Consumables for fluid delivery to bioreactors

Abstract

The present application provides a fluid delivery consumable (5b) for delivering a liquid dose to a bioreactor, the fluid delivery consumable comprising: a vial (22) for holding the liquid dose, the vial having an outlet (27) and an open end (26) opposite the outlet, a plunger (24) operable to engage the open end and urge the liquid dose toward the outlet, and a connector (19) proximal to the outlet, the connector attachable to the bioreactor such that operation of the plunger moves the liquid dose from the vial to the bioreactor.

Description

Technical Field

[0001] The present invention relates to a fluid delivery consumable for delivering a liquid dosage to a bioreactor. The bioreactor is suitable for performing one or more unit operations in a cell processing method, for example, in a cell and / or gene therapy manufacturing process. The fluid delivery consumable is operable to transfer a liquid dosage, such as a magnetic bead suspension or a virus suspension, from the fluid delivery consumable to the bioreactor.

Background Art

[0002] Cell and gene therapy manufacturing processes are often complex and involve manual or semi-automated steps that span several devices. The equipment systems used in various steps, or unit operations, of cell-based therapeutic product (CTP) manufacturing can include devices for various functions. These various functions may be, for example, cell collection, cell isolation, cell selection, cell proliferation, cell washing, volume reduction, cell storage, or transportation. Unit operations can be highly diverse, among other factors, based on the manufacturing model (i.e., autologous vs. allogeneic), cell type, and intended purpose. In addition, cells are "living" entities and are susceptible to influence even in the simplest operations, such as differences in cell transfer procedures. The role of cell manufacturing equipment to ensure scalability and reproducibility is an important factor for cell and gene therapy manufacturing.

[0003] Furthermore, cell-based therapeutic products (CTPs) have gained significant momentum, and improvements in cell manufacturing equipment for various cell manufacturing procedures are needed. These manufacturing procedures include various cell manufacturing processes such as, for example, stem cell enrichment, generation of chimeric antigen receptor (CAR) T cells, and collection, purification, genetic recombination, incubation, recovery, washing, injection into patients, or freezing.

[0004] Cell culture or processing typically requires the use of a device to hold the cells in a suitable culture medium, for example, when culturing the cells. Known devices include shaking flasks, roller bottles, T-flasks, bags, and similar. Such devices typically need to be connected to other devices, such as containers, interfaces, or similar, so that various media can be introduced into or removed from the device holding the cells. Typically, cells in the medium can be added to the device from a flexible bag attached using a connecting tube. Alternatively, cells can be transported by pipette or syringe.

[0005] The production of autologous CAR T cells is carried out through various manufacturing approaches that all involve the same common steps. First, the patient's white blood cells (WBCs) are isolated by leukocyte apheresis and washed. Then, the T cells are activated, transgenerated with CAR genes, proliferated to the number required for treatment, formulated, and filled. After quality control testing and preparatory lymphodeplegia chemotherapy are performed on the patient, the product is injected into the patient. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Publication No. 2020 / 053229 [Overview of the project] [Means for solving the problem]

[0007] According to this disclosure, fluid delivery consumables for delivering liquid doses to a bioreactor are provided. The fluid delivery consumables are, A vial for holding a liquid volume, having an outlet and an open end on the opposite side of the outlet, A plunger that engages with the open end and is operable to bias the liquid volume toward the outlet, The system includes a connector located near the outlet, which can be attached to the bioreactor to transfer a liquid volume from the vial to the bioreactor by operating a plunger.

[0008] In the example, the fluid delivery consumable may further include a seal configured to be positioned within the outlet of the vial to seal the outlet. In the example, the connector may include a hollow needle movable to puncture the seal to form a fluid connection with the vial. In the example, the seal may include a partition seal. In the example, the connector may include an actuator operable to move the needle to puncture the seal. In the example, the connector may include a first housing portion and a second housing portion, and the actuator operable to fold the first housing portion with respect to the second housing portion so that the hollow needle punctures the seal. In the example, the connector may be configured so that the hollow needle engages with the bioreactor when the first housing portion is folded with respect to the second housing portion.

[0009] In the example, the connector may further include an end seal configured to be positioned at the opposite end of the connector relative to the vial. The hollow needle may be configured to puncture the end seal when the first housing portion is folded relative to the second housing portion.

[0010] In the example, the fluid delivery consumable may further include a collar attached to the end of the vial near the outlet, and the connector is attached to the collar. In the example, the collar may surround the end of the vial, including the outlet. In the example, the fluid delivery consumable may further include a locking ring having a shape that engages with a recess in the vial to secure the collar to the vial. In the example, the connector may be screwed to the collar. In the example, the fluid delivery consumable may further include a clip member configured to prevent the connector from being detached from the collar after it has been attached to the collar.

[0011] In this example, the collar or connector may include a clipping member, which is configured to engage with a recess on the other side of the collar or connector when the connector is attached to the collar, thereby preventing the connector from rotating relative to the collar after it has been attached.

[0012] In the example, the fluid delivery consumable may further include a gaiter configured to surround the plunger between the open end of the vial and the top end of the plunger. In the example, the gaiter may include a foldable wall configured to fold when the plunger is actuated. In the example, the gaiter may be sealably attached to the vial and plunger and provide a sealed cover for the plunger.

[0013] In the example, the fluid delivery consumable may further include a cap attached to the top end of the plunger. A gaiter may be attached to the cap, and the cap may be larger than the open end of the via such that the gaiter has a frustum-shaped wall. The frustum-shaped wall may be a frustum-shaped wall. In the example, the frustum-shaped wall may include at least one inward fold and at least one outward fold arranged so that the frustum-shaped wall is foldable.

[0014] In the example, the plunger or cap may have an engaging feature that can be engaged to actuate the plunger.

[0015] In this example, the plunger may include a piston adapted to strike and seal the inner surface of the vial.

[0016] In this example, the vial may include a glass vial.

[0017] In an example, the liquid dosage can include a plurality of magnetic particles in a fluid suspension. In an example, the liquid dosage can include a virus suspension. In an example, the liquid dosage can include nanoparticles of a non-magnetic activator, such as the T Cell TransAct™ reagent. In an example, the liquid dosage can include growth factors, such as cytokines, of a concentrated growth factor.

[0018] Embodiments of the present invention are described herein while referring to the accompanying drawings.

Brief Description of the Drawings

[0019] [Figure 1] It is a diagram showing a cell processing system including a bioreactor. [Figure 2] It is a schematic diagram exemplifying a cell culture process. [Figure 3] It is a diagram exemplifying a bioreactor. [Figure 4A] It is a diagram showing an example of a consumable for fluid delivery attached to a bioreactor. [Figure 4B] It is a diagram showing an example of a consumable for fluid delivery attached to a bioreactor. [Figure 5] It is a diagram showing an exemplary connector for connecting a consumable for fluid delivery to a bioreactor. [Figure 6] It is a diagram showing an example of a consumable for fluid delivery. [Figure 7] It is a cross-sectional view of the consumable for fluid delivery of FIG. 6. [Figure 8] It is a diagram showing the vial of the consumable for fluid delivery of FIG. 6. [Figure 9] It is a diagram showing the vial, plunger, and collar of the consumable for fluid delivery of FIG. 6. [Figure 10] It is a diagram showing the collar and lock ring of the consumable for fluid delivery of FIG. 6. [Figure 11] It is a diagram showing an exemplary process for filling a consumable for fluid delivery. [Figure 12] It is a diagram showing another exemplary process for filling a consumable for fluid delivery. [Figure 13] This figure shows another exemplary process for filling consumables for fluid delivery. [Figure 14A] This diagram illustrates the operation of fluid delivery consumables used to deliver fluid to a bioreactor. [Figure 14B] This diagram illustrates the operation of fluid delivery consumables used to deliver fluid to a bioreactor. [Figure 14C] This diagram illustrates the operation of fluid delivery consumables used to deliver fluid to a bioreactor. [Figure 14D] This diagram illustrates the operation of fluid delivery consumables used to deliver fluid to a bioreactor. [Modes for carrying out the invention]

[0020] Figure 1 shows a cell processing system 1 comprising a cell processing housing 2, a cell processing platform 3, a bioreactor 4, and various accessories, such as “consumables” 5a to 5f.

[0021] The cell processing housing 2 provides a closed environment for the cell processing platform 3, which is equipped with a power supply, connectivity, and other utilities necessary for cell processing, as described below. The cell processing platform 3 is adapted to receive and support the bioreactor 4 within the cell processing housing 2. The cell processing platform 3 may include various components and systems that interact with the bioreactor 4 and / or consumables 5a-5f. For example, the cell processing platform 3 may include a stirrer that acts to agitate the bioreactor 4 to agitate the cell suspension provided within the bioreactor 4. In other examples, the cell processing platform 3 may include accessory support arms adapted to hold one or more consumables 5a-5f. In examples, the cell processing platform 3 may include actuators that can operate to actuate one or more consumables 5a-5f. The cell processing platform 3 may be configured to perform automated operation of the cell processing system 1 or may allow manual operation.

[0022] The bioreactor 4, described in more detail with reference to Figure 3, comprises a container 12 and an interface plate 13. During use, the container 12 holds the fluid in which the cell processing is carried out. In particular, the fluid contains a population of cells present in a liquid medium. The container 12 may be expandable, for example, by having a bellows wall. The bioreactor 4 is held in the cell processing housing 2 so that it can expand and contract when the container 12 is filled and emptied. The interface plate 13 may engage with the cell processing platform 3 and provide various functions related to the bioreactor 4. For example, the interface plate 13 may have one or more connectors for transferring fluid into and out of the container 12.

[0023] Consumables 5a to 5f are for connecting to the bioreactor 4, optionally via the cell processing platform 3, to facilitate the process steps of the cell culture process.

[0024] In the example, a cell delivery consumable 5a is provided. The cell delivery consumable 5a is adapted to connect to a bioreactor 4 and deliver a cell suspension to the bioreactor 4. Specifically, the cell delivery consumable 5a has a container filled with a cell suspension and a connector that connects to the bioreactor 4 (optionally via a cell processing platform 3). The cell delivery consumable 5a is operable to transfer the cell suspension from the cell delivery consumable 5a into the bioreactor 4. The cell suspension may contain "live" cells and a medium. Thus, the cell delivery consumable 5a delivers the cell suspension to the bioreactor 4.

[0025] A population of cells may include any cell type. Preferably, the population of cells may include a homogeneous population of cells. Alternatively, the population of cells may include a mixed population of cells.

[0026] The cell population may include any human or animal cell type, such as any type of adult stem cell or primary cell, T cells, CAR-T cells, monocytes, leukocytes, erythrocytes, NK cells, γδt cells, tumor-infiltrating T cells, mesenchymal stem cells, embryonic stem cells, induced pluripotent stem cells, adipose-derived stem cells, Chinese hamster ovary cells, NS0 mouse myeloma cells, HELA cells, fibroblasts, HEK cells, insect cells, organoids, etc. Preferably, the cell population may include T cells.

[0027] Alternatively, the cell population may include any type of microbial cell, such as bacteria, fungi, archaea, protists, and algal cells.

[0028] In the example, a fluid delivery consumable 5b is provided. The fluid delivery consumable 5b may hold a particle suspension, for example, a suspension of magnetic particles. The magnetic particles may be magnetic beads. The fluid delivery consumable 5b is operable to deliver the particle suspension to the bioreactor 4.

[0029] In this example, the fluid delivery consumable 5b may, alternatively or in addition, hold a virus suspension and deliver the virus suspension to the bioreactor 4.

[0030] In the example, a medium delivery consumable 5c may be provided. The medium delivery consumable 5c may comprise one or more containers filled with a medium, such as cell culture medium, and a connector for connecting to a bioreactor 4. The medium delivery consumable 5c is operable to transfer the medium to the bioreactor. In the example, the medium delivery consumable 5c is foldable, similar to the cell delivery consumable 5a. The medium may be a liquid.

[0031] In the example, the liquid medium may be any sterile liquid capable of maintaining cells. The liquid medium may be selected from physiological saline or may be a cell medium. The liquid medium may be a cell medium selected from any suitable medium, e.g., DMEM, XVIVO 15, TexMACS. The liquid medium may be suitable for the type of cells present in the population. For example, the cell population may include T cells and the liquid medium may include XVIVO 10.

[0032] In the example, the liquid medium may further contain additives, such as growth factors, nutrients, buffers, minerals, stimulants, stabilizers, and the like.

[0033] In the example, the liquid medium contains growth factors such as cytokines and / or chemokines. The growth factors may be appropriate for the type of cells present in the population and the desired process to be carried out. The liquid medium may contain stimulants such as antigens or antibodies, which can be mounted on a support. Suitable stimulants may be appropriate for the type of cells present in the population and the desired process to be carried out. For example, when culturing T cells, antibodies are provided as stimulants in the liquid medium. The antibodies can be mounted on an inert support, such as beads, for example, DynaBeads.

[0034] The additive may be present in the liquid medium at an effective concentration. The effective concentration can be determined by those skilled in the art based on the cell population and the desired process to be carried out using teachings and techniques known in the art.

[0035] In the example, the cell population is seeded in a liquid medium at concentrations ranging from 1 × 10⁴ cfu / ml to 1 × 10⁸ cfu / ml.

[0036] In the example, collection consumable 5d may be provided. Collection consumable 5d may include a collection vial. In the example, collection consumable 5d may include a vacuuminer.

[0037] In the example, a waste consumable 5e may be provided. The waste consumable 5e may include a container adapted to receive the waste removed from the bioreactor 4, such as an expandable container. The waste consumable 5e may include a filter configured to filter cells and / or other media from the fluid in the bioreactor to extract only the waste components.

[0038] In the example, a cell harvesting consumable 5f may be provided. The cell harvesting consumable 5f may comprise a container, such as an expandable container, adapted to receive cells (and optionally cell medium) at or toward the end of a cell culture process. The cell harvesting consumable 5f may include a filter configured to filter waste components from cells and / or other mediums in the bioreactor so as to extract only the cells and the desired medium.

[0039] In this example, each of the consumables 5a to 5f can be connected to the bioreactor 4 by a common connector. The connector may be one of those described in Patent Document 1, as will be further explained with reference to Figure 5.

[0040] The connector can be connected to consumables 5a-5f or can be an integral part of consumables 5a-5f. For example, by operating the connector by twisting or sliding, the needle is moved to form a fluid connection between each end of the connector. Thus, the connector allows each consumable 5a-5f to be connected to the bioreactor 4, and when the connector is operated, a fluid connection is formed between the consumables 5a-5f and the bioreactor 4 for material transfer as described above. As will be further described below, the connector ensures sterilization between the bioreactor 4 and the consumables 5 while forming a fluid connection between the bioreactor 4 and the consumables 5.

[0041] Figure 2 is a schematic diagram illustrating the cell culture process 6 based on the cell processing system 1 described with reference to Figure 1. As shown in Figure 2, first, in step 7, consumables 5a-5f are prepared. For example, cell delivery consumable 5a may be filled with a cell suspension, and bead loading consumable 5b may be filled with beads. Connectors may be attached to consumables 5a-5f before or after preparation. Preparation of consumables 5a-5f may include unpacking consumables 5a-5f from their sterile packages. It will be understood that only consumables 5a-5f required for a particular process and a particular stage of that process are prepared. For example, some processes do not use beads, and therefore bead loading consumable 5b is not required, and cell harvesting consumable 5f is only required at the end of process 6.

[0042] Next, cells are loaded into bioreactors 4 and 8. In particular, the cell delivery consumable 5a is connected to the cell delivery bioreactor 4 and operated to transfer the cell suspension from the cell delivery consumable 5a into the bioreactor 4. The cell delivery consumable 5a is connected to the bioreactor 4 via a connector, as described above, forming a fluid connection between the cell delivery consumable 5a and the bioreactor 4.

[0043] Either before or after loading cells into the bioreactors 4 and 8, the bioreactor 4 is mounted on the cell processing housings 2 and 9. In some examples, the bioreactor 4 is mounted on the cell processing platform 3 within the cell processing housing 2.

[0044] Within the cell processing housing 2, the cells are processed 10 in a bioreactor 4. During processing 10, the pressure, temperature, pH, and other environmental characteristics within the bioreactor 4 are controlled to ensure that the conditions allow for cell processing. Cell processing 10 may include, for example, reprogramming the cells by using CAR-encoded viral DNA. Cell processing 10 may include cell culture.

[0045] In cell processing 10, additional consumables 5a-5f may be used for adding material to the bioreactor 4, extracting samples from the bioreactor 4, and / or extracting waste from the bioreactor 4. For example, delivery consumable 5b may be used to add magnetic beads to the bioreactor. In the example, delivery consumable 5b may be used to add a virus suspension or solution to the bioreactor (e.g., CAR-encoded viral DNA). In the example, medium loading consumable 5c may be used to add one or more media to the bioreactor 4. For example, medium loading consumable 5c may be used to add an equilibrium salt solution or a basic culture medium to the bioreactor 4. In the example, sampling consumable 5d may be used to extract a sample from the bioreactor for testing. In the example, waste medium consumable 5e may be used to extract waste medium from the bioreactor 4 during or after cell processing 10.

[0046] After cell processing 10, the cells are harvested 11. In cell harvesting 11, waste components may first be extracted using waste consumable 5e. Harvesting consumable 5f may be attached to the bioreactor 4 to receive cells from the bioreactor 4. The cells may be harvested in a medium, for example, a cell suspension may be harvested.

[0047] As shown in Figure 3, the bioreactor 4 comprises a container 12 and an interface plate 13. The interface plate 13 includes at least one connector interface 21 for connecting to an external component, for example, one of the consumables 5a to 5f described above. In this example, the connector interface 21 includes a partition seal that maintains a sealed environment within the container 12 and allows a needle to pass through to form a fluid connection into the container 12.

[0048] The container 12 is a collapsible container. In particular, the container 12 has a bottom wall 15 disposed opposite the interface plate 13 and collapsible walls 16 that define the side walls of the container 12. The top 17 of the collapsible wall 16 is attached to the interface plate 13. The top 17 may include a rigid ring or similar for attachment to the interface plate 13. The collapsible wall 16 is collapsible so that the bottom wall 15 can move toward and away from the interface plate 13, thereby changing the internal volume of the container 12.

[0049] The foldable wall 23 may be a bellows wall having a concertina-like arrangement configuration that allows the foldable wall 23 to be folded on itself for folding. In particular, the foldable wall 23 may have a series of alternately arranged inward folds 16a and outward folds 16b that allow the foldable wall 23 to be folded like a bellows or concertina. The inward folds 16a and outward folds 16b may be formed by thinned sections in the foldable wall 23, where the inward fold 16a has a thinned section arranged on the outer surface of the foldable wall 23 and the outward fold 16b has a thinned section arranged on the inner surface of the foldable wall 23.

[0050] Therefore, the container 12 can expand and contract, or be expanded and contract, depending on the material held in the container 12. In particular, a collapsible container 12 can expand as the cell culture in the container 12 grows and / or as additional material is added. The cell processing housing (2, see Figure 1) may include actuators adapted to move, for example, the bottom wall 15 and / or interface plate 13 of the container 12 to change the volume of the container 12, for example, by pushing and / or pulling.

[0051] As illustrated, the interface plate 13 also includes an expansion container 14, also known as a breathing container. The expansion container 14 allows the container 12 to be expanded and deflated without significantly changing the pressure inside the container 12. Alternatively or in addition, the expansion container 14 may be operable to expand or retract the foldable walls 16 of the container 12, for example by being mechanically or manually compressed or expanded, thereby changing the volume of the container 12. Alternatively or in addition, the expansion container 14 may be operable to change the pressure inside the container 12, for example by being mechanically or manually compressed or expanded.

[0052] Figures 4A and 4B show an example of connecting a fluid delivery consumable 5b to the bioreactor 4 of Figure 3. As shown, the fluid delivery consumable 5b has a vial 22 and a connector 19. The vial 22 holds a fluid, for example, a particle suspension or a virus suspension, and a plunger portion 23 is provided to push the fluid out of the vial 22 toward the connector 19. The plunger portion 23, which will be described further below, has a plunger that moves into the vial 22.

[0053] As shown in Figure 4B, the connector 19 is connected to the interface plate 13 of the bioreactor 4, specifically to the connector interface 21 of the interface plate 13. In this example, the connector interface 13 includes a seal, such as a partition seal, that seals the bioreactor 4. The connector 19 is operable to form a fluid connection between the vial 22 of the fluid delivery consumable 5b and the container 12 of the bioreactor 4, as described with reference to Figure 5. In this example, the connector 19 includes a needle that pierces the seal of the connector interface 21 and moves when the connector 19 is actuated to form a fluid connection with the bioreactor.

[0054] Once the fluid connection is established, the fluid (i.e., beads and / or virus suspension) supplied to the vial 22 of the fluid delivery consumable 5b is transferred from the vial 22 to the container 12 of the bioreactor 4. The plunger portion 23 of the fluid delivery consumable 5b can be operated, in particular by being pressed down, either manually by an operator or by an actuator of the cell processing system (see Figure 1). When the plunger portion 23 of the fluid delivery consumable 5b is pressed down, the fluid is forced through the fluid connection and delivered into the container 12 of the bioreactor 4.

[0055] Once the fluid is transferred from the fluid delivery consumable 5b to the bioreactor 4, the fluid delivery consumable 5b can be detached from the bioreactor 4. After the connector 19 is detached from the connector interface 21, the seal of the connector interface 21 can be resealed. For example, the seal of the connector interface 21 may be a partition seal that reseals when the needle is withdrawn.

[0056] Figure 5 illustrates connector 19. Connector 19 is used to attach consumables 5a to 5f to the bioreactor 4, particularly to the connector interface 21 of the interface plate 13 of the bioreactor 4. Connector 19 may be as described in Patent Document 1.

[0057] In particular, as shown in Figure 5, the connector 19 comprises a housing 102 having an upper housing portion 102a and a lower housing portion 102b. The housing 102 extends along the longitudinal axis between the distal end 104 and the proximal end 106. The upper housing portion 102a may be axially movable or slidable relative to the lower housing portion 102b, as will be further described below.

[0058] The housing 102 is provided with a threaded portion 107 at its distal end 104 for connecting to the corresponding threaded portion of the vial (22, see Figure 4A) of the delivery consumable (5b, see Figure 4A). The threaded portion 107 is formed on the upper housing portion 102a. As will be apparent to those skilled in the art, the housing 102 may not have the threaded portion 107, and instead may be provided with another suitable connection mechanism for connecting to a portion of the vial (22, see Figure 4A).

[0059] Connector 19 also has a connector portion at its proximal end 106 for connecting to a bioreactor (4, see Figure 3), in particular to the connector interface of bioreactor 4 (21, see Figure 4B). The connector portion may be a groove 138 configured to receive one or more protrusions or legs on the bioreactor, as illustrated in Figure 5. Alternatively, connector 19 may have a threaded portion or other connector portion for connecting to the bioreactor.

[0060] In this embodiment, the connector 19 comprises a first partition seal 108 disposed at the distal end 104 of the housing 102 and a second partition seal 110 disposed at the proximal end 106 of the housing 102. The first partition seal 108 includes a substantially planar, i.e., flat and punctureable surface facing outward at the distal end 104. The second partition seal 110 includes a generally annular portion that extends outward at the proximal end 106 and surrounds the substantially planar, i.e., flat and punctureable surface facing outward at the proximal end 106. The housing 102 further comprises a hollow needle 112 that is offset within the housing 102. The hollow needle 112 is generally aligned coaxially with the longitudinal axis. The hollow needle 112 has a first end 114 facing the first septum seal 108 and a second end 116 facing the second septum seal 110. The first end 114 is configured to puncture the first septum seal 108 during use, and the second end 116 is configured to puncture the second septum seal 110 during use. The first septum seal 108, the second septum seal 110, or both of the first and second septum seals 108 and 110 may optionally be equipped with a removable sterile paper seal 111.

[0061] The hollow needle 112 is mounted in the housing 102 through a collar 118 that is spring-biased by a first helical spring 120 and a second helical spring 122. In other embodiments, the hollow needle 112 may be mounted in a different preferred manner, for example, the hollow needle 112 may be mounted statically, i.e., immovably, and the housing 102 may be movable relative to the hollow needle 112. The first spring 120 acts between the distal end 104 of the housing 102 and the collar 118. The first spring 122 acts between the proximal end 106 of the housing 102 and the collar 118. In this way, the first spring 120, via the collar 118, imparts a first biasing force to the hollow needle 112 in the direction toward the proximal end 106 of the housing 102, and the second spring 122, via the collar 118, imparts a second biasing force to the hollow needle 112 in the direction toward the distal end 104 of the housing 102.

[0062] The connector 19 further comprises an operating mechanism for puncturing the hollow needle 112 into the partition seals 108 and 110. By puncturing the first and second partition seals 108 and 110, the hollow needle 112 creates a fluid path between the distal end 104 and the proximal end 106 of the connector 19, and thus, during use, forms a fluid connection between the vial 22 of the delivery consumable 5b and the container 12 of the bioreactor 4, as shown in Figure 4B.

[0063] In the example shown in Figure 5, the operating mechanism includes an outer sleeve 134 configured to fold the upper housing portion 102a relative to the lower housing portion 102b. The outer sleeve 134 is rotatable with respect to the housing 102 about the central longitudinal axis of the housing 102. For example, one of the outer sleeve 134 and the housing 102 may have a helical groove, and the other of the outer sleeve 134 and the housing 102 may have a projection that engages with the groove so that the outer sleeve 134 rotates when the upper housing portion 102a is folded relative to the lower housing portion 102b.

[0064] When the connector 19 is attached to the vial (22, see Figure 4A), particularly via the threaded portion 107, the first partition seal 108 seals the end of the vial (22, see Figure 4A). The proximal end 106 of the connector 19 is then attached to the connector interface (21, see Figure 4B), for example, by a clip mechanism, a sliding mechanism, a screw connection, or a clamp. In this position, the operation of the actuation mechanism, particularly the rotation of the outer sleeve 134, causes the upper housing portion 102a to fold relative to the lower housing portion 102b, and the hollow needle 112 punctures the first partition seal 108 and the second partition seal 110, forming a fluid connection between the vial (22, see Figure 4A) and the bioreactor (4, see Figure 4B) via the connector 19.

[0065] Therefore, the connector 19 first provides a sealing closure for the vial (22, see Figure 4A), and the fluid connection portion is formed to fit completely within the connector 19, advantageously maintaining a sterile environment.

[0066] Once the fluid is transferred to the bioreactor (4, see Figure 4B) through the hollow needle 112, the operating mechanism can be reversed so that the needle is withdrawn from the first septum seal 108 and optionally from the second septum seal 110. The first and / or second septum seals 108, 110 reseal when the hollow needle 112 is withdrawn. The connector 19 and the vial (22, see Figure 4A) can then be removed from the bioreactor (4, see Figure 4B).

[0067] In the example, the end of the vial 22 of the delivery consumable 5b illustrated in Figure 4A is provided with a plug seal, such as a partition seal, which seals the vial 22 before the connector is connected. The plug seal of the vial 22 can be punctured by a hollow needle 112.

[0068] In the example, the connector interface 21 of the bioreactor 4 illustrated in Figures 3 and 4B further comprises a partition seal that is punctured by a hollow needle 112 during use. Thus, the bioreactor 4 remains sealed when the connector 19 is attached or detached.

[0069] Figure 6 illustrates a fluid delivery consumable 5b for delivering a liquid dose to a bioreactor (4, see Figure 4B), and Figure 7 illustrates a cross-sectional view of the fluid delivery consumable 5b. In particular, the fluid delivery consumable 5b delivers a suspension of beads, such as magnetic beads, or a virus suspension. As illustrated, the fluid delivery consumable 5b has a vial 22 that holds a liquid dose and a connector 19 that can be connected to a bioreactor (4, see Figure 4B). In particular, as shown in Figure 4B, the connector 19 can be connected to the connection interface 21 of the bioreactor 4. The fluid delivery consumable 5b also includes a plunger portion 23 that can be operated to forcefully dispense the liquid dose from the vial 22, through the connector 19, and into the bioreactor (4, see Figure 4B). Figure 8 shows the vial 22 separated, and Figure 9 shows the vial 22 and the plunger 24.

[0070] As shown in Figures 7, 8, and 9, the vial 22 has an open end 26 and an outlet 27 opposite the open end 26. The vial 22 has a substantially straight tubular portion 36 and a funnel portion 35 that narrows toward the outlet 27.

[0071] The plunger portion 23 includes a plunger 24 configured to pass through the open end 26 of the vial 22 and move within the vial 22 toward the outlet 27. The plunger 24 includes a piston having a seal 25 that strikes the inner surface of the vial 22, particularly the inner surface of the tubular portion 36, to seal it and provide a seal that is substantially fluid-sealed. The seal 25 may be in the form of a piston attached to the plunger 24, or the piston may be formed as part of the plunger 24. The seal 25 on the plunger 24 or piston may include one or more O-rings. Thus, from the position shown in Figures 6, 7, and 9, the plunger 24 can be pushed down to bias the fluid toward the outlet 27.

[0072] As shown in Figures 6 and 7, the plunger portion 23 also includes a gaiter 28. The gaiter 28 is formed by a foldable wall 29, for example, a bellows wall. The gaiter 28 also includes a cap 30 attached to the end of the plunger 24. The foldable wall 29 extends between the cap 30 and the open end 26 of the vial 22. The foldable wall 29 may be attached to the open end 27 of the vial 22 by adhesive or by clamps or other mounting mechanisms. Clamp rings may be provided to clamp the end of the foldable wall 29 to the vial 22. The foldable wall 29 may be attached to the cap 30 by adhesive or by clamps or other mounting mechanisms. Clamp rings may be provided to clamp the end of the foldable wall 29 to the cap 30.

[0073] The foldable wall 29 is formed by a series of alternating inward folds 31a and outward folds 31b that allow sections of the foldable wall 29 to fold relative to one another. The gaiter 28, and in particular the foldable wall 29, surrounds the plunger 24 when it is outside the vial 22, and thus provides a sealing environment for the plunger 24. As will be apparent from this, the plunger 24 is moved from inside the vial 22 to the outside of the vial 22 to fill the fluid delivery consumable 5b, and then pushed back inside the vial 22 to deliver the fluid to the bioreactor 4, so the gaiter 28 can prevent contamination of the plunger 24 and maintain the sterility of the vial 22.

[0074] As illustrated, the first end 32 of the foldable wall 29 that attaches to the cap 30 is larger than the second end 33 of the foldable wall 29 that attaches to the vial 22. In this way, the foldable wall 29 folds inward when folded.

[0075] The gaiter 28, particularly the cap 30 and the foldable wall 29, provides a sealed enclosure for the plunger 24. As will be apparent from this, the plunger 24 is moved from inside to outside the vial 22 to fill with the fluid delivery consumable 5b, and then pushed back into the vial 22 to deliver the fluid to the bioreactor 4, so the gaiter 28 can prevent contamination of the plunger 24 and maintain the sterility of the vial 22.

[0076] In this example, the cap 30 may have an engagement feature 46 that can be engaged by an actuator in another part of the cell processing system (1, see Figure 1), particularly in the cell processing housing (2, see Figure 1). The actuator may engage with the engagement feature 46 to, for example, push down or retract the plunger 24.

[0077] The connector 19, described with reference to Figure 5, can be attached to the vial 22, for example, via a screw connection (see threaded portion 107 in Figure 5). In particular, the end of the vial 22 where the outlet 27 is formed may have a male thread that engages with a female thread on the connector 19 to provide a direct connection between the vial 22 and the connector 19.

[0078] In other examples, as illustrated in Figures 6, 7, and 9, the connector 19 may be attached to the vial 22 via a collar 34. The collar 34 surrounds the end of the vial 22, which has a funnel portion 35 and an outlet 27. The collar 34 is attached to the vial 22 by a push-fit. The collar 34 may include an O-ring or other elastomer member to enhance the retention force of the push-fit. Alternatively, the collar 34 may be attached to the vial 22 by adhesive. The collar 34 includes a threaded portion, in particular a male thread 37, for connection to the threads of the connector 19. However, it will be understood that other connection mechanisms may be provided between the collar 34 and the connector 19. For example, a bayonet connection mechanism may be provided between the collar 34 and the connector 19.

[0079] In the example shown in Figure 10, the collar 34 is attached to the end of the vial 22, particularly the end of the vial 22 having an outlet 27, using a locking ring 42. The locking ring 42 comprises a ring portion 43 and a plurality of tongues 44 extending from the ring portion 43 and configured to wedge between the vial 22 and the collar 34 to secure the collar 34 to the vial 22. The tongues 44 may have a shape that clips over edges formed on the vial 22 and / or the collar 34. The vial 22, particularly the funnel portion 35, may have one or more recesses or grooves that engage with the tongues 44.

[0080] As shown in Figures 9 and 10, the collar 34 also includes a clip member 40 extending from the collar 34 in an angled counterclockwise direction. The collar 34 may include two or more clip members 40, for example, two or three clip members 40. The clip member 40 is elastically deformable so as to bend around the point from which it extends from the collar 34. The clip member 40 is positioned and configured to engage with a recess on the connector 19 when the collar 34 is screwed onto the connector 19. In particular, the free end of the clip member 40 is positioned and configured to be received in a recess on the connector 19. The clip member 40 engages with the recess on the connector 19 when the threads 37 of the collar 34 are screwed onto the threads of the connector 19. Thus, the clip member 40 prevents the collar 34 from being reversed and disengaged from the connector 19, so that once the connector 19 is attached to the collar 34 and vial 22, it cannot be removed.

[0081] As shown in Figure 10, the color 34 may include a scale 45 positioned to be placed over a portion of the vial 22 and configured to provide gradient marks indicating the amount of fluid in the vial 22.

[0082] The connector 19 can be connected to the bioreactor (4, see Figure 3), in particular to the connector interface (21, see Figure 3) of bioreactor 4, as previously described. After the connector 19 is attached to bioreactor 4, as described with reference to Figure 5, it can be activated to form a fluid connection between the delivery consumable 5b and bioreactor 4. After the fluid connection is formed by the connector 19, the plunger 24 can be pushed down to force the fluid into bioreactor 4.

[0083] As shown in the illustration, the collar 34 covers the end of the outlet 27 of the vial 22, and the gaiter 28 covers the open end 26 of the vial 22. Thus, the end of the vial 22 is not exposed, and the vial 22 is protected from damage by dropping.

[0084] In this example, the connector 19 has a seal that covers or blocks the outlet 27 of the vial 22, for example, a first partition seal 108 shown in Figure 5. As described with reference to Figure 5, the first partition seal 108 can be punctured by a hollow needle 112 during use.

[0085] In addition, or alternatively, the vial 22 may be provided with an openable valve, a breakable seal, or other sealing mechanism that initially seals the vial 22. Such a seal may be openable or perforated after the connector 19 is connected to the bioreactor and provides a fluid connection between the delivery consumable 5b and the bioreactor. In particular, as shown in Figures 7 and 8, the vial 22 may include a plug seal 41 for sealing the outlet 27. The plug seal 41 may be perforated by the hollow needle 112 of the connector 19 during use. The plug seal 41 may also be a partition seal. The plug seal 41 provides a sealed vial 22 when the connector 19 is not attached.

[0086] When connector 19 is activated, the hollow needle 112 of connector 19, shown in Figure 5, punctures the plug seal 41 and any additional seals on connector 19 (e.g., seal 108), forming a fluid connection with vial 22. The other end of the hollow needle 112 forms a fluid connection with the bioreactor (4, see Figure 4B), as previously described. Thus, after connector 19 is activated, the plunger 24 is pushed down, allowing fluid to move from vial 22 into the bioreactor.

[0087] Figures 11 to 13 illustrate options for filling the delivery consumables 5b, particularly the vials 22, with fluid.

[0088] In the example in Figure 11, vial 22 is inverted without the collar 34 or plug seal 41 and filled with fluid through the outlet 27. A syringe 47 is used to add fluid to vial 22. After the fluid has been supplied into vial 22, the plug seal 41 and collar 34 are attached to the outlet 27 of vial 22 using the locking ring 42, securing the collar 34 and plug seal 41 to vial 22. At this point, a certain amount of air is also introduced into vial 22. The air is used during use to purge the fluid delivery consumables 5, particularly vial 22 and hollow needle 112. The connector 19 can then be screwed onto the collar 34, as previously described.

[0089] In the example shown in Figure 12, the vial 22 is fitted with a plug seal 41 and a collar 34, which are attached to the end of the vial 22 using a locking ring 42. In this example, the plug seal 41 is a septum seal that is resealed after being punctured with a needle. The needle cap 49 is then attached to the vial 22 on the collar 34. The needle cap 49 comprises a needle 50 that punctures the plug seal 41 to form a fluid connection into the vial 22. As illustrated, the needle 50 may extend in the other direction and be inserted into a supply vial 48 that contains the fluid. The plunger 24 may be drawn out to draw the fluid from the supply vial 48 into the vial 22. The supply vial 48 is then removed, and the plunger 24 can be drawn out further to draw air into the vial 22. The needle cap 49 may then be removed, and the plug seal 41 is resealed. Air is used during use to purge the fluid delivery consumables 5, particularly the vials 22 and the hollow needles 112.

[0090] In the example in Figure 13, the vial 22 is provided with a plug seal 41 and a collar 34 attached to the vial 22 by a lock ring 42. In this example, the plug seal 41 is a septum seal that reseals after being punctured with a needle. A syringe 51 with a needle 52 is used to puncture the plug seal 41 and transfer fluid and some air into the vial 22. The plunger 24 can be pushed out by the fluid pressure or by manually retracting it. When the needle 52 is removed, the septum seal of the plug seal 41 reseals the vial 22.

[0091] In the examples shown in Figures 11 to 13, vial 22 may be filled with fluid in an extractor chamber, such as a Class A MSC hood, in a protected environment.

[0092] After vial 22 is supplied with fluid, connector 19 is attached as previously described. The fluid delivery consumable 5b with connector 19 can be stored and transported in this state. Before connecting to the bioreactor (4, see Figure 4B), the fluid can be mixed by loading the fluid delivery consumable 4b into an agitator, such as a vortex mixer, which shakes, rolls, and / or rotates the fluid delivery consumable 5b to mix the fluid. This is advantageous when the fluid is a suspension in order to resuspend the fluid components.

[0093] Figures 14A to 14D illustrate the operation of the fluid delivery consumable 5b after it has been connected to the bioreactor (4, see Figure 4B) via the connector 19, as shown in Figure 4B.

[0094] As shown in Figure 14A, after connection, the connector 19 is operated as described with reference to Figure 5 so that the hollow needle 112 forms a fluid connection between the vial 22 and the bioreactor (4, see Figure 4B). In particular, the hollow needle 112 punctures the plug seal 41 on the vial 22 and any seal on the bioreactor. The hollow needle 112 also moves to engage with the bioreactor (4, see Figure 4B) so that a fluid connection is provided between the vial 22 and the bioreactor (4, see Figure 4B).

[0095] As shown in Figure 14B, the plunger 24 is then pushed down, biasing the fluid through the hollow needle 112 and into the bioreactor (4, see Figure 4B). When the plunger 24 is pushed down, the gaiter 28, in particular the foldable wall 29, folds down and becomes folded. The plunger 24 can be pushed down manually or by an actuator on the cell processing housing (2, see Figure 1).

[0096] Referring to Figures 14B and 4B, when the plunger 14 is pushed down to deliver the fluid to the bioreactor 4, the base 15 of the bioreactor is lifted towards the interface plate 13, which can reduce the distance between the vial 22 and the base 15 of the bioreactor 4. This can reduce the impact on the fluid that would occur if it were to fall into the bioreactor 4.

[0097] As shown in Figures 14C and 14D, after the fluid has been delivered to the bioreactor (4, see Figure 4B), the connector 19 can be engaged and disengaged so that the hollow needle 112 is withdrawn from the bioreactor (4, see Figure 4B). The bioreactor (4, see Figure 4B) may be equipped with a partition seal that reseals after the withdrawal of the hollow needle 112. The connector 19 is then detached from the bioreactor (4, see Figure 4B), and the fluid delivery consumable 5b can be disposed of. As described above, in some examples, the connector 19 cannot be detached from the vial 22 after use because of the clip member 40. Therefore, the fluid delivery consumable 5b, including the connector 19, cannot be reused.

[0098] In the example, the fluid delivered to the bioreactor 4 by the fluid delivery consumable 5b contains a plurality of magnetic particles. The magnetic particles may be magnetic beads. The magnetic particles contain iron oxides such as magnetite (Fe3O4), which give them superparamagnetism. The magnetic particles may have surface coatings and chemicals that bind to nucleic acids, proteins, or other biomolecules in the bioreactor 4. The magnetic particles can be separated from the fluid by generating a magnetic field to attract the magnetic particles and thus the particles bound to them. The magnetic particles can be used in a separation process to separate components of the fluid in the bioreactor 4, in particular nucleic acids, proteins, or other biomolecules. The magnetic particles are supplied in a fluid suspension, such as water or another medium.

[0099] In another example, the fluid delivered to the bioreactor 4 by the delivery consumable 5b contains a virus suspension. The virus in the suspension may be provided to the bioreactor 4 to reprogram the cells within the bioreactor 4. The virus is provided in a fluid suspension, such as water or another medium.

[0100] In one example, vial 22 has a size that can hold up to approximately 20 ml of fluid, for example, up to approximately 15 ml of fluid, or for example, up to approximately 13 ml of fluid. In another example, vial 22 has a size that can hold up to approximately 10 ml of fluid and some air, for example, 3 ml of air. Vial 22 may include volume-indicating markings, such as a gradient.

[0101] In this example, vial 22 is made of glass. Glass may be beneficial in preventing magnetic particles or viruses from adhering to vial 22.

[0102] In this example, the fluid delivery consumable 5b can be stored at a low temperature of -800°C.

[0103] Throughout this specification and the claims, “includes,” “equipped with,” and their conjugations mean “includes indefinitely” and are not intended to exclude (or not exclude) other components, integers, or steps. Throughout this specification and the claims, singular forms include plural forms unless otherwise required by context. In particular, where the indefinite article is used (in the original English text), this specification should be understood to intend plural and even singular forms unless otherwise required by context.

[0104] Any features, integers, characteristics, or groups described in relation to a particular aspect, embodiment, or example of the present invention should be understood to be applicable to any other aspect, embodiment, or example described herein, unless incompatible. All feature components and / or all steps of any method or process disclosed herein (including any supplementary claims, abstracts, and drawings) can be combined in any combination, except for any combination in which at least some of such feature components and / or steps are mutually exclusive. The present invention is not limited to the details of any of the aforementioned embodiments. The present invention extends to any novel feature or any novel combination of features disclosed herein (including any supplementary claims, abstracts, and drawings), or to any novel step or any novel combination of any step of any method or process disclosed herein. [Explanation of Symbols]

[0105] 1. Cell processing system 2 Cell Processing Housing 3 Cell Processing Platform 4. Bioreactor 5 Fluid Delivery Consumables 5a~5f Consumables 5a Cell delivery consumables 5b Consumables for fluid delivery, consumables for bead loading 5c Consumables for medium delivery 5d Gathering consumables 5e Waste Disposal Supplies 5f Cell harvesting consumables 7. Prepare 10 processes 11 Harvest 12 containers 13 Interface Plate 14. Expansion container, plunger 15 Bottom wall, base 16 Foldable Walls 16a Inward fold 16b Outward fold 17 Top 19 Connectors 21 Connector Interface, Connection Interface 22 vials 23. Foldable wall, plunger section 24 plungers 25 stickers 26 Open end 27 Exit 28 Gaiters 29 Foldable Wall 30 caps 34 Colors 35 Funnel part 36. Tubular section 40 Clip component 41 Plug seal 42 Lock Rings 44 Tang 45 divisions 46 Engagement feature 48 supply vials 49 Needle cap 50 stitches 51 Syringe 52 needles 102 Housing 102a Upper housing portion 102b Lower housing section 104 Distal end 106 Proximal end 107 Threaded part 108 First bulkhead seal 110 Second bulkhead seal 111 Sterile paper seal 112 Hollow needle 114 First end 116 Second end 118 colors 120 First helical spring 122 Second helical spring 134 Outer sleeve 138 Groove

Claims

1. A consumable fluid delivery device for delivering liquid doses to a bioreactor, The aforementioned consumables for fluid delivery are A vial for holding the liquid volume, the vial having an outlet, an open end disposed on the opposite side of the outlet, and a seal disposed within the outlet of the vial to seal the outlet, A plunger engaged with the open end, the plunger being operable to bias the liquid volume toward the outlet, A gaiter is positioned between the open end of the vial and the top end of the plunger so as to surround the plunger, A connector disposed near the outlet and equipped with a hollow needle for puncturing the seal to form a flow connection with the vial, the connector being attachable to the bioreactor such that the liquid volume is transferred from the vial to the bioreactor by the operation of the plunger, A consumable for fluid delivery that is equipped with these features.

2. The fluid delivery consumable according to claim 1, wherein the hollow needle is movable to puncture the seal in order to form a fluid connection with the vial.

3. The seal is a consumable for fluid delivery according to claim 2, which includes a partition seal.

4. The fluid delivery consumable according to claim 2 or 3, wherein the connector comprises an actuator capable of moving the hollow needle to puncture the seal.

5. The fluid delivery consumable according to claim 4, wherein the connector comprises a first housing portion and a second housing portion, and the actuator is operable to fold the first housing portion with respect to the second housing portion so that the hollow needle punctures the seal.

6. The fluid delivery consumable according to claim 5, wherein the connector is configured such that the hollow needle engages with the bioreactor when the first housing portion is folded relative to the second housing portion.

7. The fluid delivery consumable according to claim 6, wherein the connector further comprises an end seal disposed at the end of the connector opposite to the vial, and the hollow needle is disposed to puncture the end seal when the first housing portion is folded with respect to the second housing portion.

8. The fluid delivery consumable according to any one of claims 1 to 7, further comprising a collar attached to the end of the vial near the outlet, wherein the connector is attached to the collar.

9. The fluid delivery consumable according to claim 8, wherein the collar surrounds the end of the vial, including the outlet.

10. The fluid delivery consumable according to claim 8 or 9, further comprising a locking ring having a shape that engages with a recess in the vial in order to fix the collar to the vial.

11. The connector is attached to the collar with screws, as described in any one of claims 8 to 10, for use as a consumable for fluid delivery.

12. The fluid delivery consumable according to claim 11, further comprising a clip member configured to prevent the connector from being attached to the collar after the connector has been attached to the collar.

13. The fluid delivery consumable according to claim 12, wherein the collar or the connector comprises the clip member, and the clip member is configured to engage with a recess in the other of the collar or the connector when the connector is attached to the collar, thereby preventing the connector from rotating relative to the collar after the connector has been attached to the collar.

14. The fluid delivery consumable according to any one of claims 1 to 13, wherein the gaiter comprises a foldable wall configured to be folded when the plunger is actuated.

15. The fluid delivery consumable according to any one of claims 1 to 14, wherein the gaiter is sealably attached to the vial and the plunger, and provides a sealed cover for the plunger.

16. The fluid delivery consumable according to any one of claims 1 to 15, further comprising a cap attached to the top end of the plunger, the gaiter being attached to the cap, and the cap being larger than the open end of the vial such that the gaiter has a frustoconical wall.

17. The fluid delivery consumable according to claim 16, wherein the frustum-shaped wall comprises at least one inward fold and at least one outward fold arranged so that the frustum-shaped wall is foldable.

18. The fluid delivery consumable according to any one of claims 1 to 17, wherein the plunger or cap comprises an engaging feature that can be engaged to actuate the plunger.

19. The fluid delivery consumable according to any one of claims 1 to 18, wherein the plunger comprises a piston adapted to strike and seal the inner surface of the vial.

20. The fluid delivery consumable according to any one of claims 1 to 19, wherein the vial is a glass vial.

21. The liquid volume comprises a plurality of magnetic particles in a fluid suspension, as described in any one of claims 1 to 20.

22. The liquid volume is a consumable for fluid delivery according to any one of claims 1 to 20, comprising a virus suspension.

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