Sampling module for a bioreactor container

Abstract

The present application provides a sampling module for a bioreactor container. The sampling module comprises a connecting portion for forming a fluid connection with a sampling port of the bioreactor container, a sample chamber for receiving a fluid sample from the bioreactor container, and a transparent window through which a sensor unit can sense at least one parameter of the fluid sample within the sample chamber.

Description

SAMPLING MODULE FOR A BIOREACTOR CONTAINER

[0001] The invention relates to a sampling module for a bioreactor container, and particularly to a sampling module including a transparent window through which a parameter of a fluid sample can be detected. The invention further relates to a bioreactor system.BACKGROUND

[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, or unit operations, of cell-based therapeutic products (CTP) manufacturing may include devices for various functions. These various functions may be, for example, cell collection, cell isolation, cell selection, cell expansion, cell washing, volume reduction, cell storage or transportation. The unit operations can vary immensely based on the manufacturing model (i.e. autologous versus allogenic), cell type, intended purpose, among other factors. In addition, cells are “living” entities sensitive to even the simplest manipulations, for example, such as differences in a cell transferring procedure. The role of cell manufacturing equipment in ensuring scalability and reproducibility is an important factor for cell and gene therapy manufacturing.

[0003] In addition, cell-based therapeutic products (CTP) have gained significant momentum thus there is a need for improved cell manufacturing equipment for various cell manufacturing procedures. These manufacturing procedures, may include, for example, stem cell enrichment, generation of chimeric antigen receptor (CAR) T cells, and various cell manufacturing processes such as collection, purification, gene modification, incubation, recovery, washing, infusion into a patient, or freezing.

[0004] The culture or processing of cells typically requires the use of a device to hold the cells, for example in an appropriate culture medium when culturing the cells. The known devices include shaker flasks, roller bottles, T-flasks, bags and the like. Such devices are typically required to be connected to other devices, such as containers, interfaces or the like, so that various media may be introduced to, or removed from, the device holding the cells. Typically, cells in a culture medium can be added to the device from a flexible bag that is attached using a connecting tube. Alternatively, cells can be transferred by a pipette or by a syringe.

[0005] The production of autologous CAR T cells is carried out by a variety of manufacturing approaches all comprising the same common steps. First, the patient’s white blood cells (WBCs) are isolated by leukapheresis and washed. Then, the T cells areactivated, transduced with the CAR transgene, expanded to the required cell numbers for therapy, formulated and filled. After quality control testing and preparatory lymphodepleting chemotherapy for the patient, the product is injected into the patient.BRIEF SUMMARY OF THE DISCLOSURE

[0006] In accordance with the present disclosure there is provided a sampling module for a bioreactor container, the sampling module comprising: a connecting portion for forming a fluid connection with a sampling port of the bioreactor container, a sample chamber for receiving a fluid sample from the bioreactor container, and a transparent window through which a sensor unit can sense at least one parameter of the fluid sample within the sample chamber.

[0007] Accordingly, the parameters of the fluid sample can be sensed in a non-invasive manner through the transparent window. The non-invasive sensing may maintain sterility of the sample and the bioreactor container.

[0008] In one example, a wall of the sample chamber may be formed of a transparent material. The transparent window may be defined in the wall. In another example, the sample chamber may comprise a wall and the transparent window may be an insert in the wall.

[0009] In examples, the sampling module may be operable to return the fluid sample to the bioreactor container. Accordingly, parameters of the fluid sample are sensed through the transparent window and may be sensed while the sampling module is connected to the sampling port of the bioreactor container. Thus, exposure of the fluid sample to contaminants is reduced, or eliminated, allowing the fluid sample to be returned to the bioreactor container. This allows for more frequent testing of fluids samples without reducing the cell count in the bioreactor container.

[0010] In examples, the sampling module may further comprise a plunger operable to draw the fluid sample into the sample chamber. The plunger may be disposed in the sample chamber. The plunger may be operable to drive the fluid sample from the sample chamber into the bioreactor container.

[0011] In examples, the connecting portion comprises a pierceable seal. The pierceable seal may be pierced by a sterile connector. Accordingly, the pierceable seal maintains an aseptic environment within the sample chamber prior to connection with the bioreactor container via the sampling port. This allows for an aseptic connection to be made betweenthe bioreactor container and the sampling module to reduce, or eliminate, exposure to contaminants.

[0012] In examples, the sampling module may further comprise a sensor element disposed within the sample chamber. The sensor element may comprise at least one of a temperature sensor, a capacitance sensor, a glucose sensor, and / or a lactate sensor.

[0013] In examples, the sensor element may comprise a material provided within the sample chamber. The material may be pre-filled in the sample chamber. The material may be a reagent configured to respond to incident light that induces a fluorescent signal based on a parameter of the contents of the sample chamber (e.g. the fluid sample received from the bioreactor). For example, the reagent may be a cell viability dye and the parameter may be cell viability. In particular, the cell viability dye may be propidium iodide or 7- aminoactinomycin D (7-AAD) or another cell viability dye as known in the art. In this way, the reagent mixes with the contents of the sample chamber (e.g. the fluid sample received from the bioreactor), and an optical receiver provided in a sensor unit can receive the fluorescent signal and a sensor meter can be used to measure the fluorescent signal to determine the parameter of the cell suspension. This allows for non-invasive sensing of at least one parameter of the cell suspension.

[0014] In another example, the sensor element may be disposed on an internal surface of the transparent window. The sensor element may comprise an oxygen-sensitive coating or a pH-sensitive coating. In examples, the sensor element may comprise a substrate having an oxygen-sensitive coating or a pH-sensitive coating on one side and an adhesive on the other side for fixing to the transparent window. The sensor element, in particular a material or coating of the sensor element, may be configured to respond to incident light that induces a fluorescent signal based on a parameter of the cell suspension within the bioreactor, for example an oxygen concentration or pH of the cell suspension. Accordingly, an optical receiver provided in a sensor unit can receive the fluorescent signal and a sensor meter can be used to measure the fluorescent signal to determine the parameter of the cell suspension. This allows for non-invasive sensing of at least one parameter of the cell suspension.

[0015] In examples, the sampling module may further comprise a port for introducing material therethrough into the sample chamber. The port may be provided in a wall of the sample chamber. Accordingly, one or more markers or dyes can be added to the fluid sample in the sample chamber to measure at least one parameter of the fluid sample such as cell count, cell density cell viability, or cell diameter.

[0016] In examples, the sampling module may further comprise a sensor unit arranged to sense the at least one parameter of the fluid sample. Accordingly, the parameters of thefluid sample can be sensed without the need to transfer the sampling module to an external sensor unit.

[0017] In examples, the sensor unit may comprise an optical sensor. The sensor unit may be arranged to sense the at least one parameter of the fluid sample through the transparent window. Accordingly, the optical sensor allows for non-invasive sensing of at least one parameter of the cell suspension.

[0018] In examples, the sensor unit may be configured to detect one or more of a pH of the fluid sample, a dissolved gas content of the fluid sample, for example dissolved oxygen or dissolved carbon dioxide, a cell density of the fluid sample, a cell count of the fluid sample, cell viability, and / or degree of cell suspension.

[0019] In examples, the sensor unit may comprise a temperature sensor. The temperature sensor may be arranged to sense the temperature of a wall of the sample chamber.

[0020] In examples, the sensor unit may comprise a wireless communications unit.

[0021] In accordance with the present disclosure there is also provided a bioreactor system comprising a bioreactor container having a sampling port, and the sampling module described above.

[0022] In examples, the bioreactor system may further comprise a sensor unit disposed to align with the transparent window of the sampling module.

[0023] In examples, the bioreactor system may further comprise a housing. The bioreactor container may be provided within the housing. The sensor unit may be disposed to align with the transparent window of the sampling module when the sampling module is fluidly connected to the sampling port of the bioreactor container. In examples, the bioreactor container may be movable within the housing. The sensor unit may be disposed to align with the transparent window when the bioreactor container is in a sensing position. In examples, the bioreactor container may be rotatable within the housing. The sensor unit may be disposed to align with the transparent window when the bioreactor container is in a rotational sensing position. Accordingly, the parameters of the fluid sample can be sensed without having to disconnect the sampling module from the bioreactor container or transfer the sampling module to an external sensor unit.

[0024] In examples, the sensor unit may comprise an optical sensor. This allows for non- invasive sensing of at least one parameter of the cell suspension.

[0025] In examples, the sensor unit may comprise a temperature sensor. The temperature sensor may be arranged to sense the temperature of a wall of the sample chamber.

[0026] In examples, the sensor unit may be a spectroscopic sensor or a digital holography sensor. The spectroscopic sensor or the digital holography sensor may be arranged to sense the at least one parameter of the fluid sample through the transparent window. The spectroscopic sensor may be a spectrophotometric sensor. This allows for non-invasive sensing of a cell count or cell characteristics, such as gene expression and / or phenotype.

[0027] In examples, the sensor unit may be disposed within the housing.

[0028] In examples, the bioreactor system may further comprise an external sensor unit and an actuator operable to disconnect the sampling module from the sampling port and transfer the sampling module to the external sensor unit.

[0029] In one example, the external sensor unit may comprise a sensor configured to sense at least one parameter of the fluid sample through the transparent window.

[0030] In another example, the external sensor unit may comprise a connector for connection to the connecting portion of the sampling module for receiving the fluid sample from the sampling module.

[0031] In examples, the external sensor unit may comprise a capacitance sensor and / or a surrogate metabolite sensor for detecting a parameter indicative of at least one of a cell count, cell density and cell viability of the fluid sample received from the sampling module.

[0032] In examples, the external sensor unit may be configured to detect at least one of a pH, dissolved oxygen, dissolved carbon dioxide, cell count, cell density, cell viability, temperature, metabolite levels, protein secretion, phenotype, cell activation, and gene expression of the fluid sample received from the sampling module.

[0033] In examples, the external sensor unit may comprise a digital holography sensor. The digital holography sensor may sense one or more of a cell count, gene expression or phenotype of the cells in the fluid sample. The digital holography sensor may be arranged to sense the at least one parameter of the fluid sample through the transparent window.

[0034] In examples, the external sensor unit may comprise a spectroscopic sensor. The spectroscopic sensor may be a spectrophotometric sensor. The spectroscopic sensor may sense one or more of a cell count, cell size, cell viability, or phenotype of the cells in the fluid sample, or analyte levels, for example protein levels or metabolite levels, of the fluid sample. The spectroscopic sensor may be arranged to sense the at least one parameter of the fluid sample through the transparent window.

[0035] In examples, the external sensor unit may be configured to conduct flow cytometry testing on the fluid sample received from the sampling module. Accordingly, flow cytometrytesting can be used to measure at least one parameter of the fluid sample, such as a phenotype, overall count, size, viability, and / or activation of the cells in the fluid sample.

[0036] In examples, the sensor unit and / or the external sensor unit may comprise a wireless communications unit for communication with a control system of the bioreactor system. Accordingly, the bioreactor system can adjust parameters of the system or otherwise adjust operation of the bioreactor in response to the measured parameters.

[0037] In examples, the bioreactor container may comprise a compressible wall and an interface plate. The sampling port may be provided in the interface plate. The compressible wall may be a bellows wall. Accordingly, the bioreactor container may be a compressible or deformable container.

[0038] In examples, the interface plate may comprise a plurality of sampling ports. In examples, at least one of the sampling ports may comprise a sampling tube extending from the interface plate into the bioreactor container. The interface plate may comprise a plurality of sampling ports each having a sampling tube, and the sampling tubes may have different lengths for sampling the fluid in the bioreactor container from different depths and / or to allow fluid samples to be taken from different fluid levels within the bioreactor container.

[0039] In accordance with the present disclosure there is also provided a bioreactor system comprising: a housing; a support disposed within the housing and configured to hold a bioreactor container; and a sensor unit disposed within the housing to align with a sampling module fluidly connected to the bioreactor container.

[0040] In examples, the support may be configured to hold an interface plate of the bioreactor container, the interface plate comprising a sampling port for fluidly connecting the sampling module to the bioreactor container.

[0041] In examples, the sensor unit may comprise an optical sensor. The sensor unit may be configured to align with a transparent window of the sampling module.

[0042] In accordance with the present disclosure there is also provided a method of sampling a fluid from a bioreactor, the method comprising: extracting a fluid sample from a bioreactor container into a sample chamber of a sampling module, the sample chamber having a transparent window, anddetecting at least one parameter of the fluid sample through the transparent window.

[0043] In examples, following the step of detecting the parameter of the sample fluid, the fluid sample may be returned to the bioreactor container.

[0044] In examples, the bioreactor system and bioreactor vessel described above are all usable for biological processing applications, in particular cell and gene therapy manufacturing. In particular, the bioreactor system may be used for cell processing for cell and gene therapy manufacturing.BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Embodiments of the invention are further described hereinafter with reference to the accompanying drawings, in which:FIG. 1 shows a bioreactor system;FIGS. 2A and 2B show the bioreactor vessel of the bioreactor system;FIG. 3 shows a support of the instrument of the bioreactor system;FIG. 4 shows a cross-section of the bioreactor vessel of FIGS. 2A and 2B;FIG. 5 shows an example sampling module;FIGS. 6A and 6B show a cross-section of the sampling module of Fig. 6 in a contracted position and in an extended position.FIG. 7 shows the sampling module of Fig. 6 and a sensor unit.DETAILED DESCRIPTION

[0046] FIG. 1 shows a bioreactor system 1 that includes an instrument 2 and a bioreactor vessel 3. The instrument 2 includes a housing 4. FIG. 1 shows the bioreactor vessel 3 loaded into the instrument 2. FIGS. 2A and 2B illustrate the bioreactor vessel 3 in isolation. During use a biological process, for example cell processing, is carried out within the bioreactor vessel 3 in the instrument 2 of the bioreactor system 1.

[0047] The instrument 2, in particular the housing 4, provides a closed environment for the bioreactor vessel 3. The instrument 2 is provided with power, connectivity and other utilities needed for the cell processing within the bioreactor vessel 3. The bioreactor system 1 includes a temperature control system to control the temperature within the housing. The bioreactor system 1 includes a humidity control system to control the humidity within the housing. The bioreactor system 1 includes a gas control system to control gas flow into and out of the housing, for example to control pressure within the housing and / or to control gas concentrations within the housing, for example oxygen andcarbon dioxide concentrations. The housing may be an incubator within which the bioreactor vessel 3 is housed during cell processing.

[0048] As shown in FIGS. 2A, 2B and 4, the bioreactor vessel 3 comprises a container 6 and an interface plate 7. The interface plate 7 is a lid of the container 6. The interface plate 7 comprises at least one port 8 for connecting to an external component, for example a consumable or a sampling module that can be temporarily attached to the bioreactor 3.

[0049] In examples, the or each port 8 may comprise a septum seal that maintains a sealed environment within the container 6. Access to the container 6 can be provided by a needle that passes through the septum seal of the port 8 to create a fluid connection into the container 6. Accordingly, external components, in particular delivery, extraction, and / or sampling modules can be connected to the port 8 to add material to, or remove material from, the bioreactor vessel 3, in particular the container 6. A plurality of ports 8 may be provided so that each port 8 can only be used once to maintain sterility. A subset of the plurality of ports 8 may be sampling ports.

[0050] The container 6 is a compressible container. In particular, the container 6 has a base plate 9 disposed opposite to the interface plate 7, and a compressible wall 10 defining a sidewall of the container 6. The base plate 9 is substantially rigid, for example rigid. The interface plate 7 is substantially rigid, for example rigid. The compressible wall 10 extends between, and is attached to, the interface plate 7 and the base plate 9. The compressible wall 10 and base plate 9 may be integrally formed or attached to one another. The compressible wall 10 is compressible such that the base plate 9 can move towards and away from the interface plate 7, changing the internal volume of the container 6. The compressible wall 10 also allows the angle of the base plate 9 with respect to the interface plate 7 to be varied, for example to mix or agitate the contents of the container 6.

[0051] The compressible wall 10 is a bellows wall, having a concertina arrangement that allows the compressible wall 10 to fold onto itself in order to collapse. In particular, the compressible wall 10 comprises a series of alternately arranged inward folds 11a and outward folds 11b that allow the compressible wall 10 to collapse like a bellows or concertina. The inward folds 11a and outward folds 11b may be formed by thinned sections in the compressible wall 10. The inward folds 11a may comprise a thinned section arranged on the outer surface of the compressible wall 10, and the outward folds 11b may comprise a thinned section arranged on the inner surface of the compressible wall 10.

[0052] The container 6 of the bioreactor vessel 3 can therefore expand and contract, or be expanded and contracted. In particular, the compressible container 6 may expand as the cell culture within the container 6 grows, and / or as additional materials are added, or it may be moved (e.g., compressed or expanded) to change the volume of the container 6.The bioreactor system (1 , see FIG. 1) may comprise an actuator adapted to move, for example push and / or pull, the base plate 9 of the container 6 and / or the interface plate 7 to change the volume of the container 6. The actuator may be operable to agitate the contents of the container 6, for example by moving the base plate 9 in a reciprocal motion. The actuator may be an agitator module as described further hereinafter.

[0053] As illustrated in FIGS. 2A, 2B and 4, the interface plate 7 also includes an expansion container 12, otherwise called a breathing bellows. The expansion container 12 may be expandable or collapsible, for example being formed with a bellows wall similar to the container 6. The expansion container 12 is in fluid communication with the container 6 through an opening in the interface plate 7. The expansion container 12 may comprise a filter 13 that filters air and other gases passing into or out of the expansion container 12. The filter 13 may be closable to seal the expansion container 12. In other examples the expansion container 12 is closed and sealed from the external environment, in which case no filter may be provided.

[0054] The bioreactor system 1, in particular the instrument 2, comprises a support 16, as illustrated in FIGS. 1 and 3, mounted within the instrument 2 to receive and support the bioreactor vessel 3. The support 16 may slide in and out of the housing in the manner of a drawer for convenience of loading and unloading the bioreactor vessel 3. The support 16 comprises a support portion 18 adapted to engage the interface plate 7 and support the bioreactor vessel 3. The support 16 also includes an opening 17 adapted to receive the container 6 of the bioreactor 3 such that the interface plate 7 rests on the support portion 18 and the container 6 is suspended below, in and through the opening 17. The support 16 holds the interface plate 7 of the bioreactor vessel 3 in a substantially horizontal position.

[0055] Referring to FIGS. 1 to 3, when the bioreactor vessel 3 is supported on the support 16 the expansion container 12 is positioned on the top of the interface plate 7 and is expandable and contractable in a substantially vertical direction. The container 6 is suspended below the interface plate 6 and may be freely hanging, supported on another plate, and / or moved by an actuator or agitation module as described further hereinafter.

[0056] In some examples the bioreactor vessel 3 is rotatable relative to the instrument 2. In such examples the support 16, in particular the support portion 18, may comprise a rotating mechanism. For example, the support portion 18 may have a pancake motor adapted to rotate the interface plate 7 and therefore rotate the bioreactor vessel 3. As shown in FIG. 2B the bioreactor vessel 3 comprises a plurality of ports 8, and the rotating mechanism may be operable to rotate the interface plate 7 to align successive ports 8 with another component or assembly. The rotating mechanism may be adapted to index the interface plate 7 to bring successive ports 8 into alignment with another component orassembly. Accordingly, each port 8 may be used only once, which may help to maintain sterility.

[0057] The bioreactor system 1 may further include one or more consumables, such as a sampling module (30, see FIGS. 5 to 7). The consumables may be attachable to the bioreactor vessel 3 and / or to another assembly provided within the instrument 2. In particular, one or more consumables may be attached to an actuator that connects the consumable to the bioreactor vessel 3. Alternatively, the one or more consumables may be connected to the bioreactor vessel 3, for example at the port(s) 8, and the bioreactor system 1 may comprise an actuator to operate the consumable. For example, the bioreactor system 1 may comprise an actuator adapted to depress or compress a consumable to move a material from the consumable into the container 6, and / or the actuator may be operable to retract or expand the consumable to draw material from the container 6. The bioreactor system 1 may include a consumable loading mechanism at which a user loads a consumable into the instrument 2. The consumable loading mechanism may then be operated to attach the consumable to the bioreactor vessel 3, for example at a port 8 as illustrated in FIGS. 2A and 2B.

[0058] In examples, the consumables may be connected to the bioreactor vessel 3, in particular to the port 8 of the interface plate 7, by a connector (50, see FIG. 7). The connector 50 may maintain sterility between the consumable and the bioreactor vessel 3, for example by having one or more seals such a septum seals. The connector 50 may be that described in applicant’s co-pending patent application PCT / GB2020 / 053229 (WO2021123760A1).

[0059] The bioreactor system 1 may additionally include various components and systems that interact with the instrument 2, bioreactor vessel 3 and / or consumables. For example, as described further hereinafter, the instrument 2 may include an agitation module that acts to agitate the bioreactor vessel 3 so as to agitate a cell suspension provided within the bioreactor vessel 3. In other examples, the bioreactor system 1 may include a consumable loading mechanism adapted to hold one or more consumables, such as the sampling module (30, see FIGS. 5 to 7). In examples, the bioreactor system 1 may include an actuator operable to actuate one or more the consumables such as the sampling module 30. The bioreactor system 1 may be configured for automated or semi-automated operation, and / or may permit manual operation.

[0060] As described above, the bioreactor vessel 3 includes a container 6 and an interface plate 7. During use for cell processing the container 6 holds a fluid in which the cell processing occurs. In particular, the fluid comprises a population of cells present in a liquid medium. The consumables may attach to the bioreactor vessel 3 to add material to thecontainer 6. For example, the consumables may add cells (e.g., a cell suspension), a cell growth media, or other material. The consumables, such as the sampling module (30, see FIGS. 5 to 7) may alternatively attach to the bioreactor vessel 3 to remove material from the container 6. For example, the consumables may remove a waste material, and / or processed cells, and the sampling module 30 may remove a fluid sample. The consumables therefore connect to the bioreactor vessel 3 in order to facilitate process steps of the cell processing.

[0061] The population of cells being processed in the bioreactor vessel 3 during use may comprise any cell type. Suitably the population of cells may comprise a homogenous population of cells. Alternatively the population of cells may comprise a mixed population of cells.

[0062] The population of cells may comprise any human or animal cell type, for example: any type of adult stem cell or primary cell, T cells, CAR-T cells, monocytes, leukocytes, erythrocytes, NK cells, gamma delta t cells, tumour 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. Suitably the population of cells may comprise T-cells.

[0063] Alternatively, the population of cells may comprise any microorganism cell type, for example: bacterial, fungal, Archaean, protozoan, algal cells.

[0064] In examples, a liquid medium may be added to the container 6 during cell processing. The liquid media may be any sterile liquid capable of maintaining cells. The liquid medium may be selected from: saline or may be a cell culture medium. The liquid medium may be a cell culture medium selected from any suitable medium, for example: DMEM, XVIVO 15, TexMACS. The liquid medium may be appropriate for the type of cells present in the population. For example, the population of cells comprises T cells and the liquid medium comprises XVIVO 10.

[0065] In examples, the liquid medium may further comprise additives, for example: growth factors, nutrients, buffers, minerals, stimulants, stabilisers or the like.

[0066] In examples, the liquid medium comprises 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 comprise stimulants such as antigens or antibodies, which may be mounted on a support. Suitable stimulants are appropriate for the type of cells present in the population and the desired process to be carried out. When culturing T-cells, for example, antibodies are provided as a stimulant in the liquid medium. The antibodies may be mounted on an inert support suchas beads, more particularly magnetic beads such as Dynabeads® by ThermoFisher Scientific.

[0067] The additives may be present in the liquid medium at an effective concentration. An effective concentration can be determined by the skilled person on the basis of the population of cells and the desired process to be carried out using known teachings and techniques in the art.

[0068] In examples, the population of cells are seeded in the liquid medium at a concentration of between 1x104 cfu / ml up to 1x108cfu / ml.

[0069] In other examples, the bioreactor system 1 may be used for other applications, for example, the bioreactor system 1 may be used for other biological processing applications such as bacterial fermentation and waste water treatment.

[0070] As shown in FIG. 4, which shows a cross-section of the bioreactor vessel 3, the bioreactor vessel 3 includes sampling tubes 21 fluidly connected to the ports 8 in the interface plate 7. The sampling tubes 21 extend from the interface plate 7 into the container 6. In this way, the sampling tube 21 provides a fluid sampling path from the container 6 to the interface plate 7. In examples, only a subset of the ports 8 in the interface plate 7 are sampling ports which are provided with a sampling tube 21. For example, half of the ports 8 are sampling ports provided with a sampling tube 21. In other examples, only one, two, or three of the ports 8 are sampling ports provided with a sampling tube 21.

[0071] In examples, the bioreactor vessel 3 includes a baffle 22 mounted to the interface plate 7. The baffle 22 includes a circular baffle member sized so as to fit within the container 6. The baffle member may be sized so as to be spaced from the compressible wall 10 of the container 6 to permit the sampling tubes 21 to pass between the compressible wall 10 and the baffle member.

[0072] FIG. 5 illustrates a sampling module 30 for extracting a fluid sample from the bioreactor vessel 3 and FIGS. 6A and 6B illustrate a cross-section of the sampling module 30. The sampling module 30 is operable to draw a fluid sample, for example a sample of a cell suspension, from a bioreactor vessel 3.

[0073] As shown in FIGS. 6A and 6B, the sampling module 30 has a sample chamber 32 in which the fluid sample is received. In the illustrated example, the sample chamber is a vial 32. The sampling module 30 also has a connecting portion 35 that is connectable to the bioreactor vessel 3 via a connector (50, see FIG. 7), for example a sterile connector. In particular, the connector 50 is connectable to the interface plate (7, see FIGS. 2A, 2B) of the bioreactor vessel 3.

[0074] The sampling module 30 also includes a plunger portion 33 that is operable to draw the fluid sample out of the bioreactor vessel 3, through the connecting portion 35, and into the vial 32. FIGS. 5 and 6A illustrate the sampling module 30 with the plunger portion 33 in an extended position. FIG. 6B illustrates the sampling module 30 with the plunger portion 33 in a retracted position.

[0075] As shown in FIGS. 6A and 6B, the vial 32 includes an open end 36 and an inlet 37 opposite to the open end 36. The vial 32 has a tubular portion 38 that is substantially straight, and a funnel portion 39 that narrows to the inlet 37.

[0076] In examples, the vial 32 is sized to hold up to about 20ml of fluid, for example up to about 15ml of fluid, for example up to about 13ml of fluid. In one example, the vial 32 is sized to hold up to about 10ml of fluid and some air, for example 3ml of air.

[0077] The plunger portion 33 comprises a plunger 34 arranged to pass through the open end 36 of the vial 32 and move in the vial 32, from near to the inlet 37 to near to the open end 36. The plunger 34 includes a piston having a seal 41 that seals against an inner surface of the vial 32, in particular against the inner surface of the tubular portion 38, to provide a substantially fluid-tight seal. The seal 41 may be in the form of a piston attached to the plunger 34, or the piston may be formed as a part of the plunger 34. The seal 41 on the plunger 34 or piston may include one or more O-rings. Accordingly, the plunger 34 can be retracted from an initial position where the piston is proximate to the inlet 27 (as shown in FIG. 6A) to the extended position (as shown in FIG. 6B) to create a negative pressure in the vial 32 to draw a fluid sample, as described further hereinafter.

[0078] The plunger portion 23 includes a gaiter 42. The gaiter 42 is formed by a collapsible wall 43, for example a bellows wall. The gaiter 42 includes a cap 44 attached to an end of the plunger 34. The collapsible wall 43 extends between the cap 44 and the open end 36 of the vial 32. The collapsible wall 43 may be attached to the open end 37 of the vial 32 by adhesive, or by clamping or other attachment mechanism. A clamping ring may be provided to clamp the end of the collapsible wall 43 to the vial 32. The collapsible wall 43 may be attached to the cap 44 by adhesive, or by clamping or other attachment mechanism. A clamping ring may be provided to clamp the end of the collapsible wall 43 to the cap 44.

[0079] The collapsible wall 43 of the gaiter 42 is formed by an alternating series of inward folds and outward folds that permit sections of the collapsible wall 43 to fold against each other. The gaiter 42, in particular the collapsible wall 43, surrounds the plunger 34 when it is outside of the vial 32, and therefore provides a sealed environment for the plunger 34. As will become clear, the plunger 34 may be moved from within the vial 32 to outside of the vial 32 to draw a fluid sample from the bioreactor container 6, and then depressedback into the vial 32 to return the fluid sample to the bioreactor container 6 or to move the fluid sample to another container or module, and therefore the gaiter 42 can prevent contamination of the plunger 34 and maintain the sterility of the vial 32 and the fluid sample received therein.

[0080] According to the example shown in FIGS. 5, 6A and 6B, the collapsible wall has a substantially cylindrical shape. According to an alternative, non-illustrated example, a first end of the collapsible wall 43 that attaches to the cap 44 may be larger than a second end of the collapsible wall 43 that attaches to the vial 32. In this way, the collapsible wall 44 collapses inwards when collapsed.

[0081] The gaiter 42, in particular the cap 44 and collapsible wall 43, provide a sealed enclosure for the plunger 34. During operation the plunger 34 may be retracted towards the open end 36 to draw a fluid sample from the bioreactor, and then depressed back into the vial 32 to return the fluid sample to the bioreactor container 6, or to move the fluid sample to another container or module, such as an external sensor unit. Therefore the gaiter 42 can prevent contamination of the plunger 34 and maintain the sterility of the vial 32.

[0082] In examples, the cap 44 may comprise an engaging feature 46 that is engageable by another part of the cell processing system (1 , see FIG. 1), in particular an actuator in the housing of the instrument (2, see FIG. 1). The actuator may engage the engaging feature 46, for example, to depress or retract the plunger 34.

[0083] The connecting portion 35 may be provided with a sleeve 46. The sleeve 46 surrounds the vial 32. The connecting portion 35 includes a threaded portion, in particular an external thread 45, for connecting to a thread of the connector (50, see FIG. 7). Such a threaded connection between the connecting portion 35 and connector 50 allows for simple connection or disconnection of the connector to, or from, the vial 32. However, it will be appreciated that other connection mechanisms may be provided between the connecting portion 35 and the connector. For example, a bayonet connecting mechanism may be provided between the connecting portion 35 and the connector. In other examples, the inlet 37 of the vial 32 may have an external thread to engage an internal thread on the connector 50 to provide direct connection between the vial 32 and the connector 50.

[0084] As shown in FIG. 5, the sleeve 46 has a cut-out 51. The cut-out 51 reveals a portion of the vial 32 to provide a transparent window 52 through which a fluid sample within the vial 32 is visible. At least the portion of the vial 32 that aligns with the cut-out 51 is formed from a transparent material. In some examples, the entirety of the vial 32 is formed from a transparent material. An optical sensor (61, see FIG. 7) may be operable to detect a parameter of the fluid sample through the transparent window 52.

[0085] According to alternative, non-illustrated examples, the sampling module may not include a sleeve and the sample chamber, for example the vial 32, may be formed an opaque material. A wall of the sample chamber 32 may formed of a transparent material, and the transparent window 52 is defined in the wall. In further examples, the transparent window 52 may be an insert provided in a portion of the wall. For example, the transparent window 52 may be co-moulded with the wall of the sample chamber 32.

[0086] The transparent window 52 and / or the vial 32 is formed from a transparent material. The transparent material may be transparent or translucent as long as the transparent material is transparent to the wavelength of light at which an optical sensor (61 , see FIG. 7) operates. That is, the transparent window 52 permits transmission of light from within the sample chamber 32 of the sampling module 30 to the optical sensor 61. Accordingly, optical sensor signals can pass between the optical sensor 61 and the sensor element 53 through the sensor window 52.

[0087] In some examples, the transparent window 52 and / or vial 32 may be made from a polymer such as polycarbonate, polyethylene terephthalate, or polymethyl methacrylate. Transparent polymers can be co-moulded with other polymer materials to form the sampling container 32 having the transparent window 52 integrally formed therein. In other examples, the transparent window 52 and / or vial 32 may be made from glass. Glass may be beneficial to prevent magnetic particles or viruses from sticking to the vial 32.

[0088] The sleeve 46 may include a scale 54 provided along a portion of the cut-out and arranged to overlay a part of the vial 32. The scale provides gradation marks indicating the volume of fluid in the vial 32.

[0089] In examples, the sleeve 46 may be made from a polymer material. For example, the sleeve 46 may be made from polypropylene, polyethylene, cyclic olefin copolymer, or cyclic olefin polymer.

[0090] The transparent window 52 may have a sensor element 53 disposed on an internal surface of the transparent window 52. The sensor element 53 comprises a parametersensitive material, for example an oxygen-sensitive, carbon dioxide-sensitive or pH- sensitive material, possibly as a coating. Alternatively, the vial 32 may include a pre-filled reagent, such as a cell viability dye. The optical properties of the sensor element 53 - or the pre-filled reagent - thereby changes according to the corresponding parameter of the fluid sample in the vial 32.

[0091] In examples, the transparent window 52 may have more than one sensor element 53 disposed on the internal surface. For example, there may be two sensor elements disposed on the internal surface of the transparent window 52. The first sensor elementmay have an oxygen-sensitive material and the second sensor element may have a pH- sensitive material.

[0092] In some examples, the sample chamber 32 may have a port for introducing material therethrough into the sample chamber 32. The port can be provided in a wall of the sample chamber 32. Alternatively, the port may be provided in the connecting portion 35. A marker or dye can be added through the port into the cell suspension in the sample chamber 32. This increases the visibility of the cells and allows for optical measurement of at least one parameter of the cell suspension through the transparent window 52. The at least one parameter is one of cell count, cell density cell viability, cell size, or cell diameter. Cell size and / or cell diameter measurements may be used as a surrogate indicator of cell activation.

[0093] The vial 32 may also have one or more sensor elements, such as probes, disposed within the vial. The sensor elements may include a temperature sensor, a capacitance sensor, a glucose sensor, or a lactate sensor. The one or more sensor elements may include a wire that extends out of the vial 32 and connects to connector of a sensing unit.

[0094] Accordingly, one or more parameters of the fluid sample may be detected when the fluid sample is within the vial 32, either using an optical sensor (61, see FIG. 7) that operates through the transparent window 52, or using a probe that contacts the fluid sample within the vial 32.

[0095] With reference to FIGS. 2A, 2B and 4 to 7, the connecting portion 35 of the sampling module 30 is connectable to a connector 50. The connector 50 is connectable to the bioreactor vessel 3, in particular to the port(s) 8 of the interface plate 7. After the connector 50 has been attached to the connecting portion 35 of the sampling module 30 and to the port 8 of the interface plate 7, the connector 50 can be actuated to create a fluid connection between the sampling module 30 and the bioreactor container 6. After the fluid connection is formed by the connector 50, the plunger 34 can be retracted to draw the fluid sample from the bioreactor container 6 into the vial 32 via sampling tube 21.

[0096] As shown in FIG. 6A, the connecting portion 35 includes a plug seal 48 to seal the inlet 37 to the vial 32. The plug seal 48 may be inserted into the inlet 37 and held there by friction. Alternatively, as shown in FIG. 6A, the plug seal 48 may be mounted to a securing ring 55 that is attachable to the connecting portion 35 so as to position the plug seal 48 within the inlet 37. The securing ring 55 may have one or more tangs arranged to engage a recess on the connecting portion so as to attach the securing ring 55 to the connecting portion 35. When attached, the plug seal 41 is positioned in the inlet 37 of the vial 32.

[0097] The plug seal 41 may be pierceable by a hollow needle of the connector (50, see Fig. 7) during use. The plug seal 41 may be a septum seal. The plug seal 41 seals the vial 32 before the connector 50 is attached and / or after the connector 50 has been detached from the connecting portion 35. Additionally or alternatively, a cap or lid may be placed over the connecting portion after disconnecting the testing module 30 from the connector 50.

[0098] When the connector (50, see FIG. 7) is actuated the hollow needle of the connector 50 pierces the plug seal 41 and any additional seal on the connector 50 to create a fluid connection between the hollow needle and the vial 32. The other end of the hollow needle creates a fluid connection with the bioreactor container (6, see FIGS. 2A, 2B and 4). Accordingly, once the connector 50 has been actuated the plunger 34 can be retracted to draw the fluid sample from the bioreactor container 6 into the vial 32.

[0099] In alternative examples, the connecting portion 35 may comprise an openable valve, a breakable seal, or other sealing mechanism that seals the sampling module 30 before use (i.e. , before a fluid sample is extracted) and / or after the fluid sample has been extracted. Such a seal may be openable or pierceable once the connecting portion 35 is connected to the connector 50 and the connector is connected to the bioreactor vessel 3 to provide a fluid connection between the sampling module 30 and the bioreactor container 6.

[0100] As shown in FIGS. 5 and 6A, the plunger 34 is positioned within the vial 32 and the gaiter 42 is in a compressed state. The sampling module 30 is then connected to a port (8, see Fig. 4) via a connector (50, see Fig. 7). Alternatively, the sampling module 30 may be directly connected to the port 8. In this state the sampling module 30 is ready to extract a fluid sample from the bioreactor container 6.

[0101] In examples, the bioreactor container 6 is agitated, as described above, prior to extracting the fluid sample. Agitation of the bioreactor container 6 mixes the contents of the bioreactor container so that the fluid sample extracted from the bioreactor container 6 provide a representative sample of the fluid contained therein. In other examples, the bioreactor container 6 is not disturbed prior to extracting the fluid sample, and the fluid sample is extracted from a specified height from the base plate 9 of the bioreactor container 6. Sampling the fluid in this way may give a measure of the degree of cell suspension or a parameter of the cell media, such as metabolite measurements, pH, dissolved oxygen, and the like, without extracting cells themselves.

[0102] The fluid level 23 in the bioreactor container 6 is then moved such that an end 21a of the sampling tube 21 is submerged in the fluid, as shown in FIG. 4. In particular, as explained with reference to FIGS. 1 to 4, the base plate 9 of the bioreactor container 6 is moved so that one or more sampling tubes 21 extending from the connector interface 7into the container 6 are at least partially submerged in the fluid. Accordingly, a fluid path is provided into the sampling module 30.

[0103] As shown in FIG. 6B, the plunger 34 is then retracted to draw the fluid sample from the bioreactor container 6 into the vial 32. As the plunger 34 is retracted the gaiter 42, in particular the collapsible wall 43, expands. The plunger 34 may be retracted manually or may be retracted by an actuator provided in the housing of the instrument (2, see FIG. 1), as described above.

[0104] FIG. 7 illustrates the bioreactor system 1 including a sensor unit 60 arranged to sense at least one parameter of the fluid sample in the sampling module 30. The sensor unit 60 is provided within the instrument 2, for example mounted to the housing 4 of the instrument 2 or on another subassembly within the instrument 2.

[0105] The sensor unit 60 may be positioned within the housing 4 of the instrument (2, see FIG. 1) above the support 16, such that the sensor is positioned to align with the sampling module 30 when the sampling module 30 is connected to a port of the interface plate 7 of the bioreactor vessel 3, as shown in FIG 1.

[0106] The sensor unit 60 includes an optical sensor 61. The optical sensor 61 includes an LED 62 to direct light through the transparent window 52 to the sensor element 53. The optical sensor 61 also includes an optical receiver to detect light from the sensor element 53 through the transparent window 52.

[0107] In some examples, the LED 62 and / or the optical receiver may be provided in another part of the instrument or external to the instrument. Optical fibres may be provided to transmit light from the LED 62 through the sensor window 52 to the sensor element 53, and to transmit light from the sensor element 53 through the sensor window 52 to the optical receiver.

[0108] The detected light is indicative of the corresponding parameter of the fluid sample in the sampling module 30, in particular dissolved oxygen, dissolved carbon dioxide, and / or pH according to the configuration of the sensor element 53. As described above, more than one sensor element may be provided. Accordingly, a corresponding number of LEDs and optical receivers may be provided, thereby allowing for more than one parameters of the fluid sample to be detected.

[0109] In some examples, the optical sensor may capture an image of the fluid sample through the transparent window. The image can be analysed to indicate a parameter of the fluid sample, such as a cell density of the fluid sample, a cell count of the fluid sample, cell viability, cell size, cell diameter, a pH of the fluid sample, or the presence of contaminationin the fluid sample. A marker or dye may be added to the fluid sample to facilitate optical sensing of one or more of the fluid sample parameters.

[0110] The sensor unit 60 may include a temperature sensor. The temperature sensor may be arranged to sense the temperature of a wall of the sample chamber so as to allow for non-invasive measurement of the temperature of the fluid sample.

[0111] In some examples, the sensor unit 60 may also include a connector that connects to the one or more sensor elements, such as sensor probes, disposed within the sample chamber or vial 32, as described above. In some examples, the sensor unit 60 may comprise a wireless communications unit for wirelessly communicating with one or more sensor elements, such as a sensor probe, within the sample chamber or vial 32. The sensor probe may be temperature probes for measuring the temperature of the fluid sample. The sensor probes may be a capacitance probe or a metabolite probe for detecting cell count, cell density, and / or cell viability of the cells in the fluid sample.

[0112] The bioreactor vessel 3 is rotatable by an actuator provided in the instrument (2, see FIG.1 ) , as described above. The bioreactor vessel 3 can be rotated to a sensing position in which the sampling module 30 aligns with the sensor unit 60 on the internal wall 4 of the instrument 2. In this position, the transparent window 52 is positioned adjacent to, or in contact with, the optical sensor 61 so that at least one parameter of the fluid sample within the sample chamber or vial 32 can be sensed by the optical sensor 61 through the transparent window 52. For example, in the sensing position the surface of the transparent window 52 of the sampling module 30 is positionable within about 10 millimetres of the sensor unit 60, preferably within about 7 millimetres of the sensor unit 60.

[0113] The sensor unit 60 may include a wireless communications unit for communication with a control system of the bioreactor system 1. The sensor unit 60 transmits sensor readings to the control system through the wireless communications unit. The control system may be configured to display sensor readings for an operator, for example on a graphical user interface (GUI). In some examples, the control system may be configured to adjust the conditions of the bioreactor system 1 in response to the sensor readings. For example, the control system may send control signals to the temperature control system, the humidity control system and / or the gas control system, as described above. In another example, the control system may control the connection of consumable / s to the bioreactor container 6 to add material to, or remove material from, the bioreactor container 6. In a further example, the control system may send an alert to a user when the bioreactor vessel 3 is ready for harvesting. Alternatively, the control system may automatically initiate a harvesting process. In some examples the sensor unit 60 may include a wired connection to the control system.

[0114] In some examples, the sensor unit 60 may be provided with the sampling module 30. The sensor unit 60 is connected to the sampling module 30 such that when the sampling module 30 is connected to the bioreactor vessel 3 and / or disconnected from the bioreactor vessel 3, the sensor unit 60 moves together with the sampling module 30 and remains aligned with the transparent window 52. That is, the sensor unit 60 may be attached to the sampling module 30. A single housing may hold the vial 32 and the sensor unit 60.

[0115] In some examples, the sensor unit 60 may be provided with an actuator that moves the sensor unit 60 to an operational position, to align the sensor unit 60 with the transparent window 52 of the sampling module 30. The actuator may move the sensor unit 60 towards, and away from, the sampling module 30, and may optionally rotate sensor unit 60 to rotationally align with the transparent window 52.

[0116] In some examples, the sampling module 30 may be disconnected from the port 8 bioreactor vessel 3 or from the connector 50 and transferred to the sensor unit 60 within the instrument (2, see FIG.1 ). An actuator may be provided in the bioreactor system 1 to disconnect the sampling module 30 and transfer the sampling module 30 to the sensor unit 60.

[0117] In other examples, the sensor unit may be an external sensor unit provided externally to the instrument (2, see FIG. 1). The external sensor unit may be provided in an analysis compartment of a modular bioreactor station. The modular bioreactor station, and the use of a robotic arm to transfer the sampling module 30 (or aliquot) from an incubation compartment to an analysis compartment in an automated or semi-automated manner, is described in applicant’s co-pending patent application GB 2212095.0. In other examples, a user may transfer the sampling module to the external sensor unit. The external sensor unit may include an optical sensor, camera, microscope, cell counter, pH meter, microfluidic analysis devices, multi-well assays, fluorescent dye assays amongst others. The optical sensor is provided for sensing at least one parameter of the sample fluid through the transparent window. The external sensor unit may include a connector for connecting the sample elements disposed within the sample chamber or vial 32 to the sensor unit. The external sensor unit may include a connector for connecting the connecting portion 35 of the sampling module 30 to the sensor unit. The fluid sample may be transferred into the external sensor unit via the connector to run further analysis on the fluid sample, such as sensing cell size, cell density, cell count, cell viability, metabolite levels, protein secretion, phenotype, cell activation, transduction efficiency, and / or gene expression.

[0118] The sensor unit 60 or the external sensor unit may measure the temperature of the fluid sample. The temperature of the fluid sample can be measured by a temperature sensor arranged in contact with a wall of the sample chamber 32. Alternatively, the temperature of the fluid sample can be measured by a temperature probe inserted into the fluid sample in the sample container 32.

[0119] The sensor unit 60 or the external sensor unit may measure the cell count, cell density, cell viability, cell size, or cell diameter of the cells in the fluid sample. These parameters may be measured by an optical sensor, for example a camera. These parameters may be measured by detecting the capacitance of the fluid sample or by detecting the surrogate metabolites of the fluid sample. The capacitance or surrogate metabolites may be measured by a probe inserted into the fluid sample in the sample container 32. Alternatively, the fluid sample may be transferred to the sensor unit or the external sensor unit and the capacitance or surrogate metabolites may be measured by sensors within the sensor unit.

[0120] The sensor unit 60 or the external sensor unit may measure the metabolite levels, protein secretion, cell phenotype, cell activation, cell size, cell density, cell count, or cell viability in the fluid sample. These parameters may be measured by sensors in the sensor unit after the fluid sample has been transferred to the sensor unit. The sensor unit may conduct automated flow cytometry testing to detect these parameters.

[0121] The sensor unit 60 or the external sensor unit may measure the gene expression or the phenotype of cells in the fluid sample. These parameters may be measured by sensors in the sensor unit after the fluid sample has been transferred to the sensor unit, or may be measured non-invasively through the sensor window 52. The sensor unit may include a digital holography arrangement to detect gene expression, cell count and / or cell phenotype. The digital holography sensor may be arranged to sense at least one parameter of the fluid sample through the sensor window 52. Detection of gene expression allows for measurement of the efficacy of transduction.

[0122] The sensor unit 60 or the external sensor unit may include a spectroscopic sensor, such as a spectrophotometric sensor. The spectroscopic sensor may measure the cell parameters of the fluid sample, such as cell count, cell size, cell viability, or phenotype. Additionally or alternatively, the spectroscopic sensor may measure environmental parameters of the fluid sample, such as analyte levels, more specifically protein levels or metabolite levels. The spectroscopic sensor may be arranged to detect at least one parameter of the fluid sample through the sensor window 52.

[0123] With reference to FIG. 7, to sense a parameter of the fluid sample in the sample chamber 32, the fluid sample is first extracted from the bioreactor container 6 as describedabove. Once the fluid sample is within the sample chamber or vial 32, the bioreactor vessel 3 is then rotated to the sensing position (if not already in the sensing position). In the sensing position, the sensor unit 60 activates the optical sensor 61 to sense a parameter of the fluid sample through the sensor window 52. The sample chamber or vial 32 can remain fluidly connected to the port 8 of the bioreactor vessel 3 during sensing of the fluid sample by the sensor unit 60. Additional parameters may also be sensed by the sensor elements disposed within the sampling module 30 and communicated to the sensor unit 60 or directly to the control system of the bioreactor system 1.

[0124] After sensing of the parameters of the fluid sample, the fluid sample can then be returned to the bioreactor container 6 by depressing the plunger 34 to force the fluid sample back into the container 6.

[0125] Alternatively, the sampling module 30 with the fluid sample contained therein may be disconnected from the connector 50 for transfer to an external sensor unit to undertake further analysis on the fluid sample. The connecting portion 35 of the sampling module 30 may be sealed by the septum seal, or by a separate seal, cap or cover applied to the connecting portion 35. The sampling module is then transferred to the external sensor unit by a user or by a robotic arm.

[0126] In examples, the sampling module 30 is storable at temperatures as low as -80C.

[0127] The sampling module 30 described herein utilises a plunger portion to extract a fluid sample from the bioreactor container 6 and optionally return the fluid sample to the bioreactor container 6. Other means for extracting a fluid sample from the bioreactor container 6 and returning the fluid sample to the bioreactor container 6 may be used. For example, the sample chamber 32 may be a vacutainer and draw the sample from the bioreactor container 6 by means of a vacuum. The connecting portion 35 of the sampling module 30 may include a valve arranged to release the fluid sample from the sample chamber 32 and allow the fluid sample to return to the bioreactor container 6 after sensing of a parameter of the fluid in the sample chamber 32 is completed.

[0128] Throughout the description and claims of this specification, the words “comprise”, “include”, “has” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0129] Features, integers, parameters or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (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 where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (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.

Claims

CLAIMS1. A sampling module for a bioreactor container, the sampling module comprising: a connecting portion for forming a fluid connection with a sampling port of the bioreactor container, a sample chamber for receiving a fluid sample from the bioreactor container, and a transparent window through which a sensor unit can sense at least one parameter of the fluid sample within the sample chamber.

2. The sampling module of claim 1 , wherein a wall of the sample chamber is formed of a transparent material, and wherein the transparent window is defined in the wall.

3. The sampling module of claim 1 or claim 2, wherein the sampling module is operable to return the fluid sample to the bioreactor container.

4. The sampling module of any one of claims 1 to 3, further comprising a plunger operable to draw the fluid sample into the sample chamber.

5. The sampling module of claim 4, wherein the plunger is disposed in the sample chamber.

6. The sampling module of claim 5, wherein the plunger is operable to drive the fluid sample from the sample chamber into the bioreactor container.

7. The sampling module of any one of claims 1 to 6, wherein the connecting portion comprises a pierceable seal.

8. The sampling module of any one of claims 1 to 7, further comprising at least one sensor element disposed within the sample chamber.

9. The sampling module of claim 8, wherein the at least one sensor element comprises a reagent configured to mix with the received fluid sample and respond toincident light to induce a fluorescent signal based on a parameter of the contents of the sample chamber.

10. The sampling module of claim 9, wherein the reagent comprises a cell viability dye.

11. The sampling module of claim 8, wherein the at least one sensor element comprises one or more of a temperature sensor, a capacitance sensor, a glucose sensor, or a lactate sensor.

12. The sampling module of claim 8, wherein the at least one sensor element is disposed on an internal surface of the transparent window.

13. The sampling module of claim 12, wherein the at least one sensor element comprises an oxygen-sensitive coating or a pH-sensitive coating.

14. The sampling module of any preceding claim, further comprising a sensor unit arranged to sense the at least one parameter of the fluid sample.

15. The sampling module of claim 14, wherein the sensor unit comprises an optical sensor, and wherein the sensor unit is arranged to sense the at least one parameter of the fluid sample through the transparent window.

16. The sampling module of claim 14 or claim 15, wherein the sensor unit is configured to detect one or more of a pH of the fluid sample, a dissolved gas content of the fluid sample, for example dissolved oxygen or dissolved carbon dioxide, a cell density of the fluid sample, a cell count of the fluid sample, cell viability, and / or degree of cell suspension.

17. The sampling module of any one of claims 14 to 16, wherein the sensor unit comprises a communications unit, for example a wireless communications unit.

18. A bioreactor system comprising: a bioreactor container having a sampling port, and a sampling module according to any one of claims 1 to 14.

19. The bioreactor system of claim 18, further comprising a sensor unit disposed to align with the transparent window of the sampling module.

20. The bioreactor system of claim 19, further comprising a housing, wherein the bioreactor container is provided within the housing and wherein the sensor unit is disposed to align with the transparent window of the sampling module when the sampling module is fluidly connected to the sampling port of the bioreactor container.

21. The bioreactor system of claim 20, wherein the bioreactor container is movable within the housing and wherein the sensor unit is disposed to align with the transparent window when the bioreactor container is in a sensing position.

22. The bioreactor system of claim 21 , wherein the bioreactor container is rotatable within the housing, and wherein the sensor unit is disposed to align with the transparent window when the bioreactor container is in a rotational sensing position.

23. The bioreactor system of any one of claims 19 to 22, wherein the sensor unit comprises an optical sensor.

24. The bioreactor system of any one of claims 19 to 23, wherein the sensor unit is disposed within the housing.

25. The bioreactor system of any one of claims 18 to 24, further comprising an external sensor unit and an actuator operable to disconnect the sampling module from the sampling port and transfer the sampling module to the external sensor unit.

26. The bioreactor system of claim 25, wherein the external sensor unit comprises a sensor configured to sense at least one parameter of the fluid sample through the transparent window.

27. The bioreactor system of claim 25 or claim 26, wherein the external sensor unit comprises a connector for connection to the connecting portion of the sampling module for receiving the fluid sample from the sampling module.

28. The bioreactor system of any one of claims 19 to 27, wherein the sensor unit and / or the external sensor unit comprises a communications unit, for example a wireless communications unit, for communication with a control system of the bioreactor system.

29. The bioreactor system of any one of claims 19 to 28, wherein the bioreactor container comprises a compressible wall and an interface plate, and wherein the sampling port is provided in the interface plate.

30. The bioreactor system of claim 29, wherein the interface plate comprises a plurality of sampling ports.

31. The bioreactor system of claim 30, wherein at least one of the sampling ports comprises a sampling tube extending from the interface plate into the bioreactor container.

32. A bioreactor system comprising: a housing; a support disposed within the housing and configured to receive and retain a bioreactor container; and a sensor unit disposed within the housing to align with a sampling module fluidly connected to the bioreactor container.

33. The bioreactor system of claim 32, wherein the support is configured to hold an interface plate of the bioreactor container, the interface plate comprising a sampling port for fluidly connecting the sampling module to the bioreactor container.

34. The bioreactor system of claim 32 or claim 33, wherein the sensor unit comprises an optical sensor, and wherein the sensor unit is configured to align with a transparent window of the sampling module.

35. A method of sampling a fluid from a bioreactor comprising: extracting a fluid sample from a bioreactor container into a sample chamber of a sampling module, the sample chamber having a transparent window, and detecting at least one parameter of the fluid sample through the transparent window.

36. The method of claim 35, wherein following the step of detecting the at least one parameter of the sample fluid, the fluid sample is returned to the bioreactor container.

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