded LDPE while the secondary container port 19 is made from nylon. The base plate 15 is made from machined HDPE and the primary container 13 is made from blow molded HDPE bonded to a machined HDPE flange which is the primary container port 14. The base plate 15 is made of three pieces which are threaded together. The primary container 13 is attached to the base plate 15 by screws.

[0268] The flexible tubing 29 includes a first end attached to the connector 26 and a second end attached to the base plate outlet 33, thereby forming a fluid communication conduit between the secondary container 11 and the primary container 13. The flexible tubing 29 can include any suitable length and cross-section. In the example shown, the flexible tubing 29 is Cole-Parmer® Platinum Cured Silicone Tubing having an inside diameter (ID) of 1 / 8" and an outside diameter (OD) of 3 / 16". In a suitable configuration, the flexible tubing will be made from a suitably non-leachable, elastic, biologically inert material, in this case silicone, although other elastic materials may be used.

[0269] Fluid flow through the fluid communication conduits, and therefore between the auxiliary container 11 and the primary container 13, is controlled by valve means 27 located in the base plate 15. In the example shown, the auxiliary container 11 is one of several, each located in a corresponding auxiliary container port 19 on the base plate 15. Each auxiliary container 11 is thus provided with its own fluid communication conduit 29 to the primary container 13, controlled by a separate valve means 27. In this way, the transfer of the contents of each storage volume 20 can be precisely and independently controlled.

[0270] One of the valve means 27 is shown in more detail in Figures 4a and 4b. The valve means 27 comprises a closure portion 37 slidably engaged in a radial channel located in the base plate 15 and defined between channel walls 41a and 41b. The closure portion 37 is substantially hollow rectangular in shape with a longer pair of opposing walls arranged parallel to the channel walls 41a and 41b and a shorter pair of opposing walls arranged at its inner and outer surfaces. An actuating portion 38 is provided on the outer shorter wall and a compressing portion 43 is provided on the inner shorter wall.

[0271] The closure part 37 is positioned on a valve wall 39 which is fixed in the channel and spaced apart from channel walls 41 a and 41 b. The closure part 37 can thus be moved between two extreme positions, a closed position (FIG. 4a) and an open position (FIG. 4b), by sliding over the valve wall 39 in the channel.

[0272] The flexible tubing 29 is arranged to extend through the valve means 27 such that a section of the tubing 29 sits between the valve wall 39 and the constricted portion 43. In the closed position, the closure portion 37 is urged towards the outer periphery of the base plate 15 by a spring 35. The spring 35 is positioned to act on the constricted portion 43, urging the constricted portion 43 against the flexible tubing 29, pinching the flexible tubing 29 against the valve wall 39. Thus, in the closed position, the pinched section of the tubing blocks the fluid communication conduit and prevents fluid flow.

[0273] To unblock the conduit, the closure portion 37 is moved toward the open position by depressing the actuation portion 38, releasing the compressed portion 43 from the valve wall 39 and allowing the pinched section of flexible tubing to return to its original shape, permitting fluid flow.

[0274] With the cell processing device installed in the cell processing unit, the valve means 27 is actuated by the actuator 38 to open while the auxiliary container 11 is being compressed by the plunger 103a. The actuator 38 may be configured such that the valve means 27 opens when the auxiliary container 11 is being compressed. Alternatively, actuation can occur as a separate step, for example when the auxiliary container 11 is received into the auxiliary container port 19. Actuation can occur automatically in conjunction with compression of the auxiliary container 11 or can be controlled to occur independently.

[0275] In the example shown, valve actuation is performed by a linear actuator 38, which is positioned at the rear of the housing 2 of the cell processing unit 1, which acts on the closure part 37 to move it towards the open position. The valve means is thus normally closed and is only actuated to open when fluid needs to be delivered to the primary container 13.

[0276] 3, each auxiliary container 11 is attached to a fill valve connector 26 in the form of a four-way stopcock. Connector 26 includes a Luer Lok™ port for filling via direct access to the auxiliary container 11. This port may be used to manually insert fluid into the auxiliary container, and does not have its own valve means 27, but is instead capped.

[0277] Two further capped Luer Lok™ ports are provided on the base plate 15 for sampling / collecting fluids or for gas exchange. The first port leads to the headspace of the primary container, while the further port is connected to the base of the primary container 13.

[0278] 5 shows the fill port 31 and lever 45 mounted above the auxiliary container port 19. The lever 45 is provided for filling the auxiliary container 11 without allowing material to flow into the valve means 27 or the primary container 13. The lever 45 is operatively connected to a four-way stopcock, which in the example described above forms the connector 26. In the fill position (lever facing down), the fill port 31 is open and the flow of material through the port 31 is directed into the auxiliary container 11. Then, in the feed position (lever facing up), the fill port 31 is closed and the flow is directed from the auxiliary container 11 through the fluid communication channel 29 into the primary container 13.

[0279] Sterile Connector 12 shows a cell processing container 200 according to an embodiment of the present invention. The cell processing container 200 includes a base section 202, an upper section 203, and a wall element 204 disposed between the upper section 203 and the base section 202. Preferably, the wall element 204 is constructed from a flexible material. The wall element 204 is preferably compressible relative to the upper section 203 and the base section 202. The cell processing container 200 may thereby have a "concertina" or "bellows arrangement", for example, it may have one or more Z-folds in the wall element 204 arrangement.

[0280] The cell processing container 200 can include one sterile connector end and preferably includes multiple connector ends 205. The connector ends 205 are preferably sterile. The sterile connector ends 205 are preferably located on the top section 203 and / or on the base section 202 of the cell processing container 200. The cell processing container 200 preferably includes at least one, at least two, at least three, at least four, or at least five sterile connector ends 205. According to a preferred embodiment, the sterile connector ends 205 are recessed within the cell processing container 200. The sterile connector ends 205 allow for easy sterile connection of auxiliary containers 11 to the cell processing container 200.

[0281] The cell processing container 200 can have any possible shape. In a preferred embodiment, the cell processing container 200 has a circular, square, rectangular, oval, or triangular cross-section.

[0282] In a preferred embodiment, when the cell processing container 200 has a circular shape, the sterile connector ends 205 are preferably connected to the top section 203 and / or the base section 202 in an essentially circular pattern. Also, the cell processing container 200 includes a sterile connector end 205 at the center of the top section 203 and the base section 202. The sterile connector ends 205 are connected to the top section 203 and / or the base section 202 in an essentially symmetrical manner, with essentially the same distance between the different connector ends 205. This allows for an easier and possibly automated process of manufacturing cell and / or gene therapy. In an alternative embodiment, when the cell processing container 200 has a circular shape, the sterile connector ends 205 are connected to the center of the top section 203 and the base section 202.

[0283] An embodiment of the invention is shown in Figures 13 and 14A-14B, which shows a cell processing system according to the invention, which includes a cell processing container 200 as described above, with one or more auxiliary containers 11 attached to the cell processing container 200. The auxiliary containers 11 are preferably connected to the cell processing container 200 via sterile connector ends 205. The auxiliary containers 11 are preferably connected to the cell processing container 200 on the top section 203 and / or base section 202. The auxiliary containers 11 can also be cell processing containers according to the invention that include sterile connector ends recessed into the base portion of the container 11.

[0284] In further embodiments, such as that shown in FIG. 2, the auxiliary containers 11 are fluidly connected to the cell processing container 13 through a body portion 15. The body portion forms part of the cell processing platform 9. The auxiliary containers 11 each include a sterile connector end that is recessed into a base section of the auxiliary containers 11. The recessed sterile connector ends interconnect and sealingly engage with corresponding sterile connector ends in the body portion 15 of the cell processing platform 9. The cell culture container 13 (which is the primary container) is sealingly engaged with the bottom of the body portion 15 to form a fluid connection between the body portion 15 and the cell culture container 13.

[0285] The fluid conduits (not shown) between the sterile connectors attaching the auxiliary containers 11 to the body portion 15 and the fluid outlets (not shown) of the body portion 15 (to which the cell processing containers 13 are attached) include pinch valves. The pinch valves are operable to open and close the fluid conduits in response to a valve actuator such that when a compressive force is applied to the respective auxiliary container 11, the contents of the auxiliary containers may be transferred to the container upon application of a compressive force. In an alternative embodiment, the pinch valves may be replaced by pressure sensitive valves (e.g., burst valves) that open when a compressive force is applied to the respective auxiliary container 11.

[0286] In the embodiment shown in Figures 14A and 14B, one or more of the feed bellows 11 are pre-attached to the primary cell processing container 200, pre-filled with reagents (e.g., liquids), and stored in a refrigerator. The cell processing system shown in Figures 14A and 14B can be used to attach heat-labile components (e.g., viruses or cells, etc.) that need to be stored at -80 degrees Celsius or in liquid nitrogen. Because storing the entire cell processing system at these temperatures is expensive, the sterile connectors 205 embedded in the feed bellows 11 and on the top of the primary container 200 serve as a way to add heat-labile components without the use of a sterile laminar flow hood or a sterile tubing welder, thus eliminating tube-based connections and keeping the system compact.

[0287] Advanced blow molding techniques can be used to deposit a second (or even third) exterior coating or layer of oxygen impermeable plastic onto the walls, top, and base of the secondary container. In this way, the shelf life of the container during storage can be extended.

[0288] 15A-15D show an exemplary sterile connection between two sterile connector ends 400. The sterile connector ends 400 each have a mechanical connection (e.g., screw threads, etc.) or latch (not shown) disposed in an internal circumferential manner on the sterile connector ends 400. The internal circumferential latch provides proper orientation of the sterile connector ends 400 relative to one another to ensure that the oppositely aligned adhesive members 40 attached to the sterile connector ends 400 achieve a sterile fluid connection. In FIG. 15B, the two adhesive members 40 are aligned such that the front second fold adhesive coating of each adhesive member 40 is mirror symmetrical to one another. This alignment is important because the rolled member 40 can only be pulled in one linear direction. Once the two front second fold adhesive coated surfaces are in contact, as shown in Figure 15C, the member pull grip 50 is pulled away from the longitudinal axis of the sterile conduit 190, thereby exposing the conduit apertures (Figure 15D). In Figures 15C and 15D, the rolled member 40 is fully withdrawn into an unfolded configuration, with the conduit apertures aligned to form a sterile corridor.

[0289] In FIG. 16A, two opposing sterile connector ends 150 are aligned such that the front second fold adhesive coatings 80, 120 of the rolled membranes of each of the sterile connector ends 150 are mirror images of each other. This alignment is important because the rolled membrane can only be pulled in one linear direction. When the two front second fold adhesive coatings 80, 120 surfaces come into contact, the entire adhesive surface area comes into contact, as shown in FIG. 16B, thereby sealing each opposing sterile connector end 150 together. In FIG. 16C, the membrane pull grip 50 is pulled away from the longitudinal axis of the sterile corridor, thereby exposing the conduit aperture 60. In FIG. 16D, the rolled member 40 is fully pulled to an unfolded configuration such that the conduit apertures 60 are aligned to form a sterile corridor between each of the sterile connector ends 150.

[0290] 17A shows a cell processing container 13 with a sterile connector end 37 recessed into the top section of the container wall. The sterile connector end 37 forms one half of a sterile connector when the cell processing container 13 is fluidly connected to a corresponding sterile connector end in the auxiliary container 11. In an alternative embodiment, the cell processing container 13 is fluidly connected to a corresponding sterile connector end in the body portion 15 of the cell processing platform 9. The sterile connector end in the body portion 15 of the cell processing platform 9 is part of the platform's primary container port.

[0291] FIG. 17B shows an exploded partial view of the sterile connector end 37 of FIG. 17A. FIG. 17B shows a male sterile connector end (one half of a sterile connector) in the top wall of the cell culture container 13. The sterile connector end 37 includes a removable paper cap 39 that, when engaged with the removable paper cap of a further sterile connector end, when removed, exposes a sterile surface surrounded by the screw cap engaged by the screw threads 41a and 41b of the sterile connector end 37, creating a fluid connection to the cell processing container lumen. Specifically, the removable paper cap is a contamination-preventing pull tab that is first folded over the sterile connector end 37 and has an end protruding therefrom. The pull tab can then be pulled out, exposing the sterile surfaces to one another.

[0292] 17C-17E show the auxiliary container 11 being filled with media in a sterilization process. This process can be manual or automated. In FIG. 17D, the sterile connector end 37 is removed and media is filled into the lumen of the container 11. Filling of the container 11 is performed under sterile conditions. In FIG. 17E, the sterile connector end 37 is replaced and the auxiliary container 11 is stored at an appropriate temperature until it is needed for assembly of a cell processing system. Once filled and ready for use, the auxiliary container 11 is inverted and the sterile connector end 37 is mated and connected with a corresponding sterile connector end on a primary container, such as a cell processing container.

[0293] 18A, the auxiliary container 11 has a screw cap 51 on one end and a sterile connector end 37 on the other end. In this manner, the integrity of the sterile connector end 37 can be maintained during storage of the auxiliary container 11 by inverting the container 11 so that the medium sits on the end of the auxiliary container 11 having the screw cap 51 and the sterile connector end 37 is not in contact with any liquid.

[0294] The recessed sterile connector end 37 ensures that the auxiliary container 11 can be easily connected to an auxiliary container port of the cell processing platform 9 or directly to a cell processing container 13 in a cell processing system according to the present invention.

[0295] 18A shows an auxiliary container 11 having a sterile connector end 37 protected by an end cap 151 in the base section of the auxiliary container 11. The container 11 also has a screw cap 51 in the top section of the container to allow for filling of the container lumen with media or the like. The screw cap 51 is compatible with automated media filling techniques and equipment.

[0296] The sterile connector end 37 facilitates a fluid connection between the lumen of the auxiliary container and the contents therein, with the cell processing container 13 having a corresponding sterile connector end in the top section of the container 13. To access the sterile connector end 37 in the base section of the auxiliary container 11, the cap 151 is removed and the sterile connector end 37 can then be mated into sealing engagement with a corresponding sterile connector end on the cell processing container 13. In an alternative embodiment, the sterile connector end 37 can be mated into sealing engagement with a corresponding sterile connector end on the cell processing platform. More specifically, the sterile connector end 37 can be mated into sealing engagement with a corresponding sterile connector end in the auxiliary container port 19 on the cell processing platform 9.

[0297] Advanced blow molding techniques can be used to deposit a second (or even third) exterior coating or layer of oxygen impermeable plastic onto the walls, top, and base of the secondary container. In this way, the shelf life of the container during storage can be extended.

[0298] FIG. 18B shows a cell processing container (reactor bellows) 13 including multiple bottom sterile connectors (that are recessed sterile connector ends 139) in the base section of the cell culture container 13. In the embodiment shown, the cell processing container 13 (e.g., reactor bellows) is equipped with multiple sterile connector ends 141 in the top section of the container 13 for connection of multiple auxiliary containers 11. The auxiliary containers 11 can contain media and / or cell nutrients required for cell culture. Alternatively, the auxiliary containers can be for sampling or waste removal from the cell processing container 13. In a sampling configuration, the cell processing container (e.g., reactor bellows) 13 can be fluidly connected to the removable auxiliary container 11 via a pinch valve. The pinch valve is opened and then the auxiliary container 11 is inflated to take a sample from the cell processing container 13. The pinch valve is then closed before removing the sample auxiliary container 11. The connection can be made via a Luer Lok or similar that maintains a sterile barrier when the pinch valve is closed. Thus, the sample can be removed from the cell processing container 13. The cell processing container 13 (e.g., reactor bellows) is equipped with multiple sterile connector ends 139 in the base section of the container 13 for connection to multiple subsequent collection / processing bellows (not shown). A pinch valve 127 is housed between the sterile connector end 141 and the cell culture container 13, which pinch valve 127 can be used to switch on / off the flow of feed from the auxiliary container 11. Such valve activation is useful / necessary, for example, when only partial volumes are required or when feed needs to be added from a single auxiliary container at more than one time point.

[0299] In an alternative embodiment, the pinch valves may be recessed into the outlet tubing from each auxiliary container 11 .

[0300] In a further alternative embodiment, the pinch valves may be pressure actuated to open when a compressive force is applied to the respective auxiliary container 11 .

[0301] FIG. 18C illustrates the use of pre-filled auxiliary containers 311 in a cell processing system 300 according to the present invention. Four auxiliary containers 311 are pre-filled with wash buffer and stored at room temperature. Four additional auxiliary containers 311 are pre-filled with growth medium and stored at 4 degrees Celsius. Five auxiliary containers 311 are pre-filled with lentivirus and stored at -80 degrees Celsius. Four additional auxiliary containers 311 are pre-filled with medium incorporating magnetic beads and stored at 4 degrees Celsius. Each of the pre-filled auxiliary containers 311 is connected to the cell processing container 313 via a sterile connector end embedded in the base portion of the respective auxiliary container 311 and in the top of the cell culture container 311. The auxiliary container port 319 is left empty and ready to receive a container containing patient cells. It should be appreciated that in alternative embodiments, the cell processing system 300 includes a different number of pre-filled auxiliary containers 311 according to the present disclosure. For example, each set of pre-filled auxiliary containers 311 can include tens or even hundreds of containers 311.

[0302] The cell processing system, including the auxiliary container 311 and the cell processing container 313, is now ready for processing in a cell processing unit according to the invention.

[0303] 18D and 18E show a pre-filled auxiliary container 311 housed above a conventional disposable wave bioreactor 413 and a CSTR bioreactor 513.

[0304] The cell processing units, cell processing platforms, cell processing devices, and cell processing containers according to the present invention may be used in any chemical, biological, or separation process. The unit processes (e.g., steps) of such processes may be performed. The cell processing devices, together with the cell processing units and, optionally, at least one cell processing container of the present invention, may be used in cell culture processes (e.g., culturing, manipulating, growing, or storing cells) or in genetic engineering processes (e.g., steps including purification processes, genetic engineering processes, recovery processes, and washing processes). Other suitable unit processes that may be performed in the cell processing units, platforms, devices, and containers of the present invention include, but are not limited to, purification (e.g., affinity, size), washing, sedimentation, centrifugation, filtration, chromatography, magnetic bead processes, transduction, electroporation, novel hydrogels, shipping and thawing, growing cells in culture, genetic engineering, and cryopreservation.

[0305] The cell treatment device and cell treatment container of the present invention are suitable for cell culture and cell treatment, respectively, including the use of the container in cell therapy, gene therapy vector production, and / or exosome production. The container or device of the present invention may be suitably sterilized (e.g., by gamma irradiation or other means) prior to use. Optionally, the interior surface of the container may be coated with or contain a biologically active agent, which may act on and / or induce differentiation of cells in culture.

[0306] The cell processing equipment described herein may be used in cell manufacturing processes and / or gene therapy manufacturing processes involving any suitable cell or gene type. For example, the device of the present invention may be used to culture any prokaryotic or eukaryotic cell, suitably an animal cell, e.g., a mammalian cell. The cells can be human or non-human. Examples of suitable sources of non-human cells include rodents, such as mice, rats, and guinea pigs, as well as ungulates selected from sheep, goats, pigs, cattle, and / or horse species, or non-human primate species. However, the cells may also be bacterial, yeast, fungal, or plant cells in origin.

[0307] The cells can be of any type, including somatic and non-somatic cells. The cells can be stem cells derived from any stage of embryonic, fetal, or adult animal development. The cells can be genetically modified cells, such as chimeric antigen receptor T-cells (CART). The cells can be from a deposited cell line, such as genetically modified Chinese Hamster Ovary (CHO) cells, and can produce recombinant proteins.

[0308] For example, embryonic stem (ES) cells include cells of non-human origin. The cells can be derived from deposited cell lines, such as ES cell lines. ES cells can be derived by means that do not require the destruction of human embryos, such as parthenogenetic activation, as described in US Pat. No. 5,399,633. The cells can be cancer or hybridoma cells that can be caused to grow rapidly in culture and / or to produce monoclonal antibodies. The cells can also be derived as a result of somatic cell nuclear transfer (SCNT), in which the nucleus of a somatic cell is placed into an enucleated oocyte.

[0309] The cells can be pluripotent stem cells, such as primate pluripotent stem (pPS) cells, such as human embryonic stem (hES) cells. If the cells are stem cells, the source can be from any tissue of the body, including mesenchymal stem cells (including umbilical cord-derived stem cells), neural stem cells, or hematopoietic stem cells. Also included are induced pluripotent stem (iPS) cells.

[0310] Thus, the present invention provides for the processing of cells in a single device with multiple unit processes occurring as desired in the cell processing device via delivery / extraction of desired reagents, waste, cells, or products into / from one or more auxiliary containers in fluid communication with the primary container, thereby avoiding the risk of contamination. The system is easier to use, further avoiding the complexities of existing approaches. The present invention provides safer processing of cells with improved reproducibility and ease of use.

[0311] The invention also provides for the extraction of cells from a patient (biopsy, such as blood or bone marrow), separation of the cells, processing of the cells (including cytokine stimulation and / or genetic modification), solid-liquid separation, and loading into a delivery device where the cells can be cultured in the same device throughout the entire process.

[0312] In an embodiment of the invention, cell processing containers for performing unit operations in the manufacture of cell and / or gene therapies can be assembled in any configuration. In this way, a cell processing system can be provided in which a wide variety of processes (both biological, chemical, and separation processes) can be performed. Similarly, a cell processing system can include the cell processing platform of the invention along with one or more cell processing containers. In this way, it is possible to provide a multi-stage bioreactor operable to perform one or more unit operations in the manufacture of cell and / or gene therapies. Since each cell processing container is based on a concertina structure (which can act as a pump), there is no need for a complex set of pumps and tubing / pipes. Thus, the system reduces the space required for any given manufacturing process. The cell processing system according to the invention is particularly well suited for autologous (patient-specific) cell and gene therapies, which require performing an entire manufacturing run for each patient. Given the amount of space required to perform so many parallel manufacturing runs, it is not feasible to use traditional manufacturing approaches when scaling up to 5000 or more patients per year.

[0313] Some embodiments of the present invention are described in the following numbered clauses. In some embodiments, any one or more of the features of one numbered clause may be combined with any one or more of the features of any other one or more of the numbered clauses, unless they are mutually incompatible. More specifically, any of clauses 1 to 16 may be combined with any one or more of clauses 17 to 56, unless they are mutually incompatible. Furthermore, any of clauses 1 to 16 may be combined with any one or more of clauses 57 to 85, unless they are mutually incompatible. Furthermore, any of clauses 17 to 56 may be combined with any one or more of clauses 57 to 85, unless they are mutually incompatible.

[0314] In some embodiments, except where mutually incompatible, any one or more of the following numbered clauses may be combined with any one or more of the appended claims.

[0315] Clause 1. A cell processing container for use in one or more unit operations in the manufacture of cell and / or gene therapy, the container comprising a base section, a top section disposed substantially parallel to the base section, and a wall element disposed between the top section and the base section and defining an internal lumen of the container, the wall element of the cell processing container preferably being compressible relative to the top section and the base section, the wall element of the cell processing container being constructed from a flexible material, the cell processing container comprising at least one sterile connector end, the at least one sterile connector end configured to operably couple with an additional sterile connector end to form a sterile connector between the cell processing container and an additional component with which the cell processing container is to be fluidly connected.

[0316] Clause 2. The cell processing container of clause 1, wherein at least one sterile connector end is a genderless sterile connector end, and the genderless sterile connector end is configured to operably couple with an additional genderless sterile connector end.

[0317] Clause 3. The cell processing container of clause 1, wherein at least one sterile connector end is a male sterile connector end, the male sterile connector end being configured to operably couple with a female sterile connector end.

[0318] Clause 4. The cell processing container of clause 1, wherein at least one sterile connector end is a female sterile connector end, the female sterile connector end being configured to operably couple with a male sterile connector end.

[0319] Clause 5. A cell processing container described in any one of clauses 1 to 4, wherein the cell processing container comprises a plurality of sterile connector ends, each configured to operably couple with a separate further sterile connector end, forming a plurality of sterile connectors between the cell processing container and at least one further component with which the cell processing container is to be fluidly connected.

[0320] Clause 6. A cell processing container according to any one of clauses 1 to 5, wherein the sterile connector end is embedded within the cell processing container.

[0321] Clause 7. The cell processing container of any one of clauses 1 to 6, wherein the sterile connector end is operably connected to a pinch valve embedded within the cell processing container.

[0322] Clause 8. The cell processing container of any one of clauses 1 to 7, wherein the cell processing container has a circular, square, rectangular, oval, or triangular cross-section.

[0323] Clause 9. A cell processing container as described in clause 8, wherein when the cell processing container has a circular shape, the sterile connector ends are connected to the top section and / or base section of the cell processing container in an essentially circular pattern.

[0324] Clause 10. A cell processing system comprising the cell processing container of any one of clauses 1 to 9, the cell processing system further comprising one or more auxiliary containers removably connected to the cell processing container.

[0325] Clause 11. The cell processing system of clause 10, wherein one or more of the auxiliary containers includes a further sterile connector end and is connected to the cell processing container via said further sterile connector end.

[0326] Clause 12. The cell processing system of clause 10 or 11, wherein one or more of the auxiliary containers are positioned above the upper section of the cell processing container.

[0327] Clause 13. The cell processing system of clause 10 or 11, wherein one or more of the auxiliary containers are positioned at or near the base section of the cell processing container.

[0328] Clause 14. The cell processing system of any one of clauses 10 to 13, wherein the one or more auxiliary containers have a base section, an upper section disposed substantially parallel to the base section, and a wall element disposed between the upper section and the base section and defining an internal lumen of the container, wherein the wall element of the auxiliary container is preferably compressible relative to the upper section and the base section, and wherein the wall element of the auxiliary container is constructed from a flexible material.

[0329] Clause 15. A multi-step method of performing one or more unit operations in the manufacture of cell and / or gene therapies using a cell processing system according to any one of clauses 10 to 14.

[0330] Clause 16. The method of clause 15, wherein the method includes the steps of introducing a cell population of interest into a cell processing container and sequentially adding one or more reagents from one or more auxiliary containers into the cell processing container to achieve one or more desired unit operations in the manufacture of a cell and / or gene therapy.

[0331] Clause 17. A cell processing device for use in performing one or more unit processes in the manufacture of cell and / or gene therapy, the cell processing device comprising a cell processing platform fluidly coupled to at least one auxiliary container and at least one primary container, the cell processing platform comprising a body portion comprising at least one fluid inlet fluidly connected to a fluid outlet and an auxiliary container port fluidly coupled to the at least one fluid inlet of the body portion, the at least one auxiliary container being received in sealing engagement with the auxiliary container port such that the auxiliary container lumen is in fluid connection with the at least one fluid inlet of the body portion, and the primary container being received in sealing engagement with the primary container port such that the primary container lumen is in fluid connection with the fluid outlet of the body portion.

[0332] Clause 18. The cell processing device of clause 17, wherein the auxiliary container port includes a container receiving sleeve connected to the body portion and configured to surround at least a portion of the auxiliary container, the portion including a fluid outlet portion of the container.

[0333] Clause 19. A cell processing device as described in clause 17 or 18, wherein the cell processing platform includes a plurality of auxiliary container ports, each of the plurality of auxiliary containers being received in sealing engagement with one of the plurality of auxiliary container ports, such that the lumen of each auxiliary container is fluidly connected to the fluid inlet portion of the main body portion.

[0334] Clause 20. The cell processing device of clause 19, wherein each auxiliary container port is coupled to a separate fluid inlet portion of the body portion.

[0335] Clause 21. A cell treatment device as described in clause 20, wherein each separate fluid inlet portion of the body portion is fluidly connected to a fluid outlet portion of the body portion.

[0336] Clause 22. A cell treatment device described in any one of clauses 17 to 21, wherein at least one fluid inlet and fluid outlet of the body portion are fluidly connected to each other by a fluid conduit.

[0337] Clause 23. The cell treatment device of clause 22, wherein the fluid conduit includes a valve operable to open and close the fluid conduit.

[0338] Clause 24. The cell processing device of clause 23, wherein the valve is one of a pinch valve, a pressure sensitive valve, a clamp valve, a membrane valve, a rupture disk, a venous valve, and an aperture valve.

[0339] Clause 25. A cell processing device according to any one of clauses 17 to 24, wherein each auxiliary container port includes a container fill port.

[0340] Clause 26. The cell processing device of clause 25, wherein the container fill port is fluidly connected to the fluid inlet portion of the auxiliary container port.

[0341] Clause 27. A cell processing device as described in clause 25 or 26, wherein each container filling port includes a valve operably connected to the fluid inlet and fluid outlet portions of the auxiliary container port and operable to control the fluid flow direction through the auxiliary container port.

[0342] Clause 28. A cell processing device described in any one of clauses 25 to 27, wherein the container fill port includes a valve which, in an open position, allows fluid to flow to the fluid inlet of the auxiliary container port but not to the fluid outlet of the auxiliary container port, and which, in a closed position, is operable to close the container fill port and allow fluid to flow from the fluid inlet of the auxiliary container port to the fluid outlet of the auxiliary container port.

[0343] Clause 29. The cell processing device of any one of clauses 17 to 28, wherein at least one auxiliary container includes a mating element, the mating element configured to fluidly connect to a corresponding mating element on the auxiliary container port.

[0344] Clause 30. The cell processing device of clause 29, wherein the mating element is at least one of a sterile connector end or a Luer Lok™.

[0345] Clause 31. The cell processing device of any one of clauses 17 to 30, wherein the primary container port includes a mating element configured to fluidly connect to a corresponding mating element on the primary container.

[0346] Clause 32. The cell processing device of clause 31, wherein the mating element includes at least one of a sterile connector end or a Luer Lok™.

[0347] Clause 33. A cell processing device described in any one of clauses 17 to 32, wherein the auxiliary container port includes a sterile connector end at the fluid inlet and / or fluid outlet of the auxiliary container port, each sterile connector end being configured to engage with a further sterile connector end on the container and / or on the body portion, respectively.

[0348] Clause 34. A cell treatment device described in any one of clauses 17 to 33, wherein the fluid outlet portion of the body portion includes a sterile connector end configured to engage with a further sterile connector end on a primary container attachable to the body portion.

[0349] Clause 35. A cell processing device according to any one of clauses 17 to 34, wherein the cell processing device comprises at least one position tracking device operable to indicate a set location on the platform.

[0350] Clause 36. The cell processing device of clause 35, wherein the position tracking device is one or more of a magnet, an RFID sensor, an optical sensor, or a cog operable to engage a further cog.

[0351] Clause 37. A cell processing device according to clause 35 or 36, wherein the cell processing device comprises a plurality of position tracking devices.

[0352] Clause 38. A cell processing device described in any one of clauses 35 to 37, wherein at least one position tracking device is positioned relative to the auxiliary container port such that the location of the position tracking device is related to the position of the auxiliary container port.

[0353] Clause 39. A cell processing device according to any one of clauses 35 to 38, wherein at least one position tracking device is positioned on the body portion relative to the auxiliary container port.

[0354] Clause 40. The cell processing device of any one of clauses 35 to 38, wherein the cell processing device includes a plurality of position tracking devices each positioned on the body portion relative to an auxiliary container port.

[0355] Clause 41. A cell treatment device according to any one of clauses 17 to 40, wherein the cell treatment device includes a sampling port within the body portion.

[0356] Clause 42. The cell treatment device of any one of clauses 17 to 41, wherein the cell treatment device includes a gas transfer port in the body portion.

[0357] Clause 43. The cell processing device of any one of clauses 17 to 42, wherein the auxiliary container port is configured to receive an auxiliary container having a base section, an upper section disposed substantially parallel to the base section, and a wall element disposed between the upper section and the base section and defining an internal lumen of the container, the wall element of the container being preferably compressible relative to the upper section and the base section, and the wall element of the container being constructed from a flexible material.

[0358] Clause 44. A cell processing device as described in any one of clauses 17 to 43, wherein the primary container port is configured to receive a primary container having a base section, an upper section disposed substantially parallel to the base section, and a wall element disposed between the upper section and the base section and defining an internal lumen of the container, the wall element of the container being preferably compressible relative to the upper section and the base section, and the wall element of the container being constructed from a flexible material.

[0359] Clause 45. The cell processing device of clause 44, wherein the primary container further comprises a mounting flange attached to the upper section of the primary container and configured to sealingly engage and mount to the primary container port.

[0360] Clause 46. The cell processing device of any one of clauses 17 to 45, wherein at least one auxiliary container is compressible.

[0361] Clause 47. A cell processing device according to any one of clauses 17 to 45, wherein at least one auxiliary container is one of a syringe or any shape of container with a moving seal allowing variable volume operation.

[0362] Clause 48. A cell processing device according to any one of clauses 17 to 45, wherein at least one auxiliary container is a bag, the bag being held within the frame and movable relative to the frame.

[0363] Clause 49. A cell processing device according to any one of clauses 17 to 48, wherein the cell processing device includes one or more auxiliary containers removably connected to auxiliary container ports of the cell processing platform.

[0364] Clause 50. The cell processing device of clause 49, wherein one or more of the auxiliary containers are connected to their respective auxiliary container ports by sterile connectors.

[0365] Clause 51. The cell processing device of any one of clauses 17 to 50, wherein at least one auxiliary container is positioned above the cell processing platform.

[0366] Clause 52. The cell processing device of any one of clauses 17 to 51, wherein the primary container is positioned at the bottom of the cell processing platform.

[0367] Clause 53. The cell processing device of any one of clauses 17 to 52, wherein the auxiliary container is one of a reagent container, a cell culture container, a waste container, a filter, an electroporator, a purifier, a waste container, a filter, an electroporator, a purifier, a holding container, an apheresis / leukapheresis, a differentiation chamber, a chromatography column, a sedimentation chamber, a sieve, a shaking / mixer, a centrifuge, and a magnetic bead separator or a bioreactor.

[0368] Clause 54. The cell processing device of any one of clauses 17 to 53, wherein the primary container is a reagent container, a bioreactor, a cell culture container, a waste container, a filter, an electroporator, a purifier, a waste container, a filter, an electroporator, a purifier, a holding container, an apheresis / leukapheresis, a differentiation chamber, a chromatography column, a sedimentation chamber, a sieve, a shaking / mixer, a centrifuge, and a magnetic bead separator, etc., a centrifuge, and a magnetic bead separator, etc.

[0369] Clause 55. A multi-step method of performing one or more unit operations in the manufacture of cell and / or gene therapies using a cell processing device according to any one of clauses 17 to 54.

[0370] Clause 56. The method of clause 55, wherein the method includes the steps of introducing a cell population of interest into a primary container and sequentially adding one or more reagents from one or more auxiliary containers into the primary container to achieve one or more desired unit operations in the manufacture of a cell and / or gene therapy.

[0371] Clause 57. A cell processing platform for use in one or more unit operations in the manufacture of cell and / or gene therapy, the platform comprising a body portion, the body portion comprising at least one fluid inlet fluidly connected to a fluid outlet, and an auxiliary container port fluidly coupled to the at least one fluid inlet of the body portion, the auxiliary container port configured and arranged to receive and sealingly engage an auxiliary container and fluidly connect the auxiliary container lumen with the at least one fluid inlet of the body portion, and the primary container port configured and arranged to sealingly engage a primary container and fluidly connect the primary container lumen with the fluid outlet of the body portion.

[0372] Clause 58. The cell processing platform of clause 57, wherein the auxiliary container port includes a container receiving sleeve connected to the body portion and configured to surround at least a portion of the auxiliary container, the portion including a fluid outlet portion of the container.

[0373] Clause 59. The cell processing platform of clause 57 or 58, wherein the auxiliary container port includes a mating element configured to fluidly connect to a corresponding mating element on the auxiliary container.

[0374] Clause 60. The cell processing platform according to clause 59, wherein the mating element is at least one of a sterile connector end or a Luer Lok™.

[0375] Clause 61. The cell processing platform of any one of clauses 57 to 60, wherein the primary container port includes a mating element configured to fluidly connect to a corresponding mating element on the primary container.

[0376] Clause 62. The cell processing platform of clause 61, wherein the mating element comprises at least one of a sterile connector end or a Luer Lok™.

[0377] Clause 63. A cell processing platform described in any one of clauses 57 to 62, wherein the auxiliary container port comprises a sterile connector end at the fluid inlet and / or fluid outlet of the auxiliary container port, each sterile connector end being configured to engage with a further sterile connector end on the container and / or on the body portion, respectively.

[0378] Clause 64. A cell processing platform described in any one of clauses 57 to 63, wherein the fluid outlet portion of the body portion includes a sterile connector end configured to engage with a further sterile connector end on a primary container attachable to the body portion.

[0379] Clause 65. A cell processing platform according to any one of clauses 57 to 64, wherein the body portion is substantially hollow.

[0380] Clause 66. A cell processing platform according to any one of clauses 57 to 65, wherein at least one fluid inlet and fluid outlet of the body portion are fluidly connected to each other by a fluid conduit.

[0381] Clause 67. The cell processing platform of clause 66, wherein the fluid conduit includes a valve operable to open and close the fluid conduit.

[0382] Clause 68. The cell processing platform of clause 67, wherein the valve is one of a pinch valve, a pressure sensitive valve, a clamp valve, a membrane valve, a rupture disk, a venous valve, and an aperture valve.

[0383] Clause 69. The cell processing platform of any one of clauses 57 to 68, wherein the auxiliary container port comprises a container fill port.

[0384] Clause 70. The cell processing platform of clause 69, wherein the container fill port is fluidly connected to the fluid inlet portion of the auxiliary container port.

[0385] Clause 71. A cell processing platform as described in clause 69 or 70, wherein the container filling port includes a valve operably connected to the fluid inlet and fluid outlet portions of the auxiliary container port and operable to control the fluid flow direction through the auxiliary container port.

[0386] Clause 72. A cell processing platform as described in any one of clauses 69 to 71, wherein the container fill port includes a valve which, in an open position, allows fluid to flow to the fluid inlet of the auxiliary container port but not to the fluid outlet of the auxiliary container port, and which, in a closed position, is operable to close the container fill port and allow fluid to flow from the fluid inlet of the auxiliary container port to the fluid outlet of the auxiliary container port.

[0387] Clause 73. The cell processing platform of any one of clauses 57 to 72, wherein the cell processing platform includes a plurality of auxiliary container ports, each configured and arranged to receive an auxiliary container and sealingly engage the auxiliary container, and to fluidly connect the container lumen with the fluid inlet portion of the main body portion.

[0388] Clause 74. The cell processing platform of clause 73, wherein each auxiliary container port is coupled to a separate fluid inlet portion of the body portion.

[0389] Clause 75. The cell processing platform of clause 74, wherein each separate fluid inlet portion of the body portion is fluidly connected to a fluid outlet portion of the body portion.

[0390] Clause 76. A cell processing platform according to any one of clauses 57 to 75, wherein the cell processing platform comprises at least one position tracking device operable to indicate a set location on the platform.

[0391] Clause 77. The cell processing platform according to clause 76, wherein the position tracking device is at least one of a magnet, an RFID sensor, an optical sensor, or a cog operable to engage a further cog.

[0392] Clause 78. The cell processing platform of clause 76 or 77, wherein the cell processing device includes a plurality of position tracking devices.

[0393] Clause 79. A cell processing platform described in any one of clauses 76 to 78, wherein at least one position tracking device is positioned relative to the auxiliary container port such that the location of the position tracking device is related to the location of the auxiliary container port.

[0394] Clause 80. The cell processing platform of any one of clauses 76 to 79, wherein at least one position tracking device is positioned on the body portion relative to the auxiliary container port.

[0395] Clause 81. The cell processing platform of any one of clauses 57 to 80, wherein the cell processing platform includes a sampling port in the body portion.

[0396] Clause 82. The cell processing platform of any one of clauses 57 to 81, wherein the cell processing platform includes a gas transfer port in the body portion.

[0397] Clause 83. A cell processing platform as described in any one of clauses 57 to 82, wherein the auxiliary container port is configured to receive a container having a base section, an upper section disposed substantially parallel to the base section, and a wall element disposed between the upper section and the base section and defining an internal lumen of the container, wherein the wall element of the container is preferably compressible relative to the upper section and the base section, and wherein the wall element of the container is constructed from a flexible material.

[0398] Clause 84. A cell processing platform as described in any one of clauses 57 to 83, wherein the primary container port is configured to receive a primary container having a base section, an upper section disposed substantially parallel to the base section, and a wall element disposed between the upper section and the base section and defining an internal lumen of the container, the wall element of the container being preferably compressible relative to the upper section and the base section, and the wall element of the container being constructed from a flexible material.

[0399] Clause 85. The cell processing platform of clause 84, wherein the primary container further comprises a mounting flange attached to the upper section of the primary container and configured to sealingly engage and removably mount to the primary container port. [Explanation of symbols]

[0400] 1 Cell Processing Unit 2. Housing 3. Chamber 5. Control Panel 7 Doors 9. Cell Processing Platform 11 Auxiliary Container 13 Primary containers, cell processing containers, cell culture containers 14 Primary Container Ports 15 Base plate 17 Bellows section 19 Auxiliary Container Port 20 Storage volume 21 Upper Section 23 Bass Section 25 Fluid outlet 26 Connector 27 Pinch valve, valve means 29 Flexible tubing, fluid communication conduit 31 Filling valve, filling port 33 Base plate outlet 35 Spring 37 Closure part, sterile connector end 38 Actuating parts, linear actuators 39 Valve wall, paper cap 40 Adhesive members 41a Channel wall, screw thread 41b Channel wall, screw thread 43 Compression section 45 Lever 50 Component Pull Grip 51 Screw Cap 80 Front 2nd fold adhesive coating 101 Part of the cell processing unit 103 Linear Actuator 103a Plunger 104 Mounting plate 106 Linear Actuator 106a Plunger 107 Friction drive mechanism, drive wheel 109 Friction drive mechanism, friction wheel 111 Friction drive mechanism, hinge wheel 112 Plate 114 Riser 118 Magnet 120 Hall effect sensor, front 2nd fold adhesive coating 127 Pinch Valve 139 Sterile Connector Ends 141 Sterile Connector Ends 150 Sterile Connector Ends 151 End Cap 190 Sterile conduit 200 Cell processing containers, cell culture containers 202 Bass Section 203 Upper Section 204 Wall Element 205 Sterile Connector Ends 300 Cell Processing System 311 Auxiliary Container 313 Cell Processing Container 319 Auxiliary Container Port 400 Sterile Connector Ends 413 Wave Bioreactor 513 CSTR Bioreactor 901 Cell processing device

Claims

1. A cell processing unit for the manufacture of cell and gene therapies, the cell processing unit comprising: a housing defining an enclosure, into which a cell processing platform can be mounted; a platform mounting bracket within the housing, the platform mounting bracket configured and arranged to receive and hold the cell processing platform; a drive device configured and arranged to operatively engage and act on the cell processing platform, to move the cell processing platform relative to the platform mounting bracket; an actuator configured and arranged to apply a force to the container mounted into the cell processing platform to expel contents from the container; and a primary actuator; The primary actuator is constructed and arranged to apply a force to a primary container mounted on the cell processing platform, causing fluid to be expelled from the primary container.

2. The cell treatment unit of claim 1 , wherein the platform mounting bracket comprises a mounting plate.

3. The cell processing unit of claim 2, wherein the platform mounting bracket includes a retention flange, the retention flange being spaced apart from the mounting plate so that the cell processing platform can be received and maintained in a suitable position within the housing between the mounting plate and the retention flange.

4. The cell treatment unit according to claim 2 or 3, wherein the mounting plate is substantially C-shaped.

5. The cell processing unit of any one of claims 1 to 4, wherein the drive device is a rotational drive device configured and arranged to operably engage with and act on the cell processing platform, and to rotate the cell processing platform relative to the platform mounting bracket.

6. The cell processing unit of claim 5, wherein the rotational drive device includes a drive wheel mounted on the platform mounting bracket, the drive wheel configured to engage a surface of the cell processing platform and impart rotational movement to the cell processing platform.

7. The cell processing unit of claim 6, wherein the rotational drive device includes a spring-loaded wheel biased toward and spaced apart from the drive wheel and mounted on the platform mounting bracket.

8. The cell processing unit of claim 6 or 7, wherein the rotational drive device includes a hinged wheel biased towards the drive wheel, spaced apart from the drive wheel, and mounted on the platform mounting bracket.

9. 9. The cell processing unit of claim 8, wherein the hinged wheels are movable to an open position and a closed position, in which the cell processing platform can be inserted into and engaged with the platform mounting bracket, and in which the hinged wheels are engaged with a surface of the cell processing platform to retain the cell processing platform within the platform mounting bracket.

10. The cell treatment unit according to claim 1 , wherein the actuator is a linear actuator.

11. The cell processing unit of claim 10, wherein the linear actuator includes a plunger operably coupled to a drive motor, the plunger configured to engage a container in the cell processing platform and exert a compressive force on the container.

12. The cell treatment unit of claim 1 , wherein the primary actuator is a linear actuator.

13. The cell processing unit of claim 12, wherein the primary actuator includes a plunger operably coupled to a drive motor, the plunger configured to engage a primary container mounted to the cell processing platform and exert a compressive force on the primary container.

14. 14. A cell processing unit according to claim 12 or 13, wherein the primary container is compressible.

15. 15. The cell processing unit of claim 12, wherein the primary container comprises a base section, an upper section arranged generally parallel to the base section, and a wall element arranged between the upper section and the base section and defining an internal lumen of the container, the wall element of the container being compressible relative to the upper section and the base section, and the wall element of the container being constructed from a flexible material.

16. The cell processing unit of any one of claims 12 to 15, wherein the primary container is a cell processing container.

17. 17. The cell processing unit of any one of claims 1 to 16, comprising a valve actuator operable to act on a pinch valve in the cell processing platform and configured to open and close the pinch valve when a force is applied to the container.

18. The cell treatment unit of claim 17 , wherein the valve actuator is a linear actuator.

19. The cell treatment unit of claim 18 , wherein the valve actuator comprises a solenoid valve.

20. The cell processing unit of claim 1 , further comprising a position detection sensor operable to detect the position of the cell processing platform relative to the platform mounting bracket.

21. The cell processing unit of claim 20 , wherein the position detection sensor is operable to detect a rotational position of the cell processing platform relative to the platform mounting bracket.

22. The cell treatment unit according to claim 20 or 21, wherein the position detection sensor comprises a Hall effect sensor.

23. 23. The cell processing unit of any one of claims 20 to 22, wherein the cell processing unit includes a home position detection sensor, the home position detection sensor operable to detect a home position of the cell processing platform relative to the platform mounting bracket.

24. The cell processing unit of claim 23 , wherein the home position detection sensor is operable to detect a single rotational position of the cell processing platform relative to the platform mounting bracket.

25. The cell treatment unit according to claim 23 or 24, wherein the home position detection sensor includes a Hall effect sensor.

26. 26. The cell treatment unit of claim 25, wherein the voltage detected by the Hall effect sensor is greater at the home position of the cell treatment platform relative to the platform mounting bracket than at any other position during rotation of the cell treatment platform relative to the platform mounting bracket.

27. 27. The cell processing unit of any one of claims 1 to 26, wherein the container is compressible.

28. 28. The cell processing unit of any one of claims 1 to 27, wherein the container comprises a base section, an upper section arranged generally parallel to the base section, and a wall element arranged between the upper section and the base section and defining an internal lumen of the container, the wall element of the container being compressible relative to the upper section and the base section, and the wall element of the container being constructed from a flexible material.

29. 29. The cell processing unit of any one of claims 1 to 28, wherein the container is one of a reagent container, a bioreactor, a cell culture container, a waste container, a filter, an electroporator, a purifier, a holding container, an apheresis / leukapheresis, a differentiation chamber, a chromatography column, a sedimentation chamber, a sieve, a shaking / mixer, a centrifuge, and a magnetic bead separator, etc.

30. 30. A cell treatment unit according to any one of claims 1 to 29, wherein control of the device is automated.

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