Package of cell production device, cell production method, and management system therefor

Abstract

The present invention provides: a package for aseptically preparing many kinds of substances and containers for a cell processing device and reducing workload of mutually connecting the containers; a cell manufacturing method using the same; and a management system for manufacturing the package.

Description

Packaging for cell manufacturing device, cell manufacturing method and management system therefor

[0001] The present invention relates to a package for a cell manufacturing device, a cell manufacturing method using the same, a management system for managing the package for the cell manufacturing device, and a quality control system for managing the manufacturing process of the package for the cell manufacturing device.

[0002] In recent years, research into regenerative medicine using differentiated cells derived from induced pluripotent stem cells (iPS cells) has been actively conducted. In particular, a therapy in which iPS cells are established from a patient's somatic cells (e.g., peripheral blood mononuclear cells) and then various differentiated cells or organoids induced to differentiate from the iPS cells are transplanted into the patient (autotransplantation) has attracted attention as a therapy that can reduce the risk of rejection (Non-Patent Documents 1 and 2). Patent Document 1 (JP 2017-195905 A) discloses a system capable of producing stem cells. Furthermore, CAR-T therapy and other therapies using the patient's own somatic cells have begun to be applied clinically, and Patent Document 2 (JP 2022-8735 A) discloses a cell production system and cell production method that can reduce costs by reducing the number of steps in a therapy using CAR-T cells.

[0003] JP 2017-195905 A JP 2022-8735 A JP 2011-505890 A

[0004] Shinsuke Yoshida., et al., CLINICAL AND TRANSLATIONAL RESOURCE AND TECHNOLOGY INSIGHTS VOLUME 4, ISSUE 1, P51-66.E10, JANUARY 13, 2023Madrid, M., et al., Current Protocols,1, e88. doi: 10.1002 / cpzl.88

[0005] One of the features of iPS cells is that they can be produced from a patient's own cells, which could be an effective means of minimizing the risk of rejection. However, according to the inventors' studies, there are many challenges, including cost, to widespread adoption of transplantation therapy using differentiated cells derived from autologous iPS cells. Specifically, it is essential to develop a new automated device that can perform the entire process from iPS cell establishment to differentiation induction in a closed system, and to package reagents and materials that can be plugged into the device, thereby achieving both high-quality cell production and significant cost reduction.

[0006] Conventionally, equipment manufacturers have proposed cell processing devices configured to automatically perform sequential processing of cells. In such cell processing devices, as shown in an example in Figure 16, various substances required for cell processing are stored in respective material supply bags X20, and the substances required for processing are sequentially supplied from each material supply bag X20 into a culture vessel X10. Flexible tubes X30 extend from each of the multiple material supply bags X20, and each flexible tube X30 passes through a pinch valve X40 that can be controlled to open and close, passes through a peristaltic pump X50, and is connected to the culture vessel X10. The pinch valves and peristaltic pump are controlled to sequentially supply the various substances required for the cell processing steps from each material supply bag X20 into the culture vessel X10, thereby automatically performing sequential cell processing.

[0007] When the conventional cell processing device described above is delivered from the device manufacturer to the user (cell manufacturer), it does not come with supply bags for aseptically storing the various materials necessary for cell production. Therefore, in order to automatically process cells in the intended order using such a cell processing device, the user must aseptically fill the supply bags X20 with various materials in a safety cabinet prior to processing, aseptically connect them to the predetermined positions on the cell processing device, and aseptically attach soft tubing to the pinch valves and peristaltic pumps according to the predetermined piping pattern.

[0008] However, for users, preparing supply bags by aseptically filling containers with many types of purchased reagents, culture media, etc., and then placing them in the designated positions of the cell processing device while ensuring sterility is cumbersome, requiring large-scale equipment such as a safety cabinet. Furthermore, the task of aseptically placing such many types of material supply bags in the designated positions is extremely cumbersome, and it is difficult to eliminate the occurrence of incorrect material supply bags, incorrect installation positions, and / or incorrect connections of flexible tubing.

[0009] In addition to the problem of ensuring sterility as mentioned above, when attempting to simultaneously produce high-quality cells and significantly reduce costs, there is also the problem of the smaller volume of liquid used compared to biopharmaceutical manufacturing using conventional cell processing equipment. Furthermore, when producing induced pluripotent stem cells or differentiated cells from patient-derived somatic cells and then autotransplanting them into that patient, it is necessary to develop a manufacturing process customized for each patient and supply manufacturing materials. A system of mass production and mass supply using a uniform manufacturing process or manufacturing materials for all patients is not suitable for cell therapy involving autotransplantation.

[0010] An object of the present invention is to provide a package for a cell manufacturing device that can alleviate the above problems. Another object of the present invention is to provide a cell manufacturing method using the cell manufacturing device in the package. Another object of the present invention is to provide a management system and a quality control system for managing the manufacturing process of the package.

[0011] The main configuration of the present invention is as follows. [1] A package for a cell manufacturing device, the package comprising the cell manufacturing device and packaging materials, the cell manufacturing device comprising, as components for manufacturing induced pluripotent stem cells, a processing vessel, at least one culture medium vessel containing a liquid culture medium, and a first supply vessel containing a fluid containing a reprogramming factor, the culture medium vessel and the first supply vessel being (i) connected to the processing vessel via a connecting pipeline that can be switched between a communicating state and a non-communicating state, or (ii) connectable to the processing vessel via the connecting pipeline and via a unique connector configured to prevent incorrect connection, so that the contents of each are sent to the processing vessel while maintaining a closed system, the processing vessel having at least an openable / closeable injection port for receiving a solution containing somatic cells from the outside, and an openable / closeable discharge port for discharging the contents, the processing vessel, the culture medium vessel, and the first supply vessel being sealed containers, the cell manufacturing device being packaged in the packaging materials in a sterilized state. [2] The packaging for the cell manufacturing device described in [1], wherein the processing vessel is configured to separate somatic cells to be used in the production of induced pluripotent stem cells from a solution containing somatic cells injected through the injection port, and is configured to discharge components other than the somatic cells to the outside of the processing vessel, leaving the somatic cells to be processed inside the processing vessel, and the somatic cells left inside the processing vessel are processed inside the processing vessel. [3] The packaging for the cell manufacturing device described in [2], wherein the processing vessel is configured to separate somatic cells to be used in the production of induced pluripotent stem cells by continuous centrifugation.[4] The packaging for the cell manufacturing device according to any one of [1] to [3], wherein the cell manufacturing device has one or more second supply containers for containing a fluid containing a differentiation inducer for induced pluripotent stem cells as a component for producing differentiated cells from induced pluripotent stem cells produced in a processing container, the second supply containers being sealed, and the second supply containers being either (iii) connected to the processing container via a connecting pipe that can be switched between a communicating state and a non-communicating state, or (iv) connectable to the processing container via a connecting pipe that can be switched between a communicating state and a non-communicating state and via a unique connector configured to prevent incorrect connection, so that the contents of the second supply container are sent into the processing container while maintaining a closed system. [5] The packaging for the cell manufacturing device according to any one of [1] to [4], wherein one or both of the culture medium container and the first supply container are each separated from the cell manufacturing device and each packaged in a different packaging material, and the packages are separated into two or more packages that are independent of each other. [5a] The package of the cell manufacturing device described in [5], wherein one or both of the culture medium container and the first supply container are separated from the cell manufacturing device and packaged in separate packaging materials for the temperature control required for each. [6] The package of the cell manufacturing device described in any one of [1] to [5] and [5a], wherein the cell manufacturing device packaged in the packaging material in the package is a closed-system processing circuit portion included in a cell processing device for processing the somatic cells, the cell processing device being configured with the closed-system processing circuit portion and a device main body portion, the device main body portion having an operating mechanism for operating the closed-system processing circuit portion and a control unit for controlling the operating mechanism, the closed-system processing circuit portion being detachable from the device main body portion while maintaining the closed system, and being assembled as a closed system when removed from the device main body portion, the closed-system processing circuit portion attached to the device main body portion being operated by the operating mechanism under the control of the control unit, thereby processing the somatic cells within the closed-system processing circuit portion.[7] The package of the cell manufacturing device described in [6] above, in which the cell manufacturing device is assembled as a closed system by an equipment assembler other than the cell manufacturer based on specification data issued by the cell manufacturer that manufactures cells using the cell processing device, packaged as the package, and provided to the cell manufacturer. [8] The package of the cell manufacturing device described in [7] above, in which the cell manufacturer and the equipment assembler are different business entities. [9] The specification data includes at least information about the donor of the somatic cells, information about the device main body part to which the cell manufacturing device is to be attached as a closed-system processing circuit part, information about the configuration of the cell manufacturing device, and the date of use of the cell manufacturing device; the cell manufacturing device displays an identification code that can be read by a reading device, and through the identification code, information about the donor of the somatic cells included in the specification data and information about the actual configuration of the manufactured cell manufacturing device can be obtained from a separately provided management device; and the information about the actual configuration of the cell manufacturing device is stored in a memory device of the management device in correspondence with the information about the configuration of the cell manufacturing device included in the specification data. A packaging for a cell manufacturing device as described in [7] or [8].

[10] A cell manufacturing method using a package of the cell manufacturing device described in any one of [1] to [9], the cell manufacturing method comprising the steps of: preparing the cell manufacturing device removed from the package; and manufacturing induced pluripotent stem cells in the processing vessel of the cell manufacturing device, wherein the manufacturing step comprises the steps of: injecting a solution containing the somatic cells into the processing vessel through the injection port, sending a liquid culture medium from the culture medium container into the processing vessel, and sending a fluid containing reprogramming factors from the first supply container into the processing vessel, thereby bringing the reprogramming factors into contact with the somatic cells in the liquid culture medium in the processing vessel; and culturing the somatic cells in the liquid culture medium in the processing vessel to establish induced pluripotent stem cells (s20).

[11] The packaging of the cell manufacturing apparatus is the packaging described in [2] or [3], and in the step (s10), a solution containing the somatic cells is injected into the processing vessel through the injection port, then the somatic cells to be used for manufacturing induced pluripotent stem cells are separated in the processing vessel, and components other than the somatic cells are discharged to the outside of the processing vessel, leaving the somatic cells to be processed inside the processing vessel, then a liquid culture medium is sent from the culture medium container, and a fluid containing reprogramming factors is sent from the first supply container, thereby contacting the somatic cells in the liquid culture medium in the processing vessel, the cell manufacturing method described in

[10] .

[12] The packaging of the cell manufacturing apparatus is the packaging of the cell manufacturing apparatus described in [4], and the cell manufacturing method described in

[11] further comprises, after the step (s20), a step (s30) of sending a fluid containing a differentiation inducer for artificial pluripotent stem cells from the second supply container into the processing container, thereby forming differentiated cells in the processing container.

[13] A management system for packaging of a cell manufacturing device described in any one of [1] to [9], the management system having a management device and a reading device, an identification code (D1) of each packaging is displayed on one or both of the cell manufacturing device and the packaging material surrounding it in all of the packaging to be manufactured so that it can be read by the reading device, the reading device is for reading the identification code, the management device has a data receiving unit and an attribute information storage unit, the data receiving unit accepts the identification code read by the reading device as input data, the attribute information storage unit stores the identification code (D1) of each of the packaging to be manufactured and the respective product attribute information (P1) in a mutually associated state, and the management device is configured to refer to the identification code (D1) accepted by the data receiving unit and the identification code (D1) and product attribute information (P1) stored in the attribute information storage unit, and output the product attribute information (P1) associated with the read identification code (D1).

[14] The cell manufacturing device displays an identification code (D10) of the cell manufacturing device so that it can be read by the reading device, and the product attribute information (P1) of each of the packages stored in the attribute information storage unit includes the identification code (D10) of each of the cell manufacturing devices in each package and the product attribute information (P10) of each package in a state where they are associated with each other, and the management device is configured to refer to the identification code (D10) received by the data receiving unit and the identification code (D10) and product attribute information (P10) stored in the attribute information storage unit, and output the product attribute information (P10) associated with the received identification code (D10), a management system as described in

[13] .

[15] The management system described in

[14] , wherein each sealed container containing a substance in the cell manufacturing device displays an identification code (D20) of each substance contained in each sealed container so that it can be read by the reading device, and each product attribute information (P10) of the cell manufacturing device in each package includes the identification code (D20) of each substance contained in each sealed container and the respective product attribute information (P20) in a state where they are associated with each other, and the management device is configured to refer to the identification code (D20) received by the data receiving unit and the identification code (D20) and product attribute information (P20) stored in the attribute information storage unit, and output the product attribute information (P20) associated with the received identification code (D20).

[16] A management system as described in

[14] or

[15] , wherein each component constituting the cell manufacturing device is marked with an identification code (D30) for that component so that it can be read by a reading device; the product attribute information (P10) for each of the cell manufacturing devices in each package contains the identification code (D30) for each component constituting the cell manufacturing device and the respective product attribute information (P30) in a state in which they are correlated with each other; and the management device is configured to refer to the identification code (D30) received by the data receiving unit and the identification code (D30) and product attribute information (P30) stored in the attribute information storage unit, and output the product attribute information (P30) correlated with the received identification code (D30).

[17] A management system described in any one of

[14] to

[16] , wherein containers holding a solution containing somatic cells to be processed by the cell manufacturing apparatus display a code (D2) of the somatic cells in each container or of their donor so that the code (D2) can be read by a reading device; the attribute information storage unit stores the codes (D2) and their respective attribute information (P2), and the codes (D2) and their respective attribute information (P2) are associated with each other and with an identification code (D1) of a package used for processing or an identification code (D10) of the cell manufacturing apparatus of the package; and the management device is configured to refer to the code (D2) received by the data receiving unit and the code and attribute information stored in the attribute information storage unit, to output the attribute information (P2) associated with the received code (D2), and to output the identification code (D1) of the package used for processing or the identification code (D10) of the cell manufacturing apparatus of the package.

[18] The attribute information storage unit stores the code (D3) of the patient to whom the cells manufactured by the cell manufacturing device should be applied and the attribute information (P3) thereof, and the patient code (D3) and the attribute information (P3) thereof are related to each other and to the identification code (D1) of the packaging used for processing or the identification code (D10) of the cell manufacturing device on the packaging, and the management device is configured to output the code (D3) of the patient to whom the manufactured cells should be applied and the attribute information (P3) thereof by referring to the identification code (D1) or identification code (D10) received by the data receiving unit and the identification code and attribute information stored in the attribute information storage unit. A management system described in any one of

[14] to

[17] .

[19] The packaged cell manufacturing device is a cell processing device comprising a detachable closed-system processing circuit portion, a mechanism for operating the detachable closed-system processing circuit portion, and a control unit, wherein the detachable closed-system processing circuit portion of the cell processing device is displayed on the portion of the cell processing device excluding the closed-system processing circuit portion so as to be readable by a reading device, the attribute information storage unit stores the identification code (D11) of the cell processing device and its product attribute information (P11), the identification code (D11) of the cell processing device and its product attribute information (P11) are associated with each other and are stored in the attribute information storage unit in association with the identification code (D1) of the package used for processing or the identification code (D10) of the cell manufacturing device of the package, and the management device is configured to output the identification code (D11) and its product attribute information (P11) by referring to the identification code (D1) or identification code (D10) received by the data receiving unit and the identification code and product attribute information stored in the attribute information storage unit. The management system according to any one of

[14] to

[18] .

[20] The packaged cell manufacturing device is a detachable closed-system processing circuit part in a cell processing device equipped with a detachable closed-system processing circuit part, a mechanism for operating it, and a control unit, and the management device further has a specification data storage unit, and the specification data storage unit stores specification data (S1a) including at least attribute information of the solution containing somatic cells to be used or the donor, product attribute information of the package or cell manufacturing device to be used, the date of use of the cell manufacturing device, and identification information of the cell processing device in which the cell manufacturing device is installed as the processing circuit part, and the management system has a data input device for inputting the specification data, and the package is assembled based on the specification data (S1a), and the management device stores the attribute information of the solution containing somatic cells to be used or the donor, the product attribute information of the package or cell manufacturing device to be used, information on the date of cell production, and identification information of the cell processing device to be used, which are input through the reading device by the cell manufacturer on the day the cells are produced.

[21] The management system according to any one of

[13] to

[19] , wherein a data receiving unit receives specification data (S1b) including at least the specification data (S1a) stored in the specification data holding unit, and, when the specification data (S1b) received by the data receiving unit matches the specification data (S1a) stored in the specification data holding unit, outputs a signal indicating a match.

[21] The management system according to

[20] , wherein a control unit of the cell processing device is configured to receive the signal indicating a match output from the management device, and is configured to enable start-up of the cell processing device only when the signal is received.

[22] A quality control system for a cell manufacturing device in a package described in any one of [7] to [9], wherein the manufacturing process of the package comprises: an element manufacturing process for each element, in which each of the multiple elements constituting the cell manufacturing device in the package is manufactured by an element manufacturer belonging to the technical field of the respective element; and an equipment assembly process, in which an equipment assembler assembles the elements manufactured in the element manufacturing processes to form the cell manufacturing device; the quality control system comprises: a process control device; and a plurality of terminal devices connected to the process control device so as to be able to communicate data with the process control device; the terminal devices are arranged to be used by users of the cell manufacturing device, namely, the cell manufacturer, the equipment assembler, and each of the element manufacturers; the cell manufacturing device is assembled based on specification data indicating the configuration of the cell manufacturing device; and the specification data is designed by a cell manufacturer who has received an order from a medical institution to manufacture target cells for patient treatment, so that the cell manufacturing device has a configuration for manufacturing the target cells and so that the cell manufacturing device is compatible with a cell processing device selected to manufacture the target cells. the specification data is associated with the patient's identification code, and the process control device receives the specification data and the patient's identification code associated therewith from the cell manufacturer or device assembler via the terminal device and stores them in a memory area, reserves a memory area for storing actual specification data corresponding to the specification data in the cell manufacturing device that is actually manufactured, receives actual data of each element manufactured by each element manufacturer that has received a manufacturing order from the device assembler based on the specification data, and stores it in the memory area for storing the actual specification data, receives data regarding the overall layout of the cell manufacturing device from the device assembler that has assembled the cell manufacturing device using each element delivered by each element manufacturer, and stores it in the memory area for storing the data, and determines whether the original specification data and the actual specification data match, and outputs the determination result.

[23] The quality control system according to

[22] above, wherein each terminal device is provided with a function for reading an identification code, and an identification code indicating each identification information is displayed on the surface of the packaging material of the package and on each element of the cell manufacturing device.

[24] The quality control system according to

[23] above, wherein the identification code is displayed in the form of a two-dimensional symbol.

[25] The quality control system according to any one of

[22] to

[24] above, wherein the cell manufacturer, the device assembler, and each element manufacturer are different business entities.

[0012] In the cell manufacturing device package (hereinafter also referred to as the package) of the present invention and the cell manufacturing method using the same, the user (cell manufacturer) is provided with sealed containers containing predetermined substances that are pre-connected to the cell processing container, or with sealed containers that are not connected but can be connected via unique connectors configured to prevent incorrect connection. This configuration prevents the user from connecting a sealed container containing the wrong substance to the cell processing container when manufacturing cells.

[0013] In a preferred embodiment of the present invention, when a cell manufacturer performs cell processing using a predetermined cell processing device, an equipment assembler is assigned to assemble a closed system processing circuit portion (the cell manufacturing device of the present invention) having the configuration required for the cell processing and provide it to the cell manufacturer. In response to requests from the cell manufacturer, the equipment assembler collects the parts and elements required for the closed system circuit portion from various component manufacturers, assembles the closed system processing circuit portion (hereinafter also referred to as the closed system portion), packages it, and sends it to the cell manufacturer.

[0014] In the past, cell manufacturers would directly order the various elements that make up the closed system from various component manufacturers that specialize in each component, and then assemble them themselves. In contrast, in the present invention, a device assembler is placed between the cell manufacturer and the component manufacturer. This allows the cell manufacturer to obtain the closed system on the day of cell production or an appropriate date before that by simply informing the device assembler of the configuration of the closed system, and eliminates the hassle and errors involved in assembling the closed system.

[0015] Furthermore, by assigning an equipment assembler, it is possible to achieve both high-quality cell production and significant cost reductions, taking into account factors such as the scale of reagent liquid volume and ensuring sterility. By having a dedicated equipment assembler design the flow path system, select bags, and design the reagent volumes, it is possible to achieve smaller liquid volumes compared to the scale of liquid volumes used in cell production with conventional biopharmaceutical manufacturing equipment. In particular, in the production of patient-derived autologous iPS cells, rather than mass-producing the package of the present invention uniformly for all patients, the package of the present invention can be optimally designed and manufactured for each cell production process (custom-made) depending on the differentiated cells required by the patient as the final product and the blood composition of the patient as the raw material. For example, depending on the differentiated cells required by the patient as the final product, additional induction factors can be added to the bag, or the amount of medium can be increased or decreased to increase or decrease the number of culture days. Furthermore, if the blood composition of the patient as the raw material is expected to make it difficult to establish iPS cells using standard protocols, it is possible to optimize the package, such as by increasing the amount of reprogramming factors. Furthermore, although the package of the present invention is single-use and disposable, eliminating waste by the equipment assembler can reduce environmental impact.

[0016] In addition, the management system of the present invention enables tracking of the manufacturing processes and raw materials of the materials and mechanical parts that make up the package (traceability), and further enables management of the relationship between the package and the somatic cells (and their donors).

[0017] Furthermore, the quality control system of the present invention manages each element and part delivered to the device assembler in accordance with the specification data issued by the cell manufacturer. This allows the cell manufacturer to manufacture cells without errors. Furthermore, medical institutions can obtain the desired cells obtained from the patient's blood provided to the cell manufacturer.

[0018] FIG. 1 is a block diagram showing an example of the configuration of a package for a cell manufacturing device of the present invention. Each thick black line, as representatively indicated by the symbol A10, indicates a connecting duct such as a flexible tube. FIG. 2 is a block diagram showing another example of the configuration of a package for a cell manufacturing device of the present invention. FIG. 3 is a block diagram showing an example of a feeding device in a package for a cell manufacturing device of the present invention. FIG. 4 is a photograph showing the main body of a commercially available automatic cell processing device, the CliniMACS Prodigy, manufactured by Miltenyi Biotec, from which the closed system (the cell manufacturing device of the present invention) has been removed. FIG. 5 is a photograph showing an example of a package containing the closed system (the cell manufacturing device of the present invention) to be attached to the CliniMACS Prodigy main body shown in FIG. 4. In this example, the lid of the packaging material constituting the package has been removed to reveal the interior of the package. FIG. 6 is a photograph showing an example of a blood collection device connected to a cell manufacturing device of the present invention. FIG. 7 is a photograph showing the state in which the closed system (the cell manufacturing device of the present invention) has been attached to the CliniMACS Prodigy main body shown in FIG. 5. The closed system portion in this figure is shown to illustrate the attached state and is not identical to the closed system portion shown in Figure 6 . Figure 8 is a photograph showing the device body from which the closed system portion (the cell production device of the present invention) has been removed from the Gibco CTS Rotea Counterflow Centrifugation System, a commercially available automatic cell processing device manufactured by Thermo Fisher Scientific. Figure 9 is a photograph showing an example of a package containing the closed system portion (the cell production device of the present invention) attached to the device body portion of the Gibco CTS Rotea Counterflow Centrifugation System shown in Figure 8 . In this example, the lid of the packaging material constituting the package has been removed to reveal the inside of the package. Figure 10 is a photograph showing an example of a disposable unit portion, called a single-use kit, of the closed system portion (the cell production device of the present invention) shown in Figure 9 , which engages with the device body portion for operation. The single-use kit is a photographic image used for advertising purposes by the manufacturer of the cell processing device.Figure 11 is a photograph illustrating the state in which a closed system portion (the cell manufacturing device of the present invention) is attached to the device main body portion of the Gibco CTS Rotea Counterflow Centrifugation System shown in Figure 8. The closed system circuit portion in this figure is used to illustrate the attached state and is not the same as the closed system portion shown in Figure 9. Figure 12 is a photograph illustrating the configuration of packaging materials for a package. Figure 13 is a block diagram showing an example configuration of a management system of the present invention. In this figure, dashed lines indicate wired or wireless communication paths. Figure 14 is a block diagram illustrating the flow of orders and goods in the package manufacturing process of the present invention. In this figure, arrows indicate the flow of orders and deliveries. Figure 15 is a block diagram showing an example configuration of a quality control system of the present invention. In this figure, dashed lines indicate wired or wireless communication paths. Figure 16 is a photograph showing an example configuration of a conventional cell processing device.

[0019] 1. Packaging of Cell Production Apparatus First, we will explain the packaging of the cell production apparatus according to the present invention. Hereinafter, the cell production apparatus constituting the packaging will also be referred to as the "production apparatus" or the "packaged manufacturing apparatus." As illustrated in FIG. 1 , the packaging 1 comprises a production apparatus 10 and packaging material 20. The production apparatus 10 is either in a state in which the sealed containers (210-230) described below are completely connected to the processing vessel 100, or, as illustrated in FIG. 2 , is in a state in which it is not connected but can be unambiguously connected using a connector that prevents incorrect connection. Furthermore, the production apparatus 10 is packaged in packaging material 20 to form the packaging 1. In the production apparatus 10, the interior of the production apparatus (inside the flow paths, inside each vessel, contents, etc.) that affect cell processing should be sterile to a degree suitable for cell processing. In a preferred embodiment, the production apparatus 10 is sterilized not only inside but also outside, and is packaged in packaging material 20 so that the sterilized state of the exterior is maintained, to form the packaging 1. In a preferred embodiment, the package manufacturing apparatus does not include a feeder, electromagnetic valve, control device, power supply, etc. (it may include a manually operable pinchcock, etc.), and is configured as a closed system (closed processing circuit portion) that can be attached to and detached from a cell processing apparatus such as that shown in Figure 16. The "circuit" in the "processing circuit portion" does not necessarily have a circulation flow path, but also includes a flow path configuration in which a processing vessel and a specific vessel are simply connected via a connecting pipe (or a flow path configuration that can simply be connected to the processing vessel via a specific connector). Examples of such cell processing apparatus include the CliniMACS Prodigy from Miltenyi Biotec, the Gibco CTS Rotea Counterflow Centrifugation System from Thermo Fisher Scientific, the Cocoon system from Lonza, and the Xuri Cell Expansion System from Cytiva.Therefore, the manufacturing apparatus 10 is ready to be provided to a user of the cell processing apparatus, who is a cell manufacturer, and the user can start cell manufacturing by simply removing the manufacturing apparatus from the package and attaching it to the cell processing apparatus as a closed system part, without working in a sterile environment in a safety cabinet and without the conventional complicated connection work, or the connection work by the user is reduced. As described in detail below, in a preferred embodiment of the present invention, an apparatus assembler who assembles the package is newly arranged, and the package assembled by the apparatus assembler is provided to the user.

[0020] (Configuration for producing iPS cells) The production apparatus 10 has at least a processing vessel 100, a culture medium vessel 210, and a first supply vessel 220 as components for producing iPS cells from somatic cells. The processing vessel 100 is a sealed vessel for processing somatic cells injected from the outside. The culture medium vessel 210 is a sealed vessel for containing a liquid culture medium. The first supply vessel 220 is a sealed vessel for containing a fluid containing reprogramming factors for establishing iPS cells. Details of each sealed vessel will be described below.

[0021] In the present invention, a "sealed container" refers not only to a container that is airtightly or liquidtightly sealed, but also to a container whose interior is sealed to such an extent that, when each port or pipe is closed, microorganisms or viruses cannot enter from the outside, i.e., to such an extent that sterility within the container is maintained. For example, a closed container having a porous filter (e.g., pore size of about 0.2 μm or less, particularly about 0.1 to 0.2 μm) at an inlet / outlet port that does not allow bacteria or viruses to pass through but allows fluids (particularly gases) to pass through is a sealed container because outside air can pass through the porous filter and into the container, but bacteria or viruses cannot enter, and the sterility within the closed container is maintained. In addition, the wall of the closed container is a gas-permeable membrane that does not allow bacteria or viruses to pass through, and O ２ Gas molecules and CO ２ A closed container that is permeable to gas molecules is also an airtight container. Similarly, a "closed system" is not only a system that is airtight or liquidtight, but also a system that is closed to the extent that microorganisms and viruses cannot enter from the outside, that is, a system that is closed to the extent that sterility is maintained within the system.

[0022] The medium container 210 and the first supply container 220 are connected or connectable to the processing vessel 100 so that their contents are delivered to the processing vessel while maintaining a closed system. As illustrated in FIG. 1 , the medium container 210 and the first supply container 220 are connected to the processing vessel 100 via a connection line A10 that can be switched between a connected and disconnected state, eliminating the opportunity for a user to connect them. Alternatively, as illustrated in FIG. 2 , the medium container 210 and the first supply container 220 can be connected to the processing vessel 100 via a unique connector C20 configured to prevent incorrect connection. In the example of FIG. 2 , for ease of explanation, three pairs of connectors C20 are represented by the same square symbol, but each pair of connectors has different specifications from the other pairs of connectors and cannot be connected. In the example of FIG. 2 , the medium container 210 and the first supply container 220 are not connected to the processing vessel 100, but a pre-connected state is always achieved via the unique connector C20. In the example of FIG. 2, each connecting pipe line A10 can also be switched between a communicating state and a non-communicating state.

[0023] (Processing vessel) The processing vessel 100 has at least an inlet port 101 that can be opened and closed to receive a solution containing somatic cells from the outside, and an outlet port 102 that can be opened and closed to discharge the contents. Various airtight containers may be connected to the inlet port 103. As shown in the example of Figure 1, in a preferred embodiment, the processing vessel 100 is equipped with a CO 2 inlet port 103 that can be used for cell culture. ２ The processing vessel may further include a gas injection port 104 for injecting gas such as nitrogen, oxygen, or air for discharging the contents, and a gas discharge port 105 for venting gas to prevent a pressure increase inside the vessel. A sterile filter may be provided on the cylinder side, and a sterile filter may be provided in the gas injection port 104. A sterile filter may be provided in the gas discharge port 105. A sensing probe may be provided on the tip of the discharge side of the processing vessel or the discharge port 102, and the oxygen concentration and pH of the contents may be measured by the sensing probe.

[0024] As used herein, "induced pluripotent stem cells (iPS cells)" are cells obtained by reprogramming mammalian somatic cells or undifferentiated stem cells through the introduction of reprogramming factors. Induced pluripotent stem cells have the ability to differentiate into various tissues and cells with different morphologies and functions in the body, and into cells of any of the three germ layers (endoderm, mesoderm, and ectoderm).

[0025] In the present specification, induced pluripotent stem cells may be patient-derived cells. Creating iPS cells from patient-derived somatic cells and using them for clinical treatment can be an effective means of minimizing the risk of rejection.

[0026] The packaging of the cell manufacturing device of the present invention can be used for any currently available induced pluripotent stem cells. The concept of the packaging of the cell manufacturing device of the present invention can also be applied to CAR-T cells.

[0027] In this specification, induced pluripotent stem cells may be cells derived from a patient with a genetic disease. Cells induced to differentiate from pluripotent stem cells derived from a patient with a genetic disease can serve as disease models that reflect the pathology of the disease, and are therefore suitable for screening therapeutic or preventive drugs for the disease. Alternatively, pluripotent stem cells derived from a patient with a genetic disease can be genetically repaired by genome editing using a CRISPR-Cas system or the like, and then differentiated into the desired cells, making it possible to use the cells as a therapeutic drug for the disease.

[0028] In the present invention, "somatic cells" refer to original cells to be processed inside the processing vessel 100. In this specification, "somatic cells" refers to cells that constitute an animal, other than germ cells. Somatic cells are not particularly limited and include both mature, healthy and diseased somatic cells, as well as primary culture cells, passaged cells, and established cell lines. Specifically, somatic cells may be, for example, floating cells (e.g., blood cells, etc.) or adhesive cells, but floating cells are preferred. Examples of somatic cells used in the production method of the present invention include, but are not limited to, mesenchymal stem cells derived from skin fibroblasts, etc., skin cells, visual cells, brain cells, hair cells, oral mucosa, dental pulp cells, lung cells, liver cells, gastric mucosa cells, intestinal cells, spleen cells, pancreatic cells, kidney cells, neural stem cells, wisdom teeth, etc., tissue stem cells, tissue progenitor cells, blood cells (e.g., hematopoietic stem cells, peripheral blood mononuclear cells (PBMCs) (including T cells and non-T cells), umbilical cord blood cells, etc.), epithelial cells, endothelial cells (e.g., vascular endothelial cells), muscle cells, and the like.

[0029] In one embodiment, when blood cells (for example, peripheral blood mononuclear cells) are used as somatic cells, the cells are obtained by centrifuging whole blood (density gradient centrifugation, specific gravity centrifugation, etc.), separating the cells using a filter (leukocyte removal filter, etc.), or by using an antibody, a magnetic substance (magnetic beads, etc.), or a hydrophilic polysaccharide (Ficoll, ＴＭ etc.)

[0030] In the present specification, the species from which the somatic cells are derived is not particularly limited, and the species from which the somatic cells are derived is preferably human.

[0031] In this specification, unless otherwise specified, the term "cell" includes a "cell population." A cell population may be composed of one type of cell, or may be composed of two or more types of cells.

[0032] As used herein, "a solution containing somatic cells" refers to raw materials such as whole blood, urine (which contains cells), and tears; diluted or concentrated versions of such raw materials; liquids containing cells in the process of being processed; or liquids containing somatic cells or processed cells after cell separation. As used herein, "processing" cells refers to treatments such as culturing cells, diluting a cell-containing solution, washing cells, and isolating target cells from a cell-containing solution. It also refers to treatments such as chemical treatments, altering biological properties, combining with non-cellular components, or genetic engineering for the purposes of artificial proliferation and differentiation of cells, establishing cell lines, or activating cells.

[0033] The configuration of the processing vessel 100 is not particularly limited, but examples include: (i) a sealed vessel made of a hard material, (ii) a sealed vessel made of a flexible material, (iii) a sealed vessel made of a composite material of a flexible material and a hard material, etc. The connection structure and material of the port portion provided in the processing vessel 100 may be appropriately selected with reference to conventionally known sealed vessels for cell culture, etc.

[0034] (Sealed container made of hard material) The sealed container made of hard material described above in (i) is preferably strong enough to be difficult to deform under the weight of a solution containing somatic cells, and may be designed and manufactured specifically for the present invention. When the manufacturing device 10 is used as a closed processing circuit part that is detachably attached to a commercially available cell processing device (such as CliniMACS Prodigy (registered trademark)), the processing container 100 is preferably a directly repurposed processing container (detachable) originally provided in such a commercially available cell processing device, or a separately manufactured compatible product.

[0035] As the hard material, known materials that have traditionally been used for hard cell culture vessels, such as glass and plastic materials (e.g., polycarbonate, polyester, polyamide, polystyrene, acrylonitrile-butadiene-styrene copolymer (ABS resin), polyethylene, polypropylene, polyvinyl chloride, and biodegradable resins), can be used.

[0036] (Sealed container made of flexible material) The structure of the sealed container made of flexible material in (ii) above is not particularly limited. Typical examples include soft bags and bottles made of flexible film or flexible sheet, which are used in conventionally known cell culture bags, infusion bags, etc. The flexible film is a film that is flexible enough to be deformed according to the amount of contents contained in the bag. The structure of the bag is not limited, but an example is a bag structure in which two rectangular or square flexible films are overlapped and the outer edges of the films are fused (thermally fused, high-frequency fused, etc.) or glued together, except for the parts that become the openings and inlet / outlet ports. The flexible film is a material that can be used to circulate the O2 required for cell culture. ２ YaCO ２ When the flexible film is gas impermeable, O necessary for cell culture can be introduced through a gas injection port or the like. ２ YaCO ２ may be supplied appropriately. Furthermore, the flexible film is preferably made of a material that is industrially excellent in moldability, can withstand gamma ray sterilization, and is transparent enough to allow observation of the state of the culture medium inside. Additional structures such as holes for hanging the bag can be provided as appropriate, with reference to conventionally known cell culture bags, etc. The bottle can be connected to a sterile filter. A porous filter (e.g., one with a pore size of approximately 0.2 μm or less, particularly approximately 0.1 to 0.2 μm) can be used as the sterile filter. Here, the sealed container may have a ventilation hole. The sealed container may have a dispensing hole.

[0037] The flexible film may be made of known materials used for cell culture bags, etc., such as polyethylene, polyethylene terephthalate, polypropylene, ethylene vinyl acetate copolymer (EVA), ultra-low density polyethylene (ULDPE) / ethyl vinyl alcohol (EVOH), ultra-low density polyethylene (ULDPE), polyolefin (PO), tank liner, polyvinylidene fluoride, polyethersulfone, etc. The flexible film may be a single-layer film or a multi-layer film made of these materials.

[0038] (Processing containers made of composite materials) Examples of the sealed containers made of the composite material of a flexible material and a hard material described above in (iii) include those whose framework is made of a hard material and whose walls are made of a flexible film. Such containers have the three-dimensional characteristics of hard containers, but are inexpensive and disposable.

[0039] (Volume of Processing Vessel) The volume of the processing vessel is not particularly limited, but for applications such as transplantation therapy using differentiated cells derived from autologous iPS cells, it is preferably about 10 to 2000 ml, more preferably about 200 to 250 ml.

[0040] The processing vessel does not necessarily need to be supplied to the user in an empty state, and a liquid culture medium or the like may be contained in the processing vessel from the beginning, in addition to the contents of each sealed container.

[0041] (Function of separating somatic cells) In a preferred embodiment of the present invention, the processing vessel 100 is configured to separate somatic cells to be used in the production of iPS cells from a solution containing somatic cells injected through an injection port, and is configured to discharge components other than the separated somatic cells to the outside of the processing vessel 100 through an outlet port 102 or the like, leaving the somatic cells to be processed inside the processing vessel. In this case, the solution containing somatic cells injected into the processing vessel 100 may be the above-mentioned raw material such as whole blood or urine, or a diluted or concentrated version of the raw material.

[0042] (Supply of solution containing somatic cells) The solution containing somatic cells may be injected from a syringe, an infusion bag, or the like connected to the openable and closable injection port 101 shown in Figure 1. When producing induced pluripotent stem cells for autologous transplantation using whole blood from a patient as the solution containing somatic cells, the amount of whole blood supplied to the device is not particularly limited, but may be approximately 1 to 200 ml.

[0043] The method and configuration for separating the target somatic cells from a solution containing somatic cells inside the processing vessel 100, discharging unnecessary materials, and leaving the somatic cells inside the processing vessel 100 are not particularly limited, but include the following examples: A separation method in which the target somatic cells are labeled with magnetic beads and magnetically attracted to the somatic cells to leave them inside the processing vessel, and a separation method in which the somatic cells are passed through a microchannel for cell separation. A configuration in which continuous centrifugation is performed by carrying out the continuous centrifugation described below.

[0044] (Configuration of Processing Vessel Performing Continuous Centrifugation) In a preferred embodiment, the processing vessel 100 is configured to perform continuous centrifugation. Configurations for performing continuous centrifugation include configurations for performing various types of centrifugation (so-called counterflow centrifugation, continuous flow centrifugation, zonal centrifugation, etc.) with different detailed configurations. However, all of these are centrifuges configured to continuously (or while controlling the flow and shutoff with a valve) feed a solution containing somatic cells into a processing vessel (centrifuge chamber), centrifuge the solution inside the processing vessel, and continuously (or while controlling the flow and shutoff with a valve) discharge the separated, unnecessary liquid, leaving the target somatic cells inside the processing vessel (or discharging the target somatic cells outside the processing vessel). The configuration of a processing vessel performing such continuous centrifugation can refer to the configuration of a conventionally known continuous centrifuge, such as a centrifuge incorporated as part of a closed system in the CliniMACS® Prodigy cell processing device from Miltenyi Biotec or the Gibco CTS Rotea Counterflow Centrifugation System cell processing device from Thermo Fisher Scientific. The centrifuge installed in the CliniMACS Prodigy is described in detail in, for example, Patent Document 3. CliniMACS Prodigy and Gibco CTS Rotea differ in the structure of the rotating part for centrifugation, but both have intake and discharge flow paths connected to the processing container, and perform centrifugation continuously (or while controlling the continuity and interruption) while the piping remains connected by the action of a rotary joint.

[0045] Substances (including centrifugation media) necessary for the separation of somatic cells inside the processing vessel 100 may be injected from the outside as appropriate, and ports necessary for injection may be provided as appropriate. When injecting the above-mentioned substances into the processing vessel 100, a preferred embodiment is that the container containing the substance is connected to the processing vessel 100 in advance via a connecting pipe A10 that can be switched between a connected state and a non-connected state, similar to the culture medium container 210 and the first supply container 220. Also preferred is an embodiment in which the container can be connected to the processing vessel via the connecting pipe A10 that can be switched between a connected state and a non-connected state, and via a unique connector configured to prevent incorrect connection.

[0046] The solution containing somatic cells may be one that has been previously processed by an external cell separation device (i.e., a suspension selectively containing only somatic cells), or may be one in which a raw material (such as whole blood or urine) has been processed into a liquid medium containing somatic cells. In this case, any conventionally known cell separation device can be used. In this case, the solution containing somatic cells may be injected from a syringe, an infusion bag, or the like connected to the openable injection port 101 shown in FIG. 1. In the processing vessel, the process can begin with the step of supplying reprogramming factors without the cell separation step.

[0047] 1 to 3 is a sealed container that holds a liquid culture medium. The sealed container may be any of the configurations described in the description of the processing container. However, when the manufacturing apparatus 10 is used as a closed-system processing circuit portion that is detachably attached to a commercially available cell processing device (such as CliniMACS Prodigy (registered trademark)), the sealed container made of the flexible material described above in (ii) (a flexible bag used for cell culture bags, infusion bags, etc.) is preferred as the culture medium container 210.

[0048] The liquid medium contained in the medium container 210 can be used not only for culturing cells but also for various purposes in the manufacturing process, such as washing cells, diluting chemical solutions, etc. Examples of liquid media that can be used in the present invention include the following:

[0049] The liquid medium is not particularly limited, but may be, for example, Essential 8 medium (CTS TM Essential 8 TM Medium, Essential 8 TM Medium, Essential 8 TM Flex Medium, Essential 6 TM Examples of suitable media include StemFit® AK02 Medium (Thermo Fisher Scientific), StemFit® AK03 Medium (Ajinomoto Co., Inc.), StemFit® Basic03 Medium, CTS® KnockOut SR XenoFree Medium (Gibco), mTeSR1 Medium, TeSR1 Medium (Stem Cell Technologies), Iscove's modified Dulbecco's medium (GE Healthcare), and Improved MEM (Thermo Fisher Scientific). These media can also be used for culture under feeder-free and xeno-free conditions. Other examples include, but are not limited to, MSCBM-CD, MSCGM-CD (both manufactured by Lonza) and mixtures thereof.

[0050] If necessary, physiologically active substances and nutritional factors necessary for cell survival or proliferation can be added to the medium.

[0051] Furthermore, antibiotics such as kanamycin, streptomycin, penicillin, or hygromycin may be added to the medium as needed.

[0052] In this specification, known serum can be used as the medium.

[0053] As used herein, the medium may or may not contain serum substitutes, as well as serum.

[0054] As used herein, the medium may contain a scaffold material (hereinafter also referred to as "scaffold") used for cell suspension culture. The scaffold material refers to a material or substrate that functions as a scaffold for cells in cell culture. The scaffold material is not particularly limited as long as it can be used for cell suspension culture (i.e., it may be free in the medium), as described above. Examples include those containing or made of synthetic resin, and those made of flexible materials such as collagen. Microcarriers may also be used as scaffold materials. As an example, the scaffold material may contain atelocollagen. Typically, the scaffold material is a material other than nanofibers. Examples of polymers used for scaffold materials include polystyrene, polyolefin, polyethylene terephthalate, polyether, polyvinyl alcohol, polyvinyl acetal, polyester, poly(meth)acrylate, epoxy resin, polyamide, polyimide, polyurethane, polycarbonate, cellulose, dextran, polypeptides (e.g., gelatin), etc. Scaffold materials may be produced by known methods or commercially available products. Examples of commercially available products include Cytodex-1 (GE Healthcare) and Corning (registered trademark) Low Concentration Synthemax (registered trademark) II Microcarriers (Corning).

[0055] 1 to 3 is a sealed container that holds a fluid containing reprogramming factors necessary for the establishment of iPS cells. The sealed container may be any of the configurations described in the description of the processing container. However, when the manufacturing apparatus 10 is used as a closed-system processing circuit portion that is detachably attached to a commercially available cell processing device (such as CliniMACS Prodigy (registered trademark)), the sealed container made of the flexible material described above in (ii) (a flexible bag used for cell culture bags, infusion bags, etc.) is preferred as the first supply container 220.

[0056] As used herein, examples of "reprogramming factors" include Oct3 / 4, Sox2, Sox1, Sox3, Sox15, Sox17, Klf4, Klf2, c-Myc, N-Myc, L-Myc, Nanog, Lin28, Fbx15, ERas, ECAT15-2, Tcl1, beta-catenin, Lin28b, Sall1, Sall4, ESrrb, Nr5a2, Tbx3, and Glis1, and these reprogramming factors may be used alone or in combination. Any known combination of reprogramming factors may be used.

[0057] The reprogramming factor introduced into the somatic cell may be in the form of a protein, a nucleic acid (RNA or DNA) encoding the protein, or an expression vector containing the nucleic acid. When the reprogramming factor is introduced in the form of RNA, immunogenic RNA introduced into the cell may activate the cellular defense mechanism, so RNA for circumventing the defense mechanism may be introduced into the somatic cell.

[0058] Examples of expression vectors include viral vectors such as retrovirus, lentivirus, adenovirus, adeno-associated virus, herpes virus, and Sendai virus, as well as plasmid vectors, episomal vectors, artificial chromosome vectors, and transposon vectors (piggyBac, piggyBat, TolII).

[0059] Nucleic acids, expression vectors containing the nucleic acids, or proteins (e.g., reprogramming factors) can be introduced into cells by various known methods, including calcium phosphate-mediated transfection, electroporation, liposome transfection, lipofection, gene guns, microinjection, viral vector methods, virus-like particle methods, Agrobacterium methods, agroinfiltration methods, PEG-calcium methods, sonoporation methods, and lipid nanoparticle methods.

[0060] (Other substances to be supplied) In addition to the substances described above, a sealed container containing a substance to be supplied to the processing vessel may be added as needed. The added sealed container can be connected to the processing vessel in the same way as the other sealed containers. Examples of other substances to be supplied to the processing vessel include liquids, powders, additives, release agents, cryoprotectants, CO ２In one embodiment, when expanding established induced pluripotent stem cells, the additive may include a factor for maintaining undifferentiation. As used herein, the term "factor for maintaining undifferentiation" refers to a substance that inhibits differentiation of induced pluripotent stem cells, and is not particularly limited as long as it is such a substance. Factors for maintaining undifferentiation commonly used by those skilled in the art include bFGF, FGF2, FGF4, FGF8, EGF, Nodal, Activin A, Activin B, TGFβ1, and TGFβ2. When the additive is, for example, a factor for maintaining undifferentiation, the sealed container may be present as a third supply container for expansion. The configuration of the third supply container may be incorporated in full as the first supply container described above and the second supply container described below. In another embodiment, when genome editing of established induced pluripotent stem cells is intended, a sealed container containing factors necessary for genome editing can be connected to a processing container. Examples of the genome editing include a method using zinc finger nuclease (ZFN) in which a zinc finger DNA binding domain and a nonspecific DNA cleavage domain are linked (Japanese Patent No. 4968498), a method using a transcription activator-like (TAL) effector that is a DNA binding module and a TALEN (TAL effector nuclease) in which a DNA endonuclease is linked (JP 2013-513389 A), or a method using the CRISPR-Cas9 system in which the DNA sequence CRISPR (ClusteredRegularlyInterspacedShortPalindroMicrorepeats) and the nuclease Cas protein family that has an important function together with CRISPR are combined (JP 2010-519929 A). For genome editing, as a necessary factor, for example, an artificial nucleic acid cleaving enzyme containing any nucleic acid binding domain such as zinc finger, TALE, or PPR (Pentatricopeptide repeat) can be used. In addition, in the case of a CRISPR / Cas system, either class I or II can be used, and as a necessary factor for genome editing, for example, gRNA and Cas protein (including Cascade complex) can be used.In addition, either wild-type or mutant Cas proteins may be used. Factors necessary for genome editing may be in the form of nucleic acids, expression vectors containing nucleic acids, or proteins. Specifically, for example, when genome editing artificial pluripotent stem cells using the CRISPR-Cas9 system, genome editing can be performed by connecting a processing container in a closed state to an electroporator in a closed state to which a sealed container containing gRNA and Cas9 protein designed to edit a target sequence is connected, and then introducing the gRNA and Cas9 protein by electroporation.

[0061] (Configuration for Producing Differentiated Cells) In a preferred embodiment of the manufacturing apparatus 10, as illustrated in FIGS. 1 to 3 , the manufacturing apparatus 10 may include one or more second supply containers 230 as a configuration for producing differentiated cells in situ from iPS cells produced in the processing container. The second supply container 230 is a sealed container that contains a fluid containing a substance for inducing differentiation of the iPS cells in the processing container. The sealed container may be any of the configurations described above for the processing container. However, when the manufacturing apparatus 10 is used as a closed-system processing circuit part that is detachably attached to a commercially available cell processing device (such as CliniMACS Prodigy®), a sealed container made of the flexible material described above in (ii) (a flexible bag used for cell culture bags, infusion bags, etc.) is preferred as the second supply container 230.

[0062] The second supply vessel 230, like the first supply vessel, may be directly connected to the processing vessel 100 so that the material contained therein is sent to the inside of the processing vessel 100 while maintaining a closed system (FIG. 1), or may be connectable to the processing vessel via a unique connector C20 configured to prevent incorrect connection (FIG. 2). In either case, it is preferable to connect to the processing vessel via a connecting pipe A10 that can be switched between a communication state and a non-communication state, as shown in FIGS. 1 to 3.

[0063] The second supply containers 230 can be provided in the same number as the number of differentiation induction stages, and the processing container 100 may be provided with the same number of injection ports as the number of second supply containers 230, or with fewer injection ports by merging connecting pipelines and using opening and closing valves.

[0064] (Differentiated cells) As used herein, "differentiated cells" refers to cells or organoids obtained by inducing differentiation of induced pluripotent stem cells. The cells obtained may be undifferentiated cells such as stem cells or progenitor cells, or may be terminally differentiated cells. As used herein, the term "differentiated cells" may be used to encompass both undifferentiated cells and terminally differentiated cells obtained by inducing differentiation of induced pluripotent stem cells. As used herein, "undifferentiated cells" refers to cells that have not reached terminal differentiation in the cell lineage, and examples of undifferentiated cells include stem cells excluding pluripotent stem cells, progenitor cells, and the like. Examples of stem or progenitor cells include ectodermal cells such as neural crest cells, neural stem cells, neural progenitor cells, glial progenitor cells, retinal stem cells, corneal stem cells, keratinocyte epidermal stem cells, melanocyte stem cells, mammary stem cells, mesodermal cells such as hematopoietic progenitor cells, myeloid stem cells, lymphoid stem cells, B progenitor cells, T progenitor cells, mesenchymal stem cells, cardiac stem cells, cardiac progenitor cells, vascular endothelial progenitor cells, vascular pericytes, platelet progenitor cells, skeletal muscle stem cells, adipose stem cells, kidney progenitor cells, and endodermal cells such as hepatic stem cells, liver progenitor cells, intestinal stem cells, and airway stem cells.

[0065] As used herein, the term "terminally differentiated cells" refers to cells that have reached terminal differentiation in a cell lineage. Examples of terminally differentiated cells include, but are not limited to, osteoblasts, chondrocytes, adipocytes, hepatic mesothelial cells, bile duct epithelial cells, hepatic stellate cells, hepatic sinusoidal endothelial cells, Kupffer cells, pit cells, vascular endothelial cells, blood cells, pancreatic duct epithelial cells, pancreatic duct cells, acinar centro-cells, acinar cells, islets of Langerhans, cardiac myocytes, fibroblasts, smooth muscle cells, type I alveolar epithelial cells, type II alveolar epithelial cells, Clara cells, ciliated epithelial cells, basal cells, goblet cells, neuroendocrine cells, Kruczykki cells, renal tubular epithelial cells, urothelial cells, columnar epithelial cells, glomerular epithelial cells, glomerular endothelial cells, octopus podocytes, mesangial cells, neurons, and glial cells. Examples of leukocytes include lymphocytes, granulocytes, and monocytes.

[0066] In one embodiment, the cells or organoids (target cells or organoids) obtained by inducing differentiation of induced pluripotent stem cells are neural crest cells, neural progenitor cells, neurons, cerebral cortical organoids, hematopoietic progenitor cells, platelets, T cells, or cardiomyocytes. Furthermore, T cells obtained by inducing differentiation of induced pluripotent stem cells can be modified into CAR-T cells (iCAR-T cells) using the method described in Nature Biomedical Engineering 5; 429:440; 2021.5.17, doi: 10.1038 / s41551-022-00969-0. Furthermore, by additionally connecting an appropriate sealed container containing the necessary materials or an electroporator or other device to the processing container, any desired genome editing can be performed on the differentiated cells.

[0067] (Substance for inducing differentiation of iPS cells) As used herein, the term "differentiation inducer" refers to a substance that can induce differentiation from induced pluripotent stem cells into the differentiated cells or organoids described above. The differentiation inducer may be a substance known per se, or may be selected from those typically used to induce differentiation of desired differentiated cells or organoids. Specific examples include substances such as those described in "2. Cell production method of the present invention" below.

[0068] The fluid used as a medium for containing the reprogramming factors, undifferentiated maintenance factors, and differentiation inducers is not particularly limited, but preferred examples include buffer solutions, culture media, and cryoprotectants such as dimethyl sulfoxide (DMSO) and glycerin.

[0069] In the package of the present invention, the liquid medium, solution, fluid, etc. contained in each sealed container may be cooled and frozen for the purpose of preservation during transportation or storage. That is, such liquid medium, solution, or fluid that is temporarily frozen corresponds to the "liquid medium," "solution," or "fluid" as used in the present invention, as long as it remains liquid or fluid at the temperature during use (cell processing).

[0070] (Syringe connection port provided on sealed container) The sealed container has an injection port for dispensing, which may be, for example, a syringe connection port. A substance can be dispensed into the sealed container through the injection port using a syringe or a pump.

[0071] (Connecting Pipeline) The tubing constituting the connecting pipeline A10 is not particularly limited, and a tube (soft tube) made of a soft material (such as silicone or polyvinyl chloride) is preferably used. The connecting pipeline may partially include a tubing member made of a hard material. The sealed containers may also be directly connected to each other via a connector, in which case the internal passage of the connector is the connecting pipeline. When the manufacturing apparatus 10 is used as a closed-system processing circuit part that is detachably attached to a commercially available cell processing device (such as CliniMACS Prodigy (registered trademark)), it is preferable to use soft tubing that is compatible with the pump (peristanic pump) and pinch valve provided in the cell processing device.

[0072] (Opening / Closing Valve) In the present invention, a "connecting conduit that can be switched between a connected state and a disconnected state" refers to a connecting conduit whose flow path opens and closes in response to the operation of an opening / closing valve. Examples of the opening / closing valve include a manually opened and closed clip incorporated into the connecting conduit A10, and a pinch valve (an electromagnetic valve that presses and releases a soft tube from the outside) provided on a commercially available cell processing device (such as CliniMACS Prodigy (registered trademark)). The valve may be provided in advance as a component of the manufacturing device for the package, or may be added appropriately by a user who produces cells using the manufacturing device for the package at the time of use. In particular, when the manufacturing device is used as a closed-system processing circuit part that is detachably attached to a commercially available cell processing device (such as CliniMACS Prodigy (registered trademark)), it is preferable to use an opening / closing valve (such as the pinch valve) provided on the cell processing device.

[0073] (Connectors) The connecting conduits may be connected to each sealed container, or to each other, by direct bonding, but connection via an appropriate connector is preferred. Connectors that can be used in the present invention are not particularly limited, and examples include luer connectors (old ISO 594-1, old ISO 594-2, etc.), sterile connection joints, push-in joints for tubing, and one-touch joints. Sterile connection joints are preferred connectors that allow connection and disconnection while maintaining sterility within the conduit (i.e., within the closed system). The unique connector C20, configured to prevent incorrect connection, is a sterile connector. Furthermore, as illustrated in FIG. 1 , it is preferable that an appropriate connector C10 be provided at the tip of each connecting conduit connected to the discharge port 102, gas injection port 104, and gas discharge port 105. More preferably, the appropriate connector C10 is heat-sealed. Even more preferably, the connecting conduit to the discharge port 102 is connected to a waste liquid bag.

[0074] In the present invention, the "unique connector configured to prevent mutual misconnection" refers to a sterile connector, such as MicroCNX from Colder Products Company. ＴＭEach pair of connectors may have different specifications from the other pairs of connectors. The unique connectors may also be configured to alert the assembly worker to prevent misconnections, such as by applying a unique color to each pair of connectors. Among these, a unique connector configuration in which each pair of connectors is structurally incapable of being connected to the other pairs of connectors is particularly preferred. These unique connectors provide the same effect of preventing misconnections as the configuration in which the connections are completed in advance. These unique connectors are also preferably sterile connecting joints.

[0075] (Feeding Device) The feeding device is a device that transfers substances (solutions, liquids, or fluids containing (somatic) cells) contained in each sealed container connected to the processing container to the processing container. The feeding device may be provided in advance as a component of the manufacturing device for the package, or may be added appropriately by a user who produces cells using the manufacturing device for the package at the time of use. Furthermore, as described above, if the manufacturing device for the package is a closed-system processing circuit part that is detachably attached to a cell processing device such as the CliniMACS Prodigy from Miltenyi Biotec, or other devices such as the Gibco CTS Rotea Counterflow Centrifugation System from Thermo Fisher Scientific, the Cocoon system from Lonza, or the Xuri from Cytiva, as shown in FIG. 16 , the hook positions for each container (e.g., medium container, first and second supply container), the position of the feeding device (peristaltic pump), the position of the processing container, the path and length of the tubing, etc., vary depending on the manufacturer. Furthermore, the pinch valves that open and close depending on the operating program of the cell processing device also change. Therefore, it is preferable to determine the tube arrangement pattern of the manufacturing apparatus of the present invention by referring to the conventional piping state so that it is compatible with the intended cell processing apparatus to which it is to be attached. The feeding device that can be used in the present invention is not particularly limited, and examples include various conventionally known pumps and mechanisms that use gravity to move the tube. The power supply circuit, control circuit, connecting pipes, electromagnetic valves, etc. necessary for operating the feeding device may be added to the present invention as appropriate, or may be provided by the user as appropriate when using the manufacturing apparatus. As described below, when the manufacturing apparatus of the present invention is a closed system part of the cell processing apparatus, the feeding device, power supply circuit, control circuit, connecting pipes, electromagnetic valves, etc. are all provided in the main body of the cell processing apparatus.

[0076] As illustrated in FIG. 3 , a peristaltic pump F10 may be used to transfer the contents of the medium container 210, the first supply container 220, and the second supply container 230 to the processing container (the peristaltic pump is represented by a symbol in the figure). To use the peristaltic pump F10, a flexible tube is used as the connecting conduit A10, and the flexible tube may have a thickness, elasticity, and length that allows it to be attached to the peristaltic pump F10. Each connecting conduit is provided with an on-off valve V10, and the connecting conduits merge into a single connecting conduit. This single connecting conduit can be attached to the peristaltic pump F10 and connected to the processing container. By selectively opening the on-off valve V1, only the connecting conduit that passes through the selected on-off valve can transfer material. Therefore, by controlling the three on-off valves V1 and the single peristaltic pump F10, only the material from the desired sealed container can be transferred to the processing container.

[0077] (Relationship between the Package Manufacturing Apparatus and Conventional Cell Processing Apparatus) In a preferred embodiment, the package manufacturing apparatus does not have a feeder, on-off valve, control device, power supply, etc., and is configured as a closed system (closed processing circuit portion) that can be attached to and detached from a cell processing apparatus such as that shown in FIG. 16. Examples of such cell processing apparatus include the CliniMACS Prodigy from Miltenyi Biotec, the Gibco CTS Rotea Counterflow Centrifugation System from Thermo Fisher Scientific, the Cocoon system from Lonza, and the Xuri from Cytiva. However, in addition to commercially available cell processing apparatus, it may also be a cell processing apparatus created specifically for the present invention (an apparatus equipped with a feeder, on-off valve, control device, power supply, etc., so that the package manufacturing apparatus can be used as a closed system portion and cells can be processed within the closed system portion). In such cell processing apparatus, the closed system portion is detachable from the mechanism portion (also referred to as the apparatus main body portion) while maintaining its own closed nature. By providing the package manufacturing apparatus of the present invention in a pre-configured form or to a large extent pre-configured so that it can be installed as such a closed system, users who wish to manufacture cells can simply install the package manufacturing apparatus on the cell processing device and begin cell production without the need to connect various sealed containers or prepare materials in a sterile environment, or with a significantly reduced amount of work. As a result, the problem of incorrect connections on the user's side is fundamentally eliminated, or at least largely eliminated. Furthermore, all of the mechanical components of the cell processing device (feeders, on-off valves, control devices (including computer programs for controlling cell culture), power sources, air pressure sources, etc.) can be utilized.

[0078] (Sterilization of the cell manufacturing device) The cell manufacturing device is aseptically filled with contents or connected. The packaged cell manufacturing device may be sterilized after being enclosed in packaging materials. The sterilization method is not particularly limited, but examples include radiation sterilization such as gamma ray sterilization.

[0079] (Packaging Materials) The packaging in the package is preferably packaging that surrounds the manufacturing equipment so as to maintain the sterilized state of the manufacturing equipment. In other words, the packaging is preferably packaging that prevents bacteria, viruses, dust, foreign matter, and fine particles from entering from the outside. Therefore, the packaging material may not only be one that isolates the inside from the outside, but also one that includes a gas-permeable membrane or porous filter (e.g., one with a pore size of approximately 0.2 μm or less, particularly approximately 0.1 to 0.2 μm). The packaging may also be one that surrounds the manufacturing equipment in a liquid-tight and airtight manner to seal the manufacturing equipment. Specific embodiments of the packaging are not particularly limited, but preferred embodiments include the following: a bag (flexible bag-like object) made of nonwoven fabric, paper, or flexible film; a sealed container having a container body such as a tray made of a hard material and a flexible film that closes the opening; and a sealed container having a container body made of a hard material and a lid made of a hard material that closes the opening. Other examples include sealed containers made of composite materials that combine flexible and hard material components.

[0080] The material of the nonwoven fabric or flexible film used in the above-mentioned bag is not particularly limited, but examples include polymer materials such as polyethylene, polypropylene, nylon, polyester, polyvinyl chloride, polyvinylidene chloride, polymethylpentene, polyvinyl alcohol, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, polycarbonate, polystyrene, polyacrylonitrile, and polyurethane, and a multilayer film formed by appropriately combining these may also be used. The flexible film may also be a gas-permeable film. Materials other than the above-mentioned polymer materials, such as a laminate layer made of aluminum film or an aluminum vapor-deposited layer, may also be used in appropriate combination.

[0081] (Configuration or method for closing the opening of the bag) The configuration or method for closing the opening of the bag is not particularly limited, and may be one that can be opened and closed repeatedly, or one that requires destruction or cutting to open, and examples include known fasteners (zippers), sealing by heat welding, sealing with an adhesive, sealing with clips or sealing tape, etc.

[0082] The hard material is not particularly limited, but examples include polymer materials that have traditionally been used as materials for hard containers, such as polyethylene, polyethylene terephthalate, polypropylene, polyester, polycarbonate, polystyrene, polyvinyl chloride, acrylonitrile-styrene, polymethylpentene, polymethyl methacrylate, acrylonitrile-butadiene-styrene, polyacetal, and polyamide, as well as metals such as stainless steel and aluminum alloys.

[0083] The above-mentioned packaging is preferably further enclosed and packaged in a packaging material with higher mechanical strength (such as a bag or box made of a thicker material) for the purpose of protecting the product from dirt and the like during transportation and storage. Examples of such materials include polystyrene foam, cardboard, and plastic cardboard. The further packaging is preferably the same packaging box used when the product is received and when it is disposed of. If the packaging box used when the product is received and the packaging box used when it is disposed of are the same, the received package will be stored in the box it was stored in when it was received and disposed of, which makes disposal tracing easier and is also preferable from the standpoint of environmental protection.

[0084] It is preferable that the packaging using packaging materials further satisfy one or more of the following conditions: - Even when subjected to vibrations or tilting, each part of the manufacturing equipment can be fixed in the internal space surrounded by the packaging material so as not to move, and can be positioned so as not to shift or be damaged by vibrations or the like. For example, a flexible bag can be used as the packaging material, and the internal pressure can be reduced as in vacuum packaging, and a flexible film can be tightly attached to each part of the manufacturing equipment to fix each part of the manufacturing equipment. - It is preferable that the packaging material does not have unintentional openings such as pinholes, and that there is no internal or external distribution. - It is preferable that the packaging material complies with the Sterilization Medical Device Packaging Guidelines. - Sterilization validation is preferably carried out during sterilization. - Packaging validation is carried out during packaging. It is preferable that compatibility with sterilization methods, stability during transportation or storage (vibration, temperature change, light-blocking performance, etc.) are taken into consideration.

[0085] (Specific examples of cell processing device, device main body, closed system part, and packaging) Figure 4 is a photograph showing the device main body from which the closed system part (the cell manufacturing device of the present invention) has been removed, of the CliniMACS Prodigy (hereinafter also referred to as Prodigy), a commercially available automatic cell processing device manufactured by Miltenyi Biotec. As shown in Figure 4, the device main body of the Prodigy has a support B10 for suspending bags such as a culture medium container and a first supply container, and also has necessary actuators such as a number of pinch valves V10 that open and close according to a predetermined program, and a peristaltic pump F10 that moves fluid inside the closed system part.

[0086] FIG. 5 is a photograph showing the interior of a package containing a closed system to be attached to the Prodigy device main body shown in FIG. 4. As shown in FIG. 5, a processing container 100a dedicated to Prodigy, a culture medium container 210, a connecting duct A1 configured to fit the layout of the device main body, a sealed container 240 used for processing, a blood collection device 250a, and other components are housed inside a packaging material (packaging container) 20a. An empty sealed container for containing the target cells to be produced may also be connected to the closed system. These elements are assembled as a closed system or are ready to be assembled via unique connectors. The blood collection device 250a is sent to a medical institution and used to collect blood from a patient. After blood collection, the blood collection device 250a is assigned an identification code, such as a patient identification number or a cell production identification code, and then sent to the cell manufacturer. In the example of FIG. 5, the blood collection device 250a is included in the package; however, it may be packaged separately from the package for delivery to the medical institution.

[0087] 6 is a photograph showing an example of the blood collection device 250a. The blood collection device 250a has a small blood collection bag 250 and a conduit (tube) A1a connected to it. A butterfly needle (or a general blood collection needle) used for blood collection is connected to the tip of the conduit A1a, and a specific connector is inserted into the middle of the conduit A1a to connect it to a predetermined position in the closed system in a sterile manner.

[0088] Figure 7 is a photograph illustrating the state in which the closed system section is attached to the main body of the Prodigy device shown in Figure 5. The various sealed containers (bags) 200 included in the closed system section are hung from the support columns B10 shown in Figure 5, the soft tubing A1 that serves as the connecting conduit is set to pass through the specified pinch valves and peristaltic pumps, the processing vessel 100a is set in the drive unit to enable rotation for centrifugation, and the computer program for cell processing is ready to start.

[0089] Figure 8 is a photograph showing the main body of a commercially available automated cell processing device, the Gibco CTS Rotea Counterflow Centrifugation System (hereinafter referred to as "Rotea") manufactured by Thermo Fisher Scientific, with the closed system removed. As shown in Figure 8, the main body of the Rotea device has a support B10 for suspending bags such as a medium container and a first supply container, as well as necessary actuators such as multiple pinch valves V10 that open and close according to a predetermined program and a peristaltic pump F10 that moves fluids inside the closed system.

[0090] Figure 9 is a photograph showing the inside of a package containing a closed system to be attached to the main body of the Rotea device shown in Figure 8. As shown in Figure 9, the unit part A1b containing a dedicated processing container for Rotea, the culture medium container 210, the connecting piping part (hidden below the unit part A1b) along the layout of the main body of the Rotea device, the sealed container 240 used for processing, the blood collection device 250a, etc. are contained inside the packaging material (packaging container) 20a. As in the example of Figure 5, these elements are assembled as a closed system or can be assembled via a dedicated connector. The blood collection device 250a is also similar to the example of Figure 5.

[0091] Fig. 10 is a photograph showing the unit part A1b shown in Fig. 9. The unit part A1b is a dedicated disposable part called a single-use kit that is connected to the main body of the Rotea device, and includes a conical processing vessel (centrifugation chamber) 100b for performing counterflow centrifugation.

[0092] Figure 11 is a photograph illustrating the state in which the closed system section is attached to the Rotea device main body shown in Figure 8. Various sealed containers (bags) 200 included in the closed system section are suspended from the support columns B10 shown in Figure 8, and the connecting pipes (flexible tubes) A1 extending from each sealed container are connected to the unit section A1b. When the computer program for cell processing starts, each connecting pipe opens and closes using a specified pinch valve. Furthermore, each connecting pipe converges into a single pipe line and passes through a peristaltic pump. The processing vessel 100b is set in a drive unit and can be rotated for centrifugation. In the example shown in Figure 11, the device main body has begun cell processing operation, the processing vessel 100b is rotating, and fluid is moving within the closed system section.

[0093] As specifically illustrated in Figures 4 to 11, the cell manufacturing device packaged in packaging material in the package is a closed system component included in various cell processing devices. That is, each cell processing device is composed of an apparatus main body and a closed system component. As illustrated in Figures 4 and 8, each apparatus main body has an operating mechanism for operating the closed system component and a control unit for controlling the operating mechanism. The closed system component is detachable from the apparatus main body while maintaining the airtightness of its own closed system. In the present invention, the closed system component is assembled in a state detached from the apparatus main body, and is provided to the cell manufacturer in a form that fits and can be attached to each apparatus main body component. The closed system component, attached along a predetermined position on the apparatus main body component, is actuated by receiving an external force from the operating mechanism. The operating mechanism operates under the control of the control unit of the apparatus main body component, which operates the operating mechanism according to a predetermined operating program. As a result, somatic cells are moved and processed within the closed system component, producing the target cells.

[0094] FIG. 12 is a photograph illustrating the configuration of the packaging material of the package. In the example of FIG. 12, the opening of a container body 20a made of a hard resin material is sealed with a flexible film (inner lid) 20b (FIG. 12(a)). Furthermore, an outer lid 20c is fixed to the container body 20a, covering the flexible film 20b. In the example of the same figure, the flexible film 20b is made of a high-density polyethylene nonwoven fabric (Tyvek (registered trademark)), which prevents the intrusion of viruses and the like from the outside while allowing gas to pass through. Furthermore, the outer lid 20c, like the container body 20a, is made of a hard resin material. This double-lid structure allows the package to withstand external forces and be stacked while maintaining sterility within the package.

[0095] (Other Preferred Aspects of the Package According to the Present Invention) The package may be in the following aspects: (a1) A package for a cell production device, the package comprising a cell production device and packaging material, the cell production device comprising a processing vessel, and one or more fluid supply vessels for accommodating fluids used in cell processing, the fluid supply vessels (i) being connected to the processing vessel via a connecting pipeline that can be switched between a connected state and a non-connected state, or (ii) being connectable to the processing vessel via the connecting pipeline and via a unique connector configured to prevent erroneous connection, so that the contents thereof are sent into the processing vessel while maintaining a closed system, the processing vessel has at least an openable / closeable inlet port for receiving a solution containing the somatic cells from the outside, and an openable / closeable outlet port for discharging the contents, the processing vessel and the fluid supply vessel are hermetically sealed containers, and the cell production device is packaged in the packaging material. (a2) The package of the cell manufacturing device according to (a1), wherein the cell manufacturing device is a detachable closed-system processing circuit portion of a cell processing device equipped with a detachable closed-system processing circuit portion, a mechanism for operating it, and a control unit. (a3) ​​The package of the cell manufacturing device according to (a1) or (a2), wherein the one or more fluid supply containers include at least one culture medium container for containing a liquid culture medium. (a4) The package of the cell manufacturing device according to any one of (a1) to (a3), wherein the one or more fluid supply containers include a first supply container for containing a fluid containing the reprogramming factor as a configuration for producing induced pluripotent stem cells. (a5) The package of the cell manufacturing device according to any one of (a1) to (a4), wherein the one or more fluid supply containers include a third supply container for containing a fluid containing the undifferentiation maintenance factor as a configuration for expanding established iPS cells.(a6) A packaging body for a cell manufacturing apparatus described in any one of (a1) to (a5), wherein the one or more fluid supply containers include one or more second supply containers containing a fluid containing a differentiation inducer for artificial pluripotent stem cells as a configuration for manufacturing differentiated cells from artificial pluripotent stem cells manufactured in the processing container.

[0096] The configuration of the "fluid supply container" in (a1) above may be the same as the configuration of the first supply container and the second supply container described above.

[0097] In the above embodiments (a1) to (a5), the package of the present invention can be used to perform the following processes, for example: A process in which a package (first package) of a cell manufacturing device configured to establish iPS cells is used, and the cell manufacturing device in the first package is attached to a known cell processing device, Rotea, thereby separating white blood cells from whole blood and establishing iPS cells; A process in which a package (second package) of a cell manufacturing device configured to expand and culture established iPS cells is used, and the cell manufacturing device in the second package is attached to a known cell processing device, Cocoon, thereby expanding and culture the iPS cells; A process in which a package (third package) of a cell manufacturing device configured to produce differentiated cells from iPS cells is used, and the cell manufacturing device in the third package is attached to a known cell processing device, Prodigy, thereby producing differentiated cells from iPS cells.

[0098] (Preferred Example of Use of the Package According to the Present Invention) From the viewpoint of convenient use by cell manufacturers, the package according to the present invention is preferably in a form in which a completed single closed system part is contained within a single package. However, in addition to such a single package form, the package may be provided to cell manufacturers in a form in which the package is separated into two or more packages depending on the request of the cell manufacturer and various circumstances, such as issues regarding management of the components. That is, the package may be in a form in which a specific component included in one closed system part is separated from the closed system part and packaged in a different packaging material. For example, one or both of the medium container and the first supply container constituting the closed system part may be separated from the closed system part and packaged in a different packaging material, resulting in the package being separated into three mutually independent packages. Even in a form in which the packages are separated into two or more packages, each of the components contained therein is properly assembled into a single closed system part via a unique connector at the cell manufacturer's premises. If each sealed container (culture medium container, first supply container, second supply container, etc.) included in the closed system portion contains contents such as reagents and the connections are complete, no work prior to cell production is required and the cell production process becomes more efficient, so it is preferable that the closed system portion includes the first supply container, and it is even more preferable that the closed system portion also includes a culture medium container.

[0099] One of the management issues related to the above-mentioned elements is the problem of different management temperatures for each element. That is, the contents of each sealed container in the cell manufacturing device package may include those that can be stored or distributed at room temperature (e.g., about 1 to 30°C) or ambient temperature (e.g., about 15 to 25°C), as well as those that require temperature control, such as cooling (e.g., about 2 to 8°C) or freezing (e.g., about -20 to -196°C), during storage or distribution. In such cases, package A containing the items that can be stored or distributed at room temperature or ambient temperature and package B containing the items that require temperature control, such as cooling or freezing, may be produced (if multiple temperatures need to be controlled, multiple packages B, C, D, etc. may be produced for each temperature). Package A may be provided to the user at ambient temperature, and the packages requiring temperature control (e.g., package B) may be provided to the user in a cooled or frozen state. The cell manufacturing device and sealed containers contained in these packages may then be assembled by the user into a single cell processing device (such as the Prodigy) to form a single closed processing circuit.

[0100] More specifically, for example, a liquid medium may require refrigeration at about 4°C during transport and storage, and a viral vector (such as SeV) for introducing reprogramming factors into somatic cells may require freezing at about -80°C during transport and storage. Therefore, most of the closed system portion may be provided to the user as package A at room temperature, package B including a medium container may be provided to the user at the required refrigeration temperature, and package C including a first supply container may be provided to the user at the required freezing temperature. Alternatively, most of the closed system portion may include a medium container, which may be provided to the user as package A at the required refrigeration temperature, and package B including a first supply container may be provided to the user at the required freezing temperature. Alternatively, a packaging material may be constructed having a room temperature region, a refrigerated region, and a freezer region, and each element may be appropriately arranged in these regions.

[0101] The medium container included in the closed system part may be an empty container for containing a liquid medium, and the cell manufacturer may pour the liquid medium into the empty container. The first supply container included in the closed system part may also be an empty container for containing a fluid containing a reprogramming factor, and the cell manufacturer may thaw the reprogramming factors stored in the cell manufacturing facility, mix them with the liquid medium in a safety cabinet, and fill the container, or fill the container via a sterile connector, and then pour the fluid containing the reprogramming factor into the empty container.

[0102] The cell production process for producing target cells by processing somatic cells (including blood) collected from a patient is preferably initiated within approximately 0 to 24 hours from the time the somatic cells are collected from the patient. Therefore, it is preferable that the start date and time of the cell production process and the date and time of collection of the raw material somatic cells are determined in association with each other.

[0103] Furthermore, the cell production process takes a long period of time, such as one month, and therefore, in addition to the materials needed on the first day of production, specific materials may be needed for each elapsed time or day. Therefore, in response to such requests, it is preferable to provide additional packages, following the initially provided package (containing all the materials needed at the start of cell production), in which sealed containers (e.g., bags) containing the specific materials needed for each elapsed time or day, such as the second day, the third day, the 28th day, etc., from the start of production. Examples of such additionally provided materials include bags, connecting pipes, reagents, culture media, etc.

[0104] 2. Cell Production Method of the Present Invention (Method for Producing iPS Cells) Next, a cell production method of the present invention (hereinafter also referred to as the production method) will be described with reference to the production apparatus illustrated in Figures 1 to 3. The production method is a cell production method using the package of the present invention described above. The production method includes the steps of preparing a production apparatus removed from the package and producing at least iPS cells inside the processing vessel 100 of the production apparatus 10 shown in Figure 1. The elements constituting the production apparatus 10 and the substances contained in each sealed vessel are as described above. The production apparatus 10 is equipped with a feeder, valves, and control devices as necessary, and the feeder and valves are operated to send substances from each sealed vessel to the processing vessel, thereby carrying out the process of producing iPS cells.

[0105] The process for producing iPS cells includes at least the following steps: Step (s10): Inject a solution containing somatic cells into the processing vessel 100 through the injection port 101, send a liquid culture medium from the culture medium container 210, and send a fluid containing reprogramming factors from the first supply container 220, thereby bringing the reprogramming factors into contact with the somatic cells in the liquid culture medium within the processing vessel. Step (s20): Cultivate the somatic cells in the liquid culture medium within the processing vessel 100 to establish iPS cells.

[0106] (When the processing vessel has the function of separating somatic cells) When the processing vessel 100 has the function of separating somatic cells, in step (s10), as illustrated in FIG. 1, raw materials such as whole blood or urine are directly injected into the processing vessel through the injection port 101. Depending on the function of somatic cell separation, substances necessary for the separation are further injected into the processing vessel 100, and somatic cells to be used for producing iPS cells are separated within the processing vessel. Components other than the somatic cells are discharged to the outside of the processing vessel, and the somatic cells to be processed remain within the processing vessel. Next, a liquid medium is delivered from the culture medium container 210, and a fluid containing reprogramming factors is delivered from the first supply container 220, thereby bringing the reprogramming factors into contact with the somatic cells in the liquid medium within the processing vessel 100. Subsequently, iPS cells are established by the above-mentioned step (s20).

[0107] (Expansion and quality evaluation after establishment of iPS cells) The induced pluripotent stem cells established by the production method of the present invention may be appropriately expanded by known methods. Furthermore, after expansion, the quality of the obtained iPS cells may be evaluated by known methods.

[0108] (Method for producing differentiated cells) In a preferred embodiment, the production method further includes a step (s30) of forming differentiated cells in the processing vessel 100 after the step (s20). To perform the step (s30), the production apparatus includes a second supply container 230. After the step (s20), a fluid containing an iPS cell differentiation inducer (a substance for inducing differentiation of iPS cells) is supplied from the second supply container 230 into the processing vessel 100, and differentiated cells are formed in the processing vessel. The differentiated cells to be produced and the substances supplied for differentiation induction are as described above. If the differentiation induction needs to be performed in multiple stages to obtain the target cells, second supply containers 230 corresponding to the number of substances required for each differentiation induction can be provided, and the substances can be controlled to be sent to the processing vessel in the order of the differentiation induction stages.

[0109] In the cell production method of the present invention, known methods can be used to induce differentiation to obtain the desired cells or organoids. For example, differentiation of pluripotent stem cells into neural crest cells can be performed by the methods described in Fukuta M. et al., PLoS One, 2014, 9(12): e112291 or Kamiya D, et al., NPJ Regen Med., 2022 Sep 15;7(1):47. Specifically, pluripotent stem cells can be seeded in a culture vessel and subjected to adhesion culture (suspension culture using a scaffold material), and then differentiated into neural crest cells by adhesion culture (suspension culture using a scaffold material) in a medium containing a TGFβ inhibitor and a GSK3β inhibitor.

[0110] It is also possible to produce cells such as mesenchymal stem cells, neural progenitor cells, neurons, glial cells, bone cells, chondrocytes, corneal cells, and melanocytes from neural crest cells. For example, differentiation into these cells can be performed based on the methods described in Fukuta M. et al., PLoS One, 2014, 9(12): e112291, Horikiri T. et al., PLoS One, 2017, 12(1): e0170342, and Kamiya D, et al., NPJ Regen Med., 2022 Sep 15;7(1):47. Specifically, for example, neural crest cells are seeded on a fibronectin-coated plate, and the medium is replaced with DMEM / F12 supplemented with N-2 Supplement, BDNF, GDNF, NT-3, and NGF, and then incubated at 37°C and 5% CO ２ Alternatively, neural crest cells can be plated and cultured in CDM medium containing SB431542 and CHIR99021 for 1 day, after which the medium is replaced with neurobasal medium supplemented with B-27 supplement, N-2 supplement, L-glutamine, penicillin / streptomycin, BDNF, GDNF, NT-3, and NGF, and the medium is incubated at 37°C, 5% CO ２ By culturing the cells under the conditions described above for about 35 days, neural progenitor cells and neural cells can be obtained.

[0111] Differentiation into mesenchymal stromal cells can be induced, for example, by the following method: Neural crest cells are seeded in a culture vessel and cultured for one day in CDM medium containing SB431542 and CHIR99021. After one day, the medium is replaced with αMEM containing FBS. Mesenchymal stromal cells can be obtained approximately 14 days after the start of differentiation induction.

[0112] Methods for differentiating pluripotent stem cells into T cells include, for example, methods comprising (1) differentiating pluripotent stem cells into hematopoietic progenitor cells, and (2) differentiating the hematopoietic progenitor cells into T cells. Step (1) can be, for example, culturing pluripotent stem cells in a hematopoietic progenitor cell induction medium, as described in WO 2013 / 075222, WO 2016 / 076415, Liu S. et al., Cytotherapy, 17 (2015); 344-358, etc. Step (2) can be, for example, (2-1) inducing CD4 / CD8 bipositive T cells from hematopoietic progenitor cells, or (2-2) inducing CD8 / positive T cells from CD4 / CD8 bipositive T cells, as described in WO 2016 / 076415, etc.

[0113] Examples of the step of inducing differentiation of pluripotent stem cells into platelets include methods comprising (1) a step of differentiating pluripotent stem cells into hematopoietic progenitor cells, and (2) a step of differentiating hematopoietic progenitor cells into platelets. Step (2) can be, for example, a step of culturing hematopoietic progenitor cells in a medium containing TPO and / or SCF for approximately 7 to 15 days, as described in WO 2012 / 157586, US 2014 / 127815, Nakamura, Eto, et al. Cell Stem Cell 14, 535-548 (2014), etc. This step allows for the production of a cell population containing megakaryocytes and platelets.

[0114] Examples of methods for inducing differentiation of pluripotent stem cells into cardiomyocytes include those described in WO2015 / 141827, Laflamme MA and Murry CE, Nature. 473(7347):326-35 (2011), etc. Other methods include, for example, a method for producing cardiomyocytes by forming embryoid bodies through suspension culture of induced pluripotent stem cells, a method for producing cardiomyocytes in the presence of a substance that suppresses BMP signaling (WO2005 / 033298), a method for producing cardiomyocytes by sequentially adding Activin A and BMP (WO2007 / 002136), and a method for producing cardiomyocytes in the presence of a substance that promotes activation of the canonical (classical) Wnt signaling pathway (WO2007 / 126077). Typically, for example, marker proteins for cardiomyocytes include NKX2.5 (a cardiac muscle-specific transcription factor) and TNNT2 (troponin T), and marker proteins for cardiac progenitor cells include KDR (a receptor for vascular endothelial growth factor (VEGF)) and ISL1 (a LIM homeodomain transcription factor).

[0115] In addition, organoid can be produced by using multiple kinds of cells.For example, in the case of hepatic organoid, as described in WO2013 / 047639 etc., hepatic progenitor cells (organ cells), mesenchymal stem cells and vascular endothelial cells are induced from pluripotent stem cells, and these mixtures are subjected to suspension culture, thereby hepatic organoid can be produced.

[0116] In the cell production method of the present invention, the cells may be cultured under feeder-free conditions and / or xeno-free conditions for all or part of the period. From the viewpoint of clinical use, the differentiation induction method of the present invention is preferably carried out under feeder-free and xeno-free conditions for the entire period.

[0117] The cell production method of the present invention may include a step of recovering the obtained target cells or organoids. The recovered cells may be cryopreserved using a cell cryopreservation solution. The recovered cells may be counted using a cell counter, or may be labeled with an antibody against a cell surface marker and purified by flow cytometry, mass cytometry, magnetic cell separation, or the like.

[0118] In the cell production method of the present invention, undifferentiated cells may be removed as appropriate. The method for removing undifferentiated cells is not particularly limited as long as it can remove cells other than cells produced by the cell production method of the present invention, and can be performed by adding a known agent for removing undifferentiated cells to the medium (e.g., Di Mao., et al., Angewandte Chemie International Edition; 9 January 2017; Ben-David, U., et al., Cell Stem Cell, 12, 167 (2013); WO2019 / 187918; JP 2016-93178 A; Yoshiki Nakashima, et al., Molecular Therapy Vol. 26 No. 7 July 2018, etc.).

[0119] Quality testing may also be performed as appropriate to determine whether the cells, organoids, etc. obtained by the cell production method of the present invention are desirable. Test items for quality testing are not particularly limited, but include basic tests such as the morphology of the cells or organoids, the presence or absence of expression of cell surface markers, sterility tests, endotoxin tests, and evaluation of cell viability, and testing devices appropriate for each test item can be used.

[0120] With regard to other matters necessary for the cell production method of the present invention, all of the contents described above in "1. Packaging of cell production device" are applicable.

[0121] 3. Management System According to the Present Invention Next, a management system according to the present invention (hereinafter also referred to as the management system) will be described. The management system is for managing the manufacturing process of the package according to the present invention described above, and in a preferred embodiment, is a system for detecting whether the package meets specifications when cells are manufactured using the package.

[0122] As shown in FIG. 13 , the management system includes a management device 300 and a reader 400 for reading identification codes. In the example of FIG. 13 , the management device 300 is a server computer (also called a web server) located on the Internet. The reader 400 is connected to a terminal computer 410 for data communication. The terminal computer 410 may be connected to the management device 300 for data communication via the Internet. In a preferred embodiment, the terminal computer 410 is a tablet terminal, and the reader 400 is a camera installed on the tablet terminal. The terminal computer 410 may also be a data input device for inputting specification data, which will be described later. The management device 300 may also be a terminal computer capable of data communication with other terminal computers.

[0123] In the management system of the present invention, an identification code (D1) assigned to each package is displayed on all of the various packages produced so that it can be read by a reading device 400. The identification code (D1) may be displayed on one or both of the packaging material and the cell manufacturing device. In the example of FIG. 13, as a preferred embodiment, the identification code (D1) is displayed on the packaging material of the package in the form of a barcode 40 (in the illustrated example, the numbers of the identification code are also displayed). The identification code may be displayed in the form of a two-dimensional symbol (two-dimensional code). Hereinafter, the display of the identification code in the form of a symbol readable by a reading device (in the form of an information carrier such as a barcode, two-dimensional symbol, or IC tag) will also be simply referred to as "the identification code being displayed."

[0124] In the present invention, an identification code is a combination of numbers, letters, symbols, figures, etc., assigned so as to be unique to each object to be identified. In the present invention, "displaying an identification code so as to be readable by a reading device" means that, depending on the reading function of the reading device, the identification code is displayed on the object as a combination of numbers, letters, symbols, figures, etc., or in the form of a one-dimensional symbol (such as a barcode (also called a one-dimensional code)), or in the form of a two-dimensional symbol (such as a data matrix or QR code (registered trademark) (also called a two-dimensional code)), or in the form of another symbol, or in the form of an IC tag. For example, if the reading device is a device that reads one-dimensional symbols, the identification code is accordingly displayed on the surface of the object in the form of a one-dimensional symbol. Attaching an IC tag also constitutes displaying an identification code. The IC tag may be located inside the object as long as it is readable by the reading device. The reading device may read the identification code using character recognition, image recognition, or voice recognition functions. An identification code in the form of a one-dimensional or two-dimensional symbol may be printed directly on the surface of an object, or a sheet with the identification code printed thereon may be attached to the surface of the object. Regarding the technology of identification codes and reading devices, reference may be made to conventionally known technologies. In the case of a product that can contain a large amount of information, such as a two-dimensional symbol or an IC tag, the identification code may be the identification information itself that should be associated with the identification code.

[0125] As shown in FIG. 13 , the management device 300 includes a data receiving unit 310 and an attribute information storage unit 331. The data receiving unit 310 receives the identification code read by the reading device 400 as input data. The attribute information storage unit 331 stores the identification codes (D1) of all packaging bodies to be manufactured and the product attribute information (P1) of all packaging bodies, in a correlated state. The management device 300 is configured to identify and output the product attribute information (P1) correlated with the read identification code (D1) by referencing the identification code (D1) received as input data by the data receiving unit 310 and the identification code (D1) and product attribute information (P1) pre-stored in the attribute information storage unit 331. As shown in FIG. 13 , the attribute information storage unit 331 may be provided within a storage device 330. The storage device may be implemented within the management device 300 or an external device, and may be what is known as "cloud storage" or "online storage." 13 , the data processing unit 320 performs the above-described identification, and the identified product attribute information (P1) may be output from the data transmission unit 340. The output product attribute information (P1) may be sent to, for example, a terminal computer and displayed on its display device.

[0126] The components of the management device 300 (e.g., the data receiving unit 310, data processing unit 320, storage device 330, attribute information storage unit 331, and data transmission unit in the example of FIG. 13 ) may be constructed by combining electronic circuits, electric circuits, or independent processing devices. However, it is preferable to configure these components using a computer and a program executed by the computer. The technology for storing the identification code and product attribute information in association with each other and outputting the product attribute information corresponding to the input identification code (e.g., the operation of the data processing unit) can refer to conventionally known relational database technology, search technology, and traceability technology. The management device 300 may be the above-mentioned web server, a server on a local area network (LAN), a computer accessible from one or more terminal computers, or a standalone terminal computer.

[0127] In the present invention, when multiple items are stored in association with each other, this means that these items can serve as queries for searching each other. For example, if an "identification code" and "product attribute information" are stored in association with each other, a search using the "identification code" as a query will output the "product attribute information," and conversely, a search using the "product attribute information" as a query will output the "identification code."

[0128] The product attribute information (P1) of the package is the highest level information indicating the configuration of the package, and may be information only about typical items such as an identification code of the packaging material or an identification code of the manufacturing equipment included in the package, or may include information necessary for process control and traceability such as detailed identification codes of parts that make up the manufacturing equipment and product attribute information. The product attribute information (P1) can be input in advance using a data input device.

[0129] (Identification Code and Product Attribute Information of Packaging Manufacturing Equipment) In a preferred embodiment, the management system manages product attribute information of the packaging manufacturing equipment. An identification code (D10) of the manufacturing equipment may be displayed at any location on the manufacturing equipment so that it can be read by the reading device 400. While the identification code of the manufacturing equipment is not shown in FIG. 13 , it is preferable to display it in an appropriate position so that it can be distinguished from the identification codes of each component. The identification code (D10) may also be attached to the surface of the packaging material so that the contents can be identified before opening. In this embodiment, the product attribute information (P1) of each of all packages stored in the attribute information storage unit can include the identification code (D10) of each packaging equipment's manufacturing equipment and the product attribute information (P10) in a mutually associated state. The relationship between the product attribute information (P1), the identification code (D10), and the product attribute information (P10), as well as the relationship between the lower-level identification code and the product attribute information described below, can be established by referring to a conventionally known relational database association method, such as a table-based association (including a table-to-table association) or a matrix-based association such as (D10, P10). As in the case of the identification code (D1) described above, the management device 300 may be configured to reference the identification code (D10) received by the data receiving unit 310 and the identification code (D10) and product attribute information (P10) stored in the attribute information storage unit 331, and output the product attribute information (P10) associated with the received identification code (D10). This configuration may be configured by the data processing unit 320, the attribute information storage unit 331, and the data transmission unit 340, as described above.

[0130] The identification code (D1) of the package and the identification code (D10) of the manufacturing equipment can be assigned by the manufacturer of the package. It is preferable that the manufacturer of the package maintains records of product attribute information and detailed management information associated with the identification code (D1) of the package and the identification code (D10) of the manufacturing equipment. It is also preferable that the manufacturer of the package maintains records of the identification code (D1) of the package, the product attribute information (P1), the identification code (D10) of the manufacturing equipment, and the product attribute information (P10) in the attribute information storage unit 331 of the management device 300 via a terminal computer or the like.

[0131] In another aspect of the management system, the identification code (D1) of each package and the identification code (D10) of the manufacturing equipment (closed system portion) of each package may be the same. That is, since the closed system portion is an important item for the cell manufacturer, who is the user of the package, the identification code (D10) of the closed system portion may be used as the identification code of the package when ordering or delivering the package. In this case, the product attribute information (P1) of each package described above may also be the same as the product attribute information (P10) of each closed system portion, and the identification code and product attribute information of each packaging material may be associated with the identification code and product attribute information of each closed system portion as information on accessory parts subordinate to each closed system portion.

[0132] (Attribute Information of Substances Containered in Each Sealed Container) In a preferred embodiment, the management system manages attribute information of substances contained in each sealed container in each packaging manufacturing device. In each manufacturing device, an identification code (D20) of each substance contained therein can be displayed on each sealed container so as to be readable by the reading device 400. Although the identification codes of each substance are not shown in FIG. 13 , they are preferably displayed in an appropriate position on each sealed container. In this embodiment, the product attribute information (P10) of each packaging manufacturing device includes the identification code (D20) of each substance contained in each sealed container and the product attribute information (P20) in a mutually associated manner. The management device 300 can be configured to reference the identification code (D20) received by the data receiving unit 310 and the identification code (D20) and product attribute information (P20) stored in the attribute information storage unit 331, and output the product attribute information (P20) associated with the received identification code (D20). Such a configuration may be configured by the data processing unit 320, the attribute information holding unit 331, and the data transmission unit 340, as described above.

[0133] The product attribute information (P20) of the substance preferably includes information necessary for quality control and traceability in the process, such as the name of the substance, the date of production of the substance, the identification code assigned by the manufacturer of the substance at the time of delivery, the date of storage in a sealed container, the identification code of the sealed container, and the expiration date of the substance.

[0134] The substance identification code (D20) may be assigned by the manufacturer who places the substance in a sealed container. The manufacturer preferably maintains a record of product attribute information and other information associated with the substance identification code. The manufacturer preferably records the identification code (D20) and the associated product attribute information (P20) in the attribute information storage unit 331 of the management device 300 via a terminal computer or the like. The manufacturer who produced the substance preferably maintains a record of the detailed product attribute information associated with the identification code assigned to the substance at the time of delivery.

[0135] (Product Attribute Information of Components Constituting the Cell Manufacturing Apparatus) In a preferred embodiment, the management system manages product attribute information for each component constituting the packaging manufacturing apparatus. Each component may be labeled with its own identification code (D30) so that it can be read by the reading device 400. While the identification codes for each component are not shown in FIG. 13 , they are preferably displayed in an appropriate location on each component. In this embodiment, the product attribute information (P10) for each packaging manufacturing apparatus includes the identification code (D30) and the product attribute information (P30) for each component constituting the manufacturing apparatus, in a mutually correlated manner. The management device 300 is configured to reference the identification code (D30) received by the data receiving unit 310 and the identification code (D30) and product attribute information (P30) stored in the attribute information storage unit 331, and output the product attribute information (P30) associated with the received identification code (D30). Such a configuration may be configured by the data processing unit 320, the attribute information holding unit 331, and the data transmission unit 340, as described above.

[0136] Parts to be managed include all parts that may directly or indirectly affect cell production, such as packaging materials, airtight containers, connectors, piping components (such as soft tubing), and valves.

[0137] The product attribute information (P30) of the part preferably includes information necessary for quality control and traceability of the process, such as the name of the part, the date of manufacture of the part, the identification code assigned by the manufacturer of the part when it was delivered, and the expiration date of the part (the period during which the sterilization state is maintained).

[0138] The identification code (D20) of a part may be assigned by the manufacturer of the part. It is preferable that the manufacturer of the part maintain a record of product attribute information and other information associated with the identification code. Furthermore, if the part is an assembly including a sealed container, its inlet / outlet port connectors, tubes connected to each connector, and a connector attached to the end of the tube, the manufacturer assembling the assembly may assign an identification code to the assembly. It is also preferable that the manufacturer assembling the assembly record the identification code (D20) and the associated product attribute information (P20) in the attribute information storage unit 331 of the management device 300 via a terminal computer or the like. Regardless of the unit into which all the parts constituting each package are assembled, it is preferable that the identification code and its product attribute information of each part are associated with the identification code of the package and are traceable.

[0139] (Somatic Cell Attribute Information) In a preferred embodiment, the management system manages attribute information of the somatic cells processed by the package manufacturing apparatus. The attribute information of the processed somatic cells may be input as part of specification data by a cell manufacturer or the like. In a preferred embodiment, a code (D2) of the somatic cells or their donor in each container is displayed so as to be readable by a reading device on a container containing a solution containing somatic cells. The code of the somatic cells or their donor in each container is a unique code assigned to the somatic cells or their donor, and is synonymous with the above-mentioned identification code (a combination of numbers, letters, symbols, figures, etc., assigned so as to be unique to each object to be identified). As with the blood collection tube 30 illustrated in FIG. 13 , a container containing a solution containing somatic cells displays a code (D2) of the somatic cells or their donor in each container so as to be readable by a reading device. The code (D2) is assigned, for example, by a medical institution or the like that collected the solution containing somatic cells. The medical institution or the like preferably maintains a record associating the code (D2) with the donor's attribute information. When a user (cell manufacturer) receives a solution containing somatic cells, the user preferably records a code (D2) and associated attribute information (P2) in the attribute information storage unit 331 of the management device 300 via a terminal computer 410 or the like. At this time, the code (D2) and its attribute information (P2) are preferably associated with the identification code (D1) of the package used for processing the cells or the identification code (D10) of the manufacturing equipment. This allows the attribute information storage unit 331 to store each code (D2) and its respective attribute information (P2), and each code (D2) and its attribute information (P2) can be associated with each other. Furthermore, each code (D2) and its attribute information (P2) can be associated with the identification code (D1) of the package used for processing or the identification code (D10) of the manufacturing equipment.

[0140] The management device 300 can be configured to output attribute information (P2) associated with the received code (D2) by referencing the code (D2) received by the data receiving unit 310 and the identification code and attribute information stored in the attribute information storage unit 331, and to output the identification code (D1) of the package used for cell processing or the identification code (D10) of the cell manufacturing device for that package. This makes it possible to know, from the code (D2) of a solution containing somatic cells obtained from a patient, which package should be used for cell processing, and, from the identification code of a certain package, which patient's solution containing somatic cells should be processed using the manufacturing device for that package.

[0141] Attribute information (P2) of somatic cells (or their donors) includes the collection date, collection hospital, donor code, age, sex, type of solution containing the somatic cells (peripheral whole blood, urine, etc.), and administration date. However, from the perspective of protecting personal information and research ethics, the information that can be obtained by cell manufacturers is limited to information that does not identify the individual donor of the somatic cells, such as the donor code and sex.

[0142] (Attribute Information of Patients to Whom Produced Differentiated Cells Are to Be Administered) Preferably, the management system identifies the patient to whom cells produced by the packaging manufacturing apparatus are to be administered as the same patient who provided the somatic cells, enabling autologous transplantation of the cells. Also, preferably, the patient to whom cells produced by the packaging manufacturing apparatus of the present invention are to be administered is the same patient as the somatic cell donor, and the management system reduces management errors such as mix-ups during autologous cell transplantation. In another preferred embodiment, the management system manages attribute information of patients to whom differentiated cells produced by the packaging manufacturing apparatus are to be administered. A person who knows the attribute information of patients to whom differentiated cells are to be administered, such as a medical institution requesting the production of differentiated cells, preferably records the code (P3) of the patient to be administered with the differentiated cells in the attribute information storage unit 331 of the management device 300 via a terminal computer or the like, in association with the package identification code (D1) or the manufacturing apparatus identification code (D10). Thus, the attribute information storage unit 331 may store the code (P3) of the patient to whom cells produced by the manufacturing apparatus are to be administered. The code of the patient to whom the cells are to be applied (P3) can be related to the identification code of the packaging used for processing (D1) or the identification code of the manufacturing equipment (D10).

[0143] The management device 300 is configured to output a code (P3) of the patient to whom the manufactured cells are to be administered, by referencing the identification code (D1) or (D10) received by the data receiving unit 310 and the identification code and attribute information stored in the attribute information storage unit 331. This clarifies the relationship between the packaging or manufacturing device used for processing and the intended patient in autologous or allogeneic transplantation, and the manufactured cells can be administered to the intended patient without mix-up.

[0144] As described above, known cell processing devices (such as MiltenyiBiotec's CliniMACS Prodigy, Thermo Fisher Scientific's Gibco CTS Rotea Counterflow Centrifugation System, Lonza's Cocoon system, and Cytiva's Xuri) are composed of a closed processing circuit section, a mechanism for operating it, and a control unit, and the closed processing circuit section is detachable from the mechanism and control unit that operate it and is a unit that can be replaced after each cell processing. In a preferred embodiment of the present invention, a packaged cell manufacturing device is provided as a detachable closed processing circuit section in such a known cell processing device.

[0145] In this case, the main body (mechanical parts, housing parts, etc.) of the known cell processing device, excluding the closed-system processing circuit part, is assigned an identification code (D11) for the cell processing device, and the identification code (D11) is displayed so as to be readable by a reading device. This allows the known cell processing device to also be managed by the management device 300. The attribute information storage unit 331 of the management device 300 stores the identification code (D11) of the cell processing device and its product attribute information (P11) by prior input. Examples of the product attribute information (P11) include the name of the cell processing device, the name of the manufacturer, the product number, and the management number. The identification code (D11) of the cell processing device and its product attribute information (P11) are associated with each other and with the identification code (D1) of the package used for processing or the identification code (D10) of the cell manufacturing device of the package, and are stored in the attribute information storage unit 331. The management device 300 is configured to reference the identification code (D1) or (D10) received by the data receiving unit and the identification code (D11) and product attribute information (P11) stored in the attribute information storage unit, and output the identification code (D11) and the product attribute information (P11). As described above, this configuration may be comprised of the data processing unit 320, attribute information storage unit 331, and data transmission unit 340. This makes it possible to track which cell processing device was used in managing the cell manufacturing process.

[0146] (Confirmation of Package Specifications by a Management System) In a preferred embodiment, the management system manages whether the package has been manufactured according to the specifications. In this embodiment, the package manufacturing apparatus according to the present invention may be formed as the detachable closed-system processing circuit portion of a cell processing apparatus such as that shown in FIG. 16. As described above, examples of such cell processing apparatus include the CliniMACS Prodigy from Miltenyi Biotec, the Gibco CTS Rotea Counterflow Centrifugation System from Thermo Fisher Scientific, the Cocoon from Ronza, and the Xuri from Cytiva, but it may also be a cell processing apparatus specially designed for the present invention. Such a cell processing apparatus may include a detachable closed-system processing circuit portion, a mechanism for operating the detachable closed-system processing circuit portion, and a control unit. In this embodiment, the package manufacturing apparatus may be configured as the detachable closed-system processing circuit portion. As illustrated in FIG. 13, the control unit of the cell processing apparatus 500 (the internal configuration of the cell processing apparatus is not shown) may be connected to a management device 300 via the Internet for data communication.

[0147] In the preferred embodiment described above, the management device 300 may further include a specification data storage unit 332. The management device 300 may include the specification data storage unit 332 in the storage device 330. The specification data storage unit 332 can store specification data (S1a) for all packages to be manufactured. As described below, the specification data (S1a) is created by the user, who is the cell manufacturer, according to the cells to be manufactured, and may include the following items: However, from the perspective of personal information protection and research ethics, the attribute information of the donor of the solution containing somatic cells used in cell manufacturing is limited to information that does not identify the individual donor of the somatic cells, such as the donor's code and gender, which the cell manufacturer can obtain; attribute information of the solution containing somatic cells used in cell manufacturing (blood, urine, etc.) or the donor; product attribute information of the package or manufacturing device (information on the material of each sealed container connected to the processing container); date of use of the manufacturing device (date on which cells are manufactured); identification information of the cell processing device in which the manufacturing device is installed as a processing circuit part (device number, control number, etc.); product type (serial number).

[0148] In the preferred embodiment described above, the management system may have a data input device for inputting the specification data (S1a). As illustrated in Fig. 13, a terminal computer 410 may function as the data input device. Also, in the embodiment described above, all of the packages to be manufactured may be assembled based on the respective specification data (S1a).

[0149] The specification data (S1a) can be created by the user of the packaging, who is the cell manufacturer, according to the cells to be produced. The created specification data (S1a) can be stored in advance in the specification data storage unit 332 of the management device 300 via a data input device. The user of the packaging can send the specification data (S1a) to the packaging manufacturer via the Internet, etc. The packaging manufacturer can send part or all of the specification data (S1a) to the manufacturers of each component via the Internet, etc. Alternatively, the user of the packaging may send part or all of the specification data (S1a) to the packaging manufacturer and the manufacturers of each component simultaneously.

[0150] The manufacturer of each part can manufacture each part based on the specification data (S1a). To ensure traceability, the manufacturer of each part preferably displays an identification code on each part and stores a record of the identification code and product attribute information. The manufacturer of each part also preferably records the identification code and product attribute information in the attribute information storage unit 331 of the management device 300 via a terminal computer or the like. The manufacturer of each part delivers the manufactured parts to the manufacturer of the packaging body.

[0151] The packaging manufacturer can use the delivered components to manufacture the packaging based on the specification data (S1a). It is also preferable for the packaging manufacturer to display identification codes on the packaging and manufacturing equipment, and to store records of each identification code and product attribute information, to ensure traceability. It is also preferable for the packaging manufacturer to record the identification codes and product attribute information for the packaging and manufacturing equipment in the attribute information storage unit 331 of the management device 300 via a terminal computer or the like. The packaging manufacturer can deliver the manufactured packaging to the user (cell manufacturer).

[0152] In the preferred embodiment described above, the management device 300 can maintain the current date through data communication with a time server or the like on the Internet. On the day of cell production, the user can input actual specification data (S1b) containing items corresponding to the previously input specification data (S1a) into the management device 300 via a data input device. The actual specification data (S1b) includes at least attribute information of the solution containing somatic cells or the donor used to produce the cells, product attribute information of the packaging or production device used to produce the cells, the date of the day, and identification information of the cell processing device to be used. The management device 300 can receive the input specification data (S1b) via a data receiving unit. The management device 300 may be configured to compare the specification data (S1b) received via the data receiving unit with the specification data (S1a) previously stored in the specification data storage unit, and, if the two data match, output a signal indicating the match. Upon receiving this signal, the terminal computer may be configured to display a symbol or character indicating "match" on a display device, or to sound a sound indicating "match," or to notify the user of the match. This prevents the user from using a manufacturing device for a package that differs from the specification data (S1a) when manufacturing cells, and also prevents errors in the manufacturing date. Furthermore, it also prevents the user from using a solution containing somatic cells that differs from the specification data (S1a).

[0153] In a more preferred embodiment, as illustrated in FIG. 13 , the control unit (not shown) of the cell processing device 500 to be used and the management device 300 can be connected to each other so as to enable data communication. The control unit of the cell processing device 500 can be configured to receive the above-mentioned “signal indicating a match” output from the management device 300 and to enable start-up of the cell processing device 500 only upon receiving the “signal indicating a match.” “Enable start-up of the cell processing device 500” means allowing the user to start the cell processing device 500, for example, by enabling input of a start signal to start the cell processing device 500, rather than immediately starting the cell processing device 500 upon receiving the “signal indicating a match.” This prevents the user from using a manufacturing device with a package that differs from the specification data (S1a) when manufacturing cells, thereby preventing errors in the manufacturing date. Furthermore, it can also prevent the user from using a solution containing somatic cells that differs from the specification data (S1a).

[0154] As described above, in a preferred embodiment of the package manufacturing apparatus according to the present invention, a sensing probe is provided at the tip of the discharge side of the processing container or the discharge port 102, and the oxygen concentration and pH of the contents are measured by the sensing probe. Data on the oxygen concentration and pH of the contents measured by such a sensor as the sensing probe may be input and stored in the attribute information storage unit 331 or other data storage unit of the management device 300, for example, in association with the product attribute information (P10) of the manufacturing apparatus. In this way, the management system according to the present invention also functions as a system for recording and managing the manufacturing conditions during cell manufacturing.

[0155] (Preferred mode for providing the package to a cell manufacturer) Figure 14 is a block diagram illustrating the order and delivery flow in the manufacturing process of the package. In Figure 14, symbols h1 to h3 indicate medical institutions that perform cell therapies such as autologous transplants. Cell manufacturers g1 to g4 are manufacturers that process cells using cell processing equipment, and component manufacturers e1 to e4 are specialists that manufacture each element (including detailed parts and units assembled from parts) that make up the closed system, divided by field. Although not shown in Figure 14, a component manufacturer may order and obtain components to be included in the element to be manufactured from another component manufacturer.

[0156] The block diagram illustrated in FIG. 14 also illustrates a method for providing a package (or a method for manufacturing the package). As illustrated in FIG. 14, the package supply method (or package manufacturing method) involves a device assembler f1 positioned between cell manufacturers g1-g4 and component manufacturers e1-e4. The supply method includes the steps of: the device assembler placing an order for components and / or parts with a designated component manufacturer based on specification data regarding the closed system portion issued by the cell manufacturer; and the device assembler assembling the closed system portion using the components and / or parts delivered by the component manufacturer in accordance with the order and based on the specification data, packaging the closed system portion as the package, and providing (delivering) the package to the cell manufacturer. The cell manufacturer then installs the provided closed system portion in the device body of a designated cell processing device to manufacture cells. The specification data regarding the closed system portion is determined by the cell manufacturer in response to a cell order received from a medical institution, as described below.

[0157] The numbers of medical institutions, cell manufacturers, device assemblers, and element manufacturers are not limited to those shown in Figure 14 and may each be one or more. Since the closed system portion contains multiple elements and the materials and parts (liquid culture medium, reagents, containers (bags), connecting pipes, joints, etc.) that make up these elements span multiple fields, there are usually multiple element manufacturers. There may also be multiple medical institutions that perform autologous transplants and multiple cell manufacturers that produce cells for autologous transplants. The number of device assemblers and element manufacturers may be increased or decreased as appropriate depending on the demand for the closed system portion.

[0158] The cell manufacturer and the device assembler may each be an individual, a company, or an organization, and are preferably separate business entities. The separate entities may be different business groups or divisions within the same company or corporation with different profit margins, or they may be independent companies or corporations. In particular, if the cell manufacturer and the device assembler are independent companies or corporations, the cell manufacturer no longer needs facilities or personnel to prepare reagents and other materials in advance, allowing them to focus on cell production, reducing risk and facilitating entry into the cell manufacturing business. From the perspective of regenerative medicine market development, each company can divide up roles in their areas of expertise, allowing many companies to enter the market. From the perspective of component manufacturers, while the market is still in the early stages of development, production lots may be small and the unit price of packages may be high, the device assembler can establish a system to manufacture and sell packages that can be delivered to multiple cell manufacturers, ensuring a certain number of lots. Furthermore, from the perspective of patients and medical institutions, such a system has the advantage of reducing total medical costs.

[0159] The process from a medical institution ordering cells to the delivery of the cells to the medical institution is, for example, as indicated by the arrows in Figure 14, as follows: (1) A medical institution (e.g., h1) performing autologous transplantation orders cells necessary for the patient's treatment from a cell manufacturer (e.g., g1). At this time, the medical institution h1 communicates the patient's identification code to the cell manufacturer g1. The medical institution h1 also collects somatic cells necessary for cell production from the patient using a blood collection device or the like described below, and sends the blood collection device or the like containing the somatic cells to the cell manufacturer g1. (2) Upon receiving an order from the medical institution h1, the cell manufacturer g1 selects a cell processing device suitable for producing the ordered cells, determines the configuration of each part of the closed system used in the cell processing device, and creates specification data defining the configuration. (3) The cell manufacturer g1 orders the device assembler f1 to manufacture the closed system, and issues (sends) the specification data for the created closed system to the device assembler f1. This issuance may be performed by uploading the specification data to a shared folder in the management device (Internet server) and notifying the management device of the completion, or by directly transmitting the specification data. (4) The device assembler f1 orders the elements to be produced in a shared folder in the management device and sends the specification data to each of the necessary element manufacturers e1 to e4. This specification data may be sent by uploading the specification data to a shared folder in the management device and notifying the management device of the completion, or by directly transmitting the specification data. The sending of the specification data may also serve as an order. The specification data may be sent directly from the cell manufacturer g1 to the element manufacturer. Each element manufacturer may receive the overall specification data issued by the cell manufacturer g1, or may receive specification data for each element to be produced. (5) Each element manufacturer e1 to e4 produces the elements to be produced based on the specification data. An identification code associated with product attribute information is displayed on the produced elements. The identification code may be a two-dimensional symbol such as a QR Code (registered trademark). The elements are packaged in a sterile manner and delivered to the equipment assembler f1. (6) The equipment assembler f1 receives the necessary elements from each of the element manufacturers e1 to e4 and assembles the closed system parts in accordance with the specification data.The closed system part also incorporates a blood collection device containing somatic cells. The assembled closed system part displays the above-mentioned identification code (D10) for the closed system part, which is related to the product attribute information or identification codes of all elements used. This identification code (D10) includes the patient's identification code. The identification code is preferably a two-dimensional symbol such as a QR code (registered trademark) (the same applies to the other identification codes described below). (7) The device assembler f1 aseptically packages the assembled closed system part in packaging material to produce a package according to the present invention and delivers it to the cell manufacturer g1. The package displays the identification code for the closed system part or the associated package identification code. (8) The cell manufacturer g1 attaches the closed system part in the package to the device main body of the cell processing device to produce the desired cells. (9) The cell manufacturer g1 displays an identification code containing information about the produced cells on a sealed container containing the produced cells and aseptically sends the sealed container to the medical institution h1. The cell information includes information about the type of cell, the manufacturing history of the cell (such as the manufacturing date, factors involved in manufacturing, and information about the cell processing equipment), and information about the raw somatic cells (including the patient's identification code). At this time, it is essential that the information (information about the target cells, patient's identification code (= somatic cell information)) received when the initial order was placed from medical institution h1 and the information (information about the manufactured cells, information about the somatic cells used as raw material (= patient's identification code)) included in the identification code displayed on the sealed container containing the cells to be delivered to medical institution h1 match each other, and that the above information is correctly attached to the bag. Matching this information enables cell therapy without errors such as mix-ups.

[0160] The blood collection device in the logistics step (1) may be, for example, the blood collection device illustrated in FIG. 6 , but may also be a sealed container that can accommodate collected somatic cells and can be connected to a closed system. The blood collection device may be included in a package, in which case the blood collection device may be sent from the cell manufacturer g1 to the medical institution h1. Alternatively, the medical institution may retain the blood collection device in advance. In either case, the cell manufacturer g1, upon receiving the order, notifies the medical institution h1 of the date and time of cell production. The medical institution h1 collects somatic cells from the patient using the blood collection device, so that the somatic cells can be provided on the date and time of cell production. The medical institution h1 then displays the patient's identification code and necessary information (such as that the cells are peripheral blood or that they have been collected from a specific site) on the blood collection device and sends it to the cell manufacturer in a sterile manner.

[0161] The specification data preferably includes at least information on the somatic cell donor (especially the patient's identification code), information on the cell processing device used, information on the configuration of the closed system, and the date of use of the closed system (start date and time of cell production). The specification data also preferably includes specifications for each element, such as the culture medium container and the first supply container, specifications for the connecting pipelines, and specifications for the layout of the connecting pipelines to which the culture medium container and the first supply container are connected.

[0162] In the logistics step (6), an identification code is displayed on the assembled closed system part, and information on the somatic cell donor included in the specification data and information on the actual configuration of the manufactured cell manufacturing device can be obtained through the identification code from the separately provided management device described above or a process management device described below. It is preferable that the information on the actual configuration of the manufactured closed system part is associated with each item of information on the configuration of the closed system part included in the specification data and sequentially recorded in the memory device of the management device.

[0163] 4. Quality control system for the closed system portion of the package Next, the quality control system according to the present invention (hereinafter also referred to as the quality control system) will be described with reference to the process flow diagram shown in Figure 14 and the block diagram shown in Figure 15. The quality control system is a system for managing the manufacturing process of the closed system portion (cell manufacturing apparatus) included in the package according to the present invention, and for managing the quality of the closed system portion.

[0164] As explained above using Figure 14, in the manufacturing process of the package, a device assembler is positioned between the cell manufacturer and the component manufacturer, and the manufacturing process includes a component manufacturing process and a device assembly process. In the component manufacturing process, each of the multiple components that make up the closed system portion of the package is manufactured by a component manufacturer in the respective technical field. Then, in the device assembly process, the components manufactured in the component manufacturing process are collected and assembled into the cell manufacturing device by a device assembler. The quality control system records data on orders and products (components, closed system portions) at each process, clarifies the history of the raw somatic cells, materials, and parts involved in the manufactured cells, and increases the reliability of the cells.

[0165] As illustrated in FIG. 15 , the quality control system includes a process control device 300a and multiple terminal devices (not shown). For ease of illustration, the number of medical institutions, cell manufacturers, and device assemblers is set to one, and the number of component manufacturers is set to two (e1, e2). The multiple terminal devices are connected to the process control device so as to enable data communication. Although the terminal devices are not shown in FIG. 15 , each of the multiple terminal devices is arranged for use by the cell manufacturer g1, the device assembler, and each component manufacturer. This allows the cell manufacturer, device assembler, and component manufacturer to communicate with the process control device 300a, as shown in FIG. 15 .

[0166] As explained above, the closed system portion is assembled based on specification data indicating its configuration. The specification data is issued by the cell manufacturer g1. After receiving an order for the production of target cells for patient treatment from the medical institution h1, the cell manufacturer selects a cell processing device according to the production of the target cells and designs the specifications of the closed system portion. Therefore, the specification data includes information about the selected cell processing device, and is designed so that the closed system portion has a configuration for producing the target cells and is compatible with the device body of the cell processing device. Furthermore, the specification data is associated with the patient's identification code. Furthermore, it is preferable that the specification data be associated with information about the somatic cells (such as information that they are the patient's peripheral blood).

[0167] The specification data is stored in the storage device 330a of the process control device 300a. In the example of FIG. 15, the specification data is stored as a table in a predetermined storage area of ​​the storage device 330a. The table associates the specification data items (xxxxxa to xxxxxf) with the design data (yyyyya to yyyyyf) that defines the configuration of each item so that they correspond in order. Furthermore, the specification data stored as the table is associated with a patient identification code (zzzzzzzzz). The design data (yyyyya to yyyyyf) may be the product attribute information described above.

[0168] The process control device 300a receives specification data and the patient identification code associated therewith from the cell manufacturer g1 or the device assembler f1 via their respective terminal devices, and stores them in the memory area 330a.

[0169] Furthermore, the process control device 300a secures a memory area for storing actual data. This actual data corresponds to each item of the specification data for each configuration of the closed system portion actually manufactured. This memory area may be secured automatically or may be created by the cell manufacturer g1 or the device assembler f1. In the example of FIG. 15, the memory area for the actual data is provided as blank columns (areas with no data written) in the table corresponding to the specification data items (xxxxxa to xxxxxf), but the manner in which each data is associated and stored is not limited.

[0170] Each element manufacturer (e1, e2) that receives a manufacturing order from the equipment assembler f1 manufactures each element based on the specification data and transmits actual data of each element to the process control device 300a. The process control device 300a receives the actual data of each element and stores it in a storage area for actual specification data (the blank field of "actual data" shown in FIG. 15).

[0171] The equipment assembler f1 assembles a closed system part using each element delivered by the element manufacturers (e1, e2). The equipment assembler f transmits data relating to the overall layout of the assembled closed system part to the process control device 300a. The process control device 300a receives the data relating to the overall layout and stores it in a storage area for actual specification data (the blank field for "actual data" shown in FIG. 15). In this way, all actual data corresponding to the specification data is recorded.

[0172] In this state, the process control device 300a determines whether the original specification data and the actual specification data match and outputs the determination result, allowing the device assembler f1 and the cell manufacturer g1 to confirm that the assembled closed system part has the configuration ordered by the cell manufacturer g1.

[0173] The process control system may utilize the configuration of the control system described above, and the process control device 300a shown in Fig. 15 can utilize the control device 300 shown in Fig. 13. Each of the terminal devices can utilize the terminal computer 410 shown in Fig. 13. The terminal computer is preferably a tablet computer or the like, and preferably has a function for reading two-dimensional symbols such as QR Code (registered trademark).

[0174] The data management configuration shown in FIG. 15 is one example, and data indicating the configuration of each manufactured element may be recorded in a two-dimensional symbol and displayed on each element.

[0175] It is preferable that an identification code indicating the respective identification information is displayed on the surface of the packaging material of the package, on a representative part of the closed system portion, and on each element. In particular, if the identification code is a two-dimensional symbol such as a QR code (registered trademark), it can include the URL of a process control device installed as a server computer on the Internet. This makes it possible to easily access the table stored in the storage device of the process control device by using the two-dimensional symbol and the reading function of a terminal device.

[0176] The packaging of the present invention and the cell manufacturing method using the same eliminate the conventional process of aseptically preparing many types of substances and containers, significantly reducing the work of connecting many types of substance supply bags to specified ports when operating the cell processing device, and reducing the occurrence of incorrect substance supply bags, incorrect installation positions, and / or incorrect soft tubing connections, etc. This reduces cell manufacturing errors and enables the stable production of desired cells.

[0177] Furthermore, the management system of the present invention allows the manufacturing process of the package of the present invention to be preferably managed, and the use of packages that do not meet the specifications is prevented.

[0178] Furthermore, by placing an equipment assembler between the cell manufacturer and the component manufacturer and by using a computer-controlled quality control system, the cell manufacturer can obtain the closed system parts on the day of cell production or at an appropriate date before that, and is free from the hassle and errors involved in assembling the closed system parts.

[0179] This application is based on Japanese Patent Application No. 2023-184314 (filing date: October 26, 2023) and Japanese Patent Application No. 2024-117090 (filing date: July 22, 2024), the contents of which are incorporated in their entirety herein.

[0180] 1 Packaging body 10 Cell manufacturing device 20 Packaging material 100 Processing container 101-105 Processing container port 210 Culture medium container 220 First supply container 230 Second supply container

Claims

1. A package for a cell manufacturing device, the package comprising a cell manufacturing device and packaging materials, the cell manufacturing device comprising, as components for manufacturing artificial pluripotent stem cells, a processing vessel, at least one culture medium container for accommodating a liquid culture medium, and a first supplying vessel for accommodating a fluid containing a reprogramming factor, the culture medium container and the first supplying vessel being either (i) connected to the processing vessel via a connecting pipeline that can be switched between a communicating state and a non-communicating state, or (ii) connectable to the processing vessel via the connecting pipeline and via a unique connector configured to prevent erroneous connection between the containers, so that their respective contents are sent to the processing vessel while maintaining a closed system, the processing vessel having at least an openable / closable injection port for receiving a solution containing somatic cells from the outside, and an openable / closable discharge port for discharging the contents, the processing vessel, the culture medium container, and the first supplying vessel being sealed containers, and the cell manufacturing device being packaged in the packaging materials in a sterilized state.

2. The packaging of the cell manufacturing apparatus described in claim 1, wherein the processing container is configured to separate somatic cells to be used in the production of artificial pluripotent stem cells from a solution containing somatic cells injected through the injection port, and is configured to discharge components other than the somatic cells to the outside of the processing container, leaving the somatic cells to be processed inside the processing container, and the somatic cells left inside the processing container are processed inside the processing container.

3. The packaging of the cell manufacturing apparatus described in claim 2, wherein the processing vessel is configured to separate somatic cells used in the production of induced pluripotent stem cells by continuous centrifugation.

4. The cell manufacturing apparatus according to any one of claims 1 to 3, wherein the cell manufacturing apparatus has one or more second supply containers for containing a fluid containing a differentiation inducer for artificial pluripotent stem cells as a component for manufacturing differentiated cells from artificial pluripotent stem cells manufactured in the processing container, the second supply containers being sealed containers, and the second supply containers are either (iii) connected to the processing container via a connecting pipe that can be switched between a communicating state and a non-communicating state, or (iv) connectable to the processing container via a connecting pipe that can be switched between a communicating state and a non-communicating state, and via a unique connector configured to prevent erroneous connection between the two containers, so that the contents of the second supply containers are sent to the processing container while maintaining a closed system.

5. A packaging body for a cell manufacturing apparatus described in any one of claims 1 to 4, wherein one or both of the culture medium container and the first supply container are each separated from the cell manufacturing apparatus and each packaged in a different packaging material, such that the package is separated into two or more packages independent of each other.

6. A package for a cell manufacturing device as described in any one of claims 1 to 5, wherein the cell manufacturing device packaged in the packaging material in the package is a closed system processing circuit portion included in a cell processing device for processing the somatic cells, the cell processing device is configured to have the closed system processing circuit portion and an apparatus main body portion, the apparatus main body portion has an operating mechanism for operating the closed system processing circuit portion and a control unit for controlling the operating mechanism, the closed system processing circuit portion is detachable from the apparatus main body portion while maintaining the closed system, and is assembled as a closed system when removed from the apparatus main body portion, and the closed system processing circuit portion attached to the apparatus main body portion is operated by the operating mechanism under the control of the control unit, whereby the somatic cells are processed inside the closed system processing circuit portion.

7. A packaging for a cell manufacturing equipment as described in claim 6, wherein the cell manufacturing equipment is assembled as a closed system by an equipment assembler separate from a cell manufacturer that manufactures cells using the cell processing equipment based on specification data issued by the cell manufacturer, packaged as the package, and provided to the cell manufacturer.

8. The packaging of the cell production device described in claim 7, wherein the cell manufacturer and the device assembler are different entities.

9. A packaging for a cell manufacturing device as described in claim 7 or 8, wherein the specification data includes at least information about the somatic cell donor, information about the device main body part to which the cell manufacturing device is to be installed as a closed system processing circuit part, information about the configuration of the cell manufacturing device, and the date of use of the cell manufacturing device; the cell manufacturing device displays an identification code that can be read by a reading device, and through the identification code, information about the somatic cell donor contained in the specification data and information about the actual configuration of the manufactured cell manufacturing device can be obtained from a separately provided management device; and the information about the actual configuration of the cell manufacturing device is stored in a memory device of the management device in correspondence with the information about the cell manufacturing device contained in the specification data.

10. A cell manufacturing method using a package of a cell manufacturing apparatus according to any one of claims 1 to 9, comprising: a step of preparing the cell manufacturing apparatus removed from the package; and a step of manufacturing induced pluripotent stem cells in the processing vessel of the cell manufacturing apparatus, the step of manufacturing the induced pluripotent stem cells comprising: a step (s10) of injecting a solution containing the somatic cells into the processing vessel through the injection port, and sending a liquid medium from the medium vessel into the processing vessel, and sending a fluid containing reprogramming factors from the first supply vessel into the processing vessel, thereby bringing the reprogramming factors into contact with the somatic cells in the liquid medium in the processing vessel; and a step (s20) of culturing the somatic cells in the liquid medium in the processing vessel to establish induced pluripotent stem cells.

11. The cell manufacturing method of claim 10, wherein the packaging body of the cell manufacturing apparatus is the packaging body of claim 2 or 3, and in the step (s10), a solution containing the somatic cells is injected into the processing vessel through the injection port, then the somatic cells to be used in the production of induced pluripotent stem cells are separated in the processing vessel and components other than the somatic cells are discharged to the outside of the processing vessel, leaving the somatic cells to be processed inside the processing vessel, then a liquid culture medium is sent from the culture medium container and a fluid containing reprogramming factors is sent from the first supply container, thereby contacting the somatic cells in the liquid culture medium in the processing vessel with the reprogramming factors.

12. The cell manufacturing method of claim 11, wherein the packaging of the cell manufacturing apparatus is the packaging of the cell manufacturing apparatus described in claim 4, and further comprises, after the step (s20), a step (s30) of sending a fluid containing a differentiation inducer for artificial pluripotent stem cells from the second supply container into the processing container, thereby forming differentiated cells in the processing container.

13. A management system for packaging of a cell manufacturing apparatus as claimed in any one of claims 1 to 9, the management system having a management device and a reading device, wherein an identification code (D1) of each packaging is displayed on one or both of the cell manufacturing apparatus and the packaging materials surrounding it in all of the packaging to be manufactured so as to be readable by the reading device, the reading device is for reading the identification code, the management device has a data receiving unit and an attribute information holding unit, the data receiving unit receives the identification code read by the reading device as input data, and the attribute information holding unit stores the identification code (D1) and product attribute information (P1) of each of the packaging bodies to be manufactured in a mutually associated state, and the management device is configured to refer to the identification code (D1) received by the data receiving unit and the identification code (D1) and product attribute information (P1) stored in the attribute information holding unit, and output the product attribute information (P1) associated with the read identification code (D1).

14. The management system described in claim 13, wherein the cell manufacturing apparatus displays an identification code (D10) of the cell manufacturing apparatus so that it can be read by the reading device, the product attribute information (P1) of each of the packages stored in the attribute information storage unit contains the identification code (D10) of each of the cell manufacturing apparatuses of each package and the respective product attribute information (P10) in a state in which they are associated with each other, and the management device is configured to refer to the identification code (D10) received by the data receiving unit and the identification code (D10) and product attribute information (P10) stored in the attribute information storage unit, and output the product attribute information (P10) associated with the received identification code (D10).

15. The management system described in claim 14, wherein each sealed container for holding a substance in the cell manufacturing apparatus is marked with an identification code (D20) for each substance held in each sealed container so as to be readable by the reading device, and each product attribute information (P10) of the cell manufacturing apparatus in each package includes an identification code (D20) for each substance held in each sealed container and each product attribute information (P20) in a state in which the identification code (D20) and the product attribute information (P20) are associated with each other, and the management device is configured to refer to the identification code (D20) received by the data receiving unit and the identification code (D20) and product attribute information (P20) stored in the attribute information storage unit, and output the product attribute information (P20) associated with the received identification code (D20).

16. A management system as described in claim 14 or 15, wherein each component constituting the cell manufacturing apparatus is marked with an identification code (D30) for each component so that it can be read by a reading device, and the product attribute information (P10) of each of the cell manufacturing apparatuses in each package contains the identification code (D30) for each component constituting the cell manufacturing apparatus and each product attribute information (P30) in a state in which they are correlated to each other, and the management device is configured to refer to the identification code (D30) received by the data receiving unit and the identification code (D30) and product attribute information (P30) stored in the attribute information storage unit, and output the product attribute information (P30) correlated to the received identification code (D30).

17. A management system as described in any one of claims 14 to 16, wherein containers holding a solution containing somatic cells to be processed by the cell manufacturing apparatus display a code (D2) of the somatic cells in each container or of their donor so that the code (D2) can be read by a reading device, the attribute information storage unit stores the codes (D2) and their respective attribute information (P2), the codes (D2) and the respective attribute information (P2) being associated with each other and with an identification code (D1) of a package used for processing or an identification code (D10) of the cell manufacturing equipment of the package, and the management device is configured to refer to the code (D2) received by the data receiving unit and the code and attribute information stored in the attribute information storage unit, to output the attribute information (P2) associated with the received code (D2), and to output the identification code (D1) of the package used for processing or the identification code (D10) of the cell manufacturing equipment of the package.

18. A management system as described in any one of claims 14 to 17, wherein the attribute information storage unit stores a code (D3) of a patient to whom the cells manufactured by the cell manufacturing apparatus should be applied and attribute information (P3) thereof, and the patient's code (D3) and attribute information (P3) are related to each other and to an identification code (D1) of a package used for processing or an identification code (D10) of the cell manufacturing apparatus of the package, and the management device is configured to output the code (D3) of the patient to whom the manufactured cells should be applied and attribute information (P3) thereof by referring to the identification code (D1) or identification code (D10) received by the data receiving unit and the identification code and attribute information stored in the attribute information storage unit.

19. The packaged cell manufacturing device is a detachable closed system processing circuit part in a cell processing device equipped with a detachable closed system processing circuit part and a mechanism and control unit for operating the detachable closed system processing circuit part, the identification code (D11) of the cell processing device is displayed on the part of the cell processing device excluding the closed system processing circuit part so as to be readable by a reading device, the attribute information storage unit stores the identification code (D11) of the cell processing device and its product attribute information (P11), the identification code (D11) of the cell processing device and its product attribute information (P11) are stored in the attribute information storage unit in association with each other and in association with the identification code (D1) of the package used for processing or the identification code (D10) of the cell manufacturing device of the package, and the management device is configured to output the identification code (D11) and its product attribute information (P11) by referring to the identification code (D1) or identification code (D10) received by the data receiving unit and the identification code and product attribute information stored in the attribute information storage unit. The management system according to any one of claims 14 to 18.

20. The cell manufacturing device in the package is a detachable closed-system processing circuit part in a cell processing device equipped with a detachable closed-system processing circuit part, a mechanism for operating the detachable closed-system processing circuit part, and a control unit, and the management device further has a specification data storage unit, which stores specification data (S1a) including at least attribute information of the solution containing somatic cells or the donor to be used, product attribute information of the package or the cell manufacturing device to be used, the date of use of the cell manufacturing device, and identification information of the cell processing device in which the cell manufacturing device is installed as the processing circuit part, the management system has a data input device for inputting the specification data, the package is assembled based on the specification data (S1a), and the management device stores the attribute information of the solution containing somatic cells or the donor to be used, the product attribute information of the package or the cell manufacturing device to be used, information on the date of cell production, and the identification information of the cell processing device to be used, which are input by the cell manufacturer through the reading device on the day the cells are produced. The management system according to any one of claims 13 to 19, configured to receive at least the included specification data (S1b) in a data receiving unit, and, when the specification data (S1b) received by the data receiving unit matches the specification data (S1a) stored in the specification data holding unit, output a signal indicating a match.

21. The management system described in claim 20, wherein the control unit of the cell processing device is configured to receive a signal indicating the match output from the management device, and is configured to enable startup of the cell processing device only when the signal is received.

22. A quality control system for a cell manufacturing device in a package according to any one of claims 7 to 9, wherein the manufacturing process of the package comprises: an element manufacturing process for each of a plurality of elements constituting the cell manufacturing device in the package, in which each of the elements is manufactured by an element manufacturer belonging to the technical field of the respective element; and an equipment assembly process in which an equipment assembler assembles the elements manufactured in the element manufacturing processes to form the cell manufacturing device; the quality control system comprises: a process control device; and a plurality of terminal devices connected to the process control device so as to be capable of data communication, the terminal devices being arranged for use by users of the cell manufacturing device, that is, the cell manufacturer, the equipment assembler, and each of the element manufacturers; the cell manufacturing device being assembled based on specification data indicating the configuration of the cell manufacturing device, the specification data being designed by a cell manufacturer who has received an order from a medical institution for the manufacture of target cells for the treatment of a patient, so that the cell manufacturing device has a configuration for manufacturing the target cells and is compatible with a cell processing device selected for manufacturing the target cells; the specification data is associated with an identification code of the patient, the process control device receives the specification data and the patient's identification code associated therewith from the cell manufacturer or equipment assembler through the terminal device, and stores it in a memory area; secures a memory area for storing actual specification data corresponding to the specification data in the cell manufacturing equipment that is actually manufactured; receives actual data of each element manufactured by each element manufacturer who has received a manufacturing order from the equipment assembler based on the specification data, from each element manufacturer, and stores it in the memory area for storing the actual specification data; receives data regarding the overall layout of the cell manufacturing equipment from the equipment assembler who has assembled the cell manufacturing equipment using each element delivered by each element manufacturer, and stores it in the memory area for storing the data; and determines whether the original specification data and the actual specification data match, and outputs the determination result.

23. The quality control system described in claim 22, wherein each of the terminal devices is provided with a function for reading an identification code, and an identification code indicating each of the identification information is displayed on the surface of the packaging material of the package and on each element of the cell manufacturing apparatus.

24. The quality control system according to claim 23, wherein the identification code is displayed in the form of a two-dimensional symbol.

25. The quality control system of any one of claims 22 to 24, wherein the cell manufacturer, the device assembler, and each of the component manufacturers are distinct entities.

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