JP2024051101A - Cell loading system and method for producing cell pharmaceutical preparation - Google Patents

Abstract

[Problem] To provide a cell filling system capable of efficiently and stably filling a storage container with a cell suspension, and a method for producing a cell pharmaceutical preparation using the same. [Solution] The cell filling system fills a cell suspension into a cell pharmaceutical preparation container, comprising: (A1) a cell pharmaceutical preparation container 10 having an internal space 11 and a communication part communicating with the internal space, (B1) a cell filling part 20 having a stopcock 21 for switching the flow of fluid and a tubular body 22 connecting the cell pharmaceutical preparation container and the stopcock, (C1) a manifold 30 having a branch part 31 connected to the cell filling part, (D1) an air suction means 40 for reducing the pressure in the internal space of the cell pharmaceutical preparation container, and (E1) a cell suspension container 50 containing a cell suspension. [Selected Figure] Figure 2

Description

The present invention relates to a cell filling system and a method for producing a cellular pharmaceutical preparation. More specifically, the present invention relates to a cell filling system that can efficiently fill a container with a cell suspension, for example when cells collected from a living body are frozen and stored as a cell suspension, and a method for producing a cellular pharmaceutical preparation using the same.

In the field of regenerative medicine, cells collected from living organisms, such as umbilical cord blood and stem cells, are sometimes used. After being collected from the living organism, these cells are frozen and stored as a cell suspension. When freezing and storing such cell suspensions, the volume of each container is relatively small, and so the suspension must be divided and filled into multiple containers.

Various types of containers for cryopreserving cell suspensions have been proposed, but a typical one is one that has a structure including, for example, a flexible resin bag with an internal space and a tubular connection part that communicates with the internal space. For each container, the cell suspension is filled into the internal space of the container through the connection part, for example, using a syringe, and after filling, the connection part is sealed by heat sealing or the like.

International Patent Publication WO2015/147077

However, if there is a large amount of gas in the container when the cell suspension is filled into the container, there is a risk that the cell viability will decrease and the container will be damaged when the cell suspension is frozen and stored. In addition, the operation of connecting and disconnecting a syringe or the like to each individual container to fill the container is not only cumbersome and inefficient when filling many containers, but also increases the possibility of contamination due to frequent connection and disconnection operations.

For example, Patent Document 1 and the like have proposed a container structured to have two or three internal spaces that are partitioned from one another and communicated by a communication flow path. The method of filling this container with a cell suspension includes connecting a pressure reducing device such as an air pump or syringe pump to a cell injection port that opens the first internal space to the outside, reducing the pressure inside, disconnecting the cell injection port from the pressure reducing device, and injecting the cell suspension through the cell injection port. It also shows that the cell suspension is moved from the first internal space through the communication passage to the second and third internal spaces, and then the communication flow path is sealed by heat fusion, so that the cell suspension filled in each internal space can be used independently.

The configuration proposed in Patent Document 1 thus allows for the filling of two or three containers by a single injection of cell suspension, but does not provide sufficient effectiveness in terms of efficient filling of a larger number of containers. Patent Document 1 also describes that a pressure reducing device is connected to a cell injection port that opens the first internal space to the outside, and after a pressure reducing process, the cell injection port is disconnected from the pressure reducing device and the cell suspension is filled through the cell injection port. However, no configuration is disclosed for closing the cell injection port between the time the pressure reducing device is disconnected and the time the cell injection port is connected to the path for filling the cell suspension. For example, it is conceivable to use a known tube clip or the like to fasten the tube portion extending from the cell injection port, but this is difficult to operate and there is also doubt as to whether the reduced pressure state of the internal space of the container can be reliably maintained.

The operational efficiency of filling the cell suspension as described above is a concern not only in terms of workability but also in terms of the possibility of contamination, and improvements are desired.

In view of the above problems, the present invention aims to provide an improved cell loading system and a method for producing a cellular pharmaceutical preparation. Another objective of the present invention is to provide a cell loading system that can efficiently and stably load a cell suspension into a storage container, and a method for producing a cellular pharmaceutical preparation using the same.

The inventors conducted intensive research and studies to solve the above problems, and discovered that it is possible to reduce the pressure inside a container beforehand and to reliably maintain this state while filling the container with a cell suspension, thereby making it possible to achieve a state in which there is almost no gas inside the container. Furthermore, in order to perform this method efficiently, the inventors added new ideas to the structure of the flow path or filling system connected to the storage container, and created a flow path that can simultaneously reduce the pressure inside multiple containers, and a structure that allows the containers after depressurization to be attached and detached while maintaining the reduced pressure state. This has led to the discovery that cell filling can be performed easily and stably with regular operations, regardless of the number or variation of storage containers used to store cell suspensions, and has led to the completion of the present invention. More specifically, the present invention provides the following.

(1) A cell filling system for filling a cell suspension into a cell pharmaceutical preparation container, comprising:
(A1) a cellular pharmaceutical preparation container having an internal space and a communication part communicating with the internal space;
(B1) a cell loading section having a stopcock for switching the flow of a fluid and a tubular body connecting the cell pharmaceutical preparation container and the stopcock;
(C1) a manifold having a branch portion connected to the cell loading portion;
(D1) a suction means for reducing the pressure in the internal space of the cell pharmaceutical preparation container;
(E1) a cell suspension container containing a cell suspension;
A cell loading system comprising:

(2) The cell filling system described in (1), in which the manifold (C1) has at least two or more branching sections.

(3) The cell filling system described in (2), in which at least two or more of the branching sections are arranged in a straight line in the manifold (C1).

(4) A cell filling system according to any one of (1) to (3), in which a stopcock is provided at the branch of the manifold (C1).

(5) A cell filling system according to any one of (1) to (4), in which the cellular pharmaceutical preparation container (A1) has at least two or more communication parts.

(6) A cell filling system according to any one of (1) to (5), having a stopcock between one of the manifolds and the intake means.

(7) A cell filling system according to any one of (1) to (6), having a stopcock between one of the manifolds and the cell suspension container.

(8) A method for producing a cellular pharmaceutical preparation, comprising the steps of: reducing the pressure in the internal space of a cellular pharmaceutical preparation container having an internal space and a communication part that communicates with the internal space, using an air intake means; and filling the reduced pressure internal space of the cellular pharmaceutical preparation container with a cell suspension.

(9) The manufacturing method described in (8), in which the cellular pharmaceutical preparation container has a cell-filling section having a stopcock for switching the flow of fluid and a tubular body connecting the cellular pharmaceutical preparation container and the stopcock.

(10) In the step of reducing the pressure using the suction means, the internal space of the cell pharmaceutical preparation container is reduced in pressure via a manifold having a branch portion connected to the cell filling portion. The manufacturing method according to (9).

(11) The manufacturing method according to any one of (8) to (10), in which in the step of reducing the pressure using the suction means, the internal space of the cellular pharmaceutical preparation container is reduced in pressure via the cell filling section.

(12) The manufacturing method according to any one of (8) to (11), wherein the cell pharmaceutical preparation container comprises at least two or more containers.

(13) The manufacturing method according to any one of (9) to (12), further comprising a step of disconnecting the suction means from the manifold after reducing the pressure in the internal space of the cellular pharmaceutical preparation container.

(14) The manufacturing method according to any one of (9) to (13), further comprising a step of disconnecting the manifold from the pharmaceutical preparation container after reducing the pressure in the internal space of the cellular pharmaceutical preparation container.

(15) The manufacturing method according to any one of (10) to (14), wherein in the step of filling the cell suspension, the cell suspension is filled into the internal space of the cellular pharmaceutical preparation container via the cell filling section.

(16) The manufacturing method according to any one of (8) to (15), comprising a step of filling the internal space of the cellular pharmaceutical preparation container with the cell suspension and then sealing the cellular pharmaceutical preparation container.

According to the present invention, when a cell suspension is filled into a cellular pharmaceutical preparation container, a state in which almost no gas is present in the container can be efficiently achieved, and multiple containers can be depressurized at once, thereby improving work efficiency. Furthermore, by configuring the container after depressurization to be detachable while maintaining the depressurized state, the filling work can be divided among multiple people, improving work efficiency, and regardless of the number or fluctuation of the number of cellular pharmaceutical preparation containers used to store the cell suspension, easy and stable cell filling can be performed with regular operations.

FIG. 2 is a plan view showing the main configuration of one embodiment of the cell filling system. FIG. 13 is a plan view showing the main configuration of another embodiment of the cell filling system. FIG. 13 is a plan view (photograph in lieu of drawing) showing the use of yet another embodiment of the cell loading system.

The cell filling system and the method for producing a cell pharmaceutical preparation of the present invention will be described in detail below based on the embodiments.

(Cell medicine preparations)
The cellular pharmaceutical preparation is a pharmaceutical preparation containing a medically and/or pharma- ceutical acceptable cell suspension, specifically, a pharmaceutical preparation containing medically and/or pharma- ceutical acceptable cells and a pharma- ceutical acceptable drug. The cellular pharmaceutical preparation is preferably prepared using a cellular pharmaceutical preparation container according to the present invention described below.

The type of cells is not particularly limited as long as it is medically and/or pharmacologic acceptable, and examples thereof include pluripotent stem cells (induced pluripotent stem cells (iPS cells), embryonic stem cells (ES cells), GS cells, which are pluripotent stem cells derived from the testis, EG cells derived from fetal primordial germ cells, Muse cells derived from bone marrow, etc.), somatic stem cells (mesenchymal stem cells, hematopoietic stem cells, neural stem cells, etc. derived from bone marrow, adipose tissue, dental pulp, placenta, fetal membrane, umbilical cord blood, amnion, chorion, etc.), leukocytes, monocytes, granulocytes, lymphocytes (T cells, B cells, NK cells, etc.), megakaryocytes, macrophages, nerve cells, cardiomyocytes, cardiomyocyte progenitor cells, hepatocytes, liver progenitor cells, α cells, β cells, γ cells, fibroblasts, chondrocytes, corneal cells, vascular endothelial cells, vascular endothelial progenitor cells, pericytes, etc., and the cells may be in a form in which genes have been introduced or in which target genes on the genome have been knocked down.

The cells used in the present invention are typically human, but may also be derived from mammals such as rodents, e.g., mice, rats, hamsters, etc., primates, e.g., gorillas, chimpanzees, marmosets, etc., and even livestock or pets, e.g., dogs, cats, rabbits, cows, horses, sheep, goats, etc.

The pharmaceutically acceptable drug in the cell medicine preparation is not particularly limited as long as it can maintain the cells in a form that can be used as a medicine and is a medium that can be administered to animals such as humans. The pharmaceutically acceptable drug may be mixed with the cell medicine preparation at the stage of manufacturing the pharmaceutical preparation, or at the stage of administering the cell medicine preparation to a patient or subject. The pharmaceutically acceptable drug is not particularly limited, and examples thereof include physiological saline, electrolyte solutions, Ringer's solution, high-calorie infusion, glucose solution, water for injection, and amino acid electrolytes. In addition, the pharmaceutically acceptable drug may contain salts, vitamins, amino acids, polysaccharides, dimethyl sulfoxide, buffers, albumin, culture medium, cell cryoprotectants, and the like as necessary. In addition, it may contain immunosuppressants, antibiotics, albumin preparations, vitamin preparations, anti-inflammatory agents, and the like, which are components that have pharmaceutical activity.

Examples of the salts include, but are not limited to, salts of alkali metals such as lithium, sodium, and potassium; salts of alkaline earth metals such as calcium, barium, and magnesium; salts of aluminum, zinc, copper, and iron; ammonium salts; quaternary ammonium salts such as tetraethylammonium, tetrabutylammonium, methyltributylammonium, cetyltrimethylammonium, benzylmethylhexyldecylammonium, and choline; salts with organic amines such as pyridine, triethylamine, diisopropylamine, ethanolamine, diolamine, tromethamine, meglumine, procaine, and chloroprocaine; and salts with amino acids such as glycine, alanine, and valine.

Examples of vitamins include, but are not limited to, folic acid, niacinamide, pyridoxine hydrochloride, biotin, calcium D-pantothenate, riboflavin, vitamin B12, thiamine, vitamin A, and vitamin E.

The amino acids include, but are not limited to, all essential amino acids (L-tryptophan, L-leucine, L-lysine, L-phenylalanine, L-isoleucine, L-threonine, L-histidine, L-methionine, and L-valine), all non-essential amino acids (L-alanine, L-arginine, L-asparagine, L-aspartic acid, glycine, L-glutamine, L-glutamic acid, L-cysteine, L-serine, L-tyrosine, and L-proline), and other natural amino acids such as L-cystine.

Examples of the polysaccharides include, but are not limited to, water-insoluble polysaccharides such as cellulose, chitin, and chitosan, and water-soluble polysaccharides such as hyaluronic acid, gellan gum, deacylated gellan gum, rhamsan gum, diutan gum, xanthan gum, carrageenan, xanthan gum, hexuronic acid, fucoidan, pectin, pectic acid, pectinic acid, heparan sulfate, heparin, heparitin sulfate, keratosulfate, chondroitin sulfate, dermatan sulfate, rhamnan sulfate, alginic acid, and salts thereof.

The medium is not particularly limited as long as it is composed of a component composition that allows cells to survive and can be administered to animals such as humans. For example, BME medium, BGJb medium, CMRL1066 medium, Glasgow MEM medium, Improved MEM Zinc Option medium, IMDM medium (Iscove's Modified Dulbecco's Medium), Medium 199 medium, Eagle MEM medium, αMEM medium, DMEM medium (Dulbecco's Modified Eagle's Medium), Ham's F10 medium, Ham's F12 medium, RPMI medium, and the like can be used. 1640 medium, Fischer's medium, and mixed media thereof (e.g., DMEM/F12 medium (Dulbecco's Modified Eagle's Medium/Nutrient Mixture F-12 Ham)), CHO-S-SFM II (Life Technologies Japan, Inc.), Hybridoma-SFM (Life Technologies Japan, Inc.), eRDF Dry Powdered Media (Life Technologies Japan, Inc.), UltraCULTURE ^TM (BioWhittaker), UltraDOMA (trade name) (BioWhittaker), UltraCHO (trade name) (BioWhittaker), UltraMDCK (trade name) (BioWhittaker), etc. For example, media such as STEMPRO (registered trademark) hESC SFM (Life Technologies Japan, Inc.), mTeSR1 (Veritas), and TeSR2 (Veritas) can be used.

The cell cryoprotectant is not particularly limited, but examples thereof include CP-1 (manufactured by Kyokuto Pharmaceutical Industries Co., Ltd.), BAMBANKER (manufactured by Lymphotec Co., Ltd.), STEM-CELLBANKER (manufactured by Nippon Zenyaku Kogyo Co., Ltd.), ReproCryo RM (manufactured by ReproCell Co., Ltd.), CryoNovo (manufactured by Akron Biotechnology Co., Ltd.), MSC Freezing Solution (manufactured by Biological Industries Co., Ltd.), and CryoStor (manufactured by HemaCare Co., Ltd.).

Examples of the immunosuppressants include, but are not limited to, tacrolimus, cyclosporine, methotrexate, azathiprine, and 6-mercaptopurine. Examples of the biological agents include, but are not limited to, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab, brodalumab, tocilizumab, vedolizumab, filgotinib, golimumab, certolizumab pegol, abatacept, and etanercept.

Examples of the antibiotics include sulfa preparations, penicillin, phenethicillin, methicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, nafcillin, ampicillin, amoxicillin, cyclacillin, carbenicillin, ticarcillin, piperacillin, azlocillin, mexocillin, mecillinam, anginocillin, cephalosporin and its derivatives, oxolinic acid, amifloxacin, temafloxacin, nalidixic acid, piromidic acid, ciprofloxacin, cinoxacin, norfloxacin, perfloxacin, rozaxacin, ofloxacin, enoxacin, pipemidic acid, sulba Examples of suitable antibacterial agents include, but are not limited to, cyclopentamin, clavulinic acid, β-bromopenicillanic acid, β-chloropenicillanic acid, 6-acetylmethylene-penicillanic acid, cefoxazole, sultanpicillin, formaldehyde fodolate esters of adinocillin and sulbactam, tazobactam, aztreonam, sulfazetine, isosulfazetine, norcadicine, m-carboxyphenyl, methyl phenylacetamidophosphonate, chlortetracycline, oxytetracycline, tetracycline, demeclocycline, doxycycline, methacycline, and minocycline.

The anti-inflammatory agent includes, but is not limited to, 5-aminosalicylic acid preparations, steroid preparations, immunosuppressants, biological preparations, etc. Examples of the 5-aminosalicylic acid preparations include, but are not limited to, salazosulfapyridine, mesalazine, etc. Examples of the steroid preparations include, but are not limited to, cortisone, prednisolone, methylprednisolone, etc.

In addition to cells, the cell pharmaceutical preparation may also contain various additives for increasing storage stability, isotonicity, absorbency and/or viscosity, such as emulsifiers, dispersants, buffers, preservatives, humectants, antioxidants, chelating agents, thickeners, gelling agents, pH adjusters, etc.

Examples of the thickening agent include, but are not limited to, hydroxyethyl starch (HES), dextran, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropylcellulose, etc. The concentration of the thickening agent depends on the thickening agent selected, but can be set arbitrarily within the range of concentrations that are safe when administered to a patient or subject and achieve the desired viscosity.

The pH of the cellular pharmaceutical preparation of the present invention can be near neutral, for example, pH 6.5 or higher or pH 7.0 or higher, and can be pH 8.5 or lower or pH 8.0 or lower, but is not limited thereto.

The volume (mL) of a cellular pharmaceutical preparation is the volume when the cellular pharmaceutical preparation is prepared to have a cell concentration (cells/mL) that has been confirmed to be safe for a patient or subject when administered to the patient or subject, and is the volume per bag. The volume of the cell pharmaceutical preparation is not particularly limited, but may be, for example, 1 mL or more, 2 mL or more, 3 mL or more, 4 mL or more, 5 mL or more, 6 mL or more, 7 mL or more, 8 mL or more, 9 mL or more, 10 mL or more, 15 mL or more, 20 mL or more, 25 mL or more, 30 mL or more, 35 mL or more, 40 mL or more, 45 mL or more, 50 mL or more, 55 mL or more, 60 mL or more, 65 mL or more, 70 mL or more, 75 mL or more, 80 mL or more, 85 mL or more, 90 mL or more, 95 mL or more, 100 mL or more, or 5000 mL or less, 4000 mL or less, 3000 mL or less, 2000 mL or less, 1000 mL or less, 900 mL or less, 800 mL or less, 700 mL or less, 600 mL or less, 500 mL or less, 400 mL or less, 300 mL or less, 200 mL or less, or 150 mL or less.

The cell concentration (cells/mL) of a cellular pharmaceutical preparation is the concentration of cells contained in the cellular pharmaceutical preparation that, when administered to a patient or subject, can provide a therapeutic effect against a disease compared to a patient or subject not administered the cellular pharmaceutical preparation. The cell concentration of the cell pharmaceutical preparation is not particularly limited, and may be, for example, 1×10 ⁴ cells/mL or more, 2×10 ⁴ cells/mL or more, 3×10 ⁴ cells/mL or more, 4×10 ⁴ cells/mL or more, 5×10 ⁴ cells/mL or more, 6×10 ⁴ cells/mL or more, 7×10 ⁴ cells/mL or more, 8×10 ⁴ cells/mL or more, 9×10 ⁴ cells/mL or more, 1×10 ⁵ cells/mL or more, 2×10 ⁵ cells/mL or more, 3×10 ⁵ cells/mL or more, 4×10 ⁵ cells/mL or more, 5×10 ⁵ cells/mL or more, 6×10 ⁵ cells/mL or more, 7×10 ⁵ cells/mL or more, 8×10 ⁵ cells/mL or more, 9×10 ⁵ cells/mL or more, 1×10 ⁶ cells/mL or more, and also 1×10 ¹¹ cells/mL or less, 1×10 ¹⁰ cells/mL or less, 2×10 ⁹ cells/mL or less, 1×10 ⁹ cells/mL or less, 9×10 ⁸ cells/mL or less, 8×10 ⁸ cells/mL or less, 7×10 ⁸ cells/mL or less, 6×10 ⁸ cells/mL or less, 5×10 ⁸ cells/mL or less, 4×10 ⁸ cells/mL or less, 3×10 ⁸ cells/mL or less, 2×10 ⁸ cells/mL or less, 1×10 ⁸ cells/mL or less, ^9x107 cells/mL or less, ^8x107 cells/mL or less, 7x107 cells/mL or less, ^6x107 cells/mL ^or less, ^5x107 cells/mL or less, ^4x107 cells/mL or less, ^3x107 cells/mL or less, ^2x107 cells/mL or less, ^1x107 cells/mL or less. In addition to the above, the concentration can be appropriately determined depending on the administration form, administration method, purpose of use, and the age, weight, and symptoms of the patient or subject. The cell concentration in the cell suspension may be the same as that of the cell pharmaceutical preparation.

The number of cells in a cellular pharmaceutical preparation is the number of cells that can provide a therapeutic effect against a disease when the cellular pharmaceutical preparation is administered to a patient or subject, compared to a patient or subject not administered the cellular pharmaceutical preparation. The number of cells in the cell pharmaceutical preparation is not particularly limited, and may be, for example, 1×10 ⁴ cells or more, 2×10 ⁴ cells or more, 3×10 ⁴ cells or more, 4×10 ^{4 cells or more, 5×10 4 cells} or more, 6×10 ⁴ cells or more, 7×10 ⁴ cells or more, 8×10 ⁴ cells or more, 9×10 ⁴ cells or more, 1×10 ^{5 cells or more, 2×10 5 cells} or more, 3×10 ⁵ cells or more, 4×10 ^{5 cells or more, 5×10 5 cells} or more, 6×10 ⁵ cells or more, 7×10 ⁵ cells or more, 8×10 ⁵ cells or more, 9×10 ⁵ cells or more, 1×10 ⁶ cells or more, and also 1×10 ¹² cells or less, 1×10 ¹¹ cells or less, 1×10 ¹⁰ cells or less, 1×10 ⁹ cells or less, 9×10 ⁸ cells or less, 8×10 ⁸ cells or less, 7×10 ⁸ cells or less, 6×10 ⁸ cells or less, 5×10 ⁸ cells or less, 4×10 ⁸ cells or less, 3×10 ⁸ cells or less, 2×10 ⁸ cells or less, 1×10 ⁸ cells or less, 9×10 ⁷ cells or less, 8×10 ⁷ cells or less, 7×10 ⁷ cells or less, 6×10 ⁷ cells or less, 5×10 ⁷ The cell concentration is preferably 1×10 7 cells or less, 4×10 ⁷ cells or less, 3×10 ⁷ cells or less, 2×10 ⁷ cells or less, or 1×10 ⁷ cells or less. In addition to the above, the cell concentration can be appropriately determined depending on the administration form, administration method, purpose of use, and the age, weight, and symptoms of the patient or subject. The number of cells in the cell suspension may be the same as that of the cell pharmaceutical preparation.

The dose (cells/kg) of a cellular pharmaceutical preparation is the number of cells per kg of body weight of a patient or subject that, when administered to a patient or subject, can provide a therapeutic effect against a disease compared to a patient or subject not administered the cellular pharmaceutical preparation. The dose of the cell pharmaceutical preparation is not particularly limited, and may be, for example, 1×10 ⁴ cells/kg or more, 1×10 ⁵ cells/kg or more, 5×10 ⁵ cells/kg or more, 1×10 ⁶ cells/kg or more, 2×10 ⁶ cells/kg or more, 4×10 ⁶ cells/kg or more, 6×10 ⁶ cells/kg or more, or 8×10 ⁶ cells/kg or more, and may be 1×10 ¹² cells/kg or less, 1×10 ¹¹ cells/kg or less, 1×10 ¹⁰ cells/kg or less, 1×10 ⁹ cells/kg or less, 5×10 ⁸ cells/kg or less, 1×10 ⁸ cells/kg or less, 8×10 ⁷ cells/kg or less, 6×10 ⁷ cells/kg or less, 4×10 ⁷ cells/kg or less, or 2×10 ⁷ cells/kg or less.

Patients and subjects are typically humans, but may also be non-human animals such as rodents, e.g., mice, rats, hamsters, etc., primates, e.g., gorillas, chimpanzees, marmosets, etc., and even mammals, such as livestock or pets, e.g., dogs, cats, rabbits, cows, horses, sheep, goats, etc.

The cellular pharmaceutical preparation contained in the cellular pharmaceutical preparation container according to the present invention is delivered through an infusion port described below and administered to a patient. The route of administration to a patient is not particularly limited, but may be, for example, subcutaneous injection, intralymph node injection, intravenous injection, intraarterial injection, intraperitoneal injection, intrathoracic injection, or direct injection into a local area.

(Cell filling system)
1 and 2 are plan views showing the essential configuration of one embodiment of the cell loading system of the present invention, and FIG. 3 is a diagram showing the use of yet another embodiment of the cell loading system of the present invention.

As illustrated in Figures 1 and 2, the cell filling system of the present invention, as described above, comprises (A1) a cellular pharmaceutical preparation container 10 having an internal space 11 and a communication section 12 that communicates with the internal space, (B1) a cell filling section 20 having a stopcock 21 that switches the flow of fluid and a tubular body 22 that connects the cellular pharmaceutical preparation container 10 and the stopcock 21, (C1) a manifold 30 having a branch section 31 that connects to the cell filling section 20, (D1) an aspiration means 40 that reduces the pressure in the internal space of the cellular pharmaceutical preparation container, and (E1) a cell suspension container 50 that contains a cell suspension 51.

Each component will be described in turn.
(Cellular pharmaceutical preparation container: A1)
First, the cell pharmaceutical preparation container 10 is not particularly limited as long as it has an internal space 11 capable of storing a cell suspension therein and has a communication part 12 connecting this internal space 11 with the outside of the container, and various types of containers for filling cells that are commonly used in the field can be used.

The cellular pharmaceutical preparation container 10 shown in Figs. 1 and 2 is a container in which a bag mainly made of a flexible resin sheet is used. Although not particularly limited, examples of the flexible resin sheet constituting the bag include resin sheets made of thermoplastic resins such as polyethylene, polypropylene, polyvinyl chloride, ethylene-vinyl acetate copolymer, polyester, silicone-based elastomer, polystyrene-based elastomer, and tetrafluoroethylene-hexafluoropropylene copolymer (FEP). These resins may be used in a single layer, or the same or different resins may be laminated. In addition, when selecting a material, it is preferable to consider whether the material can provide the cell suspension stored inside with appropriate oxygen permeability and carbon dioxide permeability, low cytotoxicity, low elution, resistance to freezing, suitability for radiation sterilization, etc., as necessary. In addition, it is preferable that the material has a transparency to the extent that the inside can be seen through so that the state of the cell suspension stored inside can be observed from the outside. Although not particularly limited, the flexible resin constituting the cellular pharmaceutical preparation container 10 is preferably made of, for example, (polyvinyl chloride, ethylene-vinyl acetate copolymer).

The cellular pharmaceutical preparation container 10 is made using such flexible resin, and has an internal space 11 and a communication section 12 that communicates with the outside of the container. For example, by stacking two flexible resin sheets and heat sealing a predetermined portion, as shown in FIG. 1, a roughly rectangular internal space 11 with a heat-sealed periphery and a communication section 12 formed by providing a certain width portion of the periphery that is not heat-sealed can be formed.

However, in the present invention, the configuration of the cellular pharmaceutical preparation container 10 is not limited to a bag-like shape made of such flexible resin, and may be of other shapes as long as the internal space can be kept at reduced pressure and the cell suspension can be stored inside. For example, it may be a container body such as a tubular body or a tube bottle with higher rigidity, and the internal space 11 may not only have one, but may have two or more internal spaces divided by partitions. Furthermore, each of the two or more internal spaces may have a configuration that allows them to be closed as independent spaces, for example by heat sealing, as necessary after filling with the cell suspension.

In the embodiment of the cellular pharmaceutical preparation container 10 shown in Figs. 1 and 2, in addition to the communication part 12, two injection/exit ports 13a, 13b that can each communicate with the internal space 11 are provided. In addition to the above-mentioned communication part 12, such injection/exit ports 13a, 13b are provided as separate communication parts, that is, by providing multiple communication parts, for example, it is possible to inject a cell suspension into the internal space 11 through the injection/exit ports 13a, 13b without going through the communication part 12 that performs the decompression operation of the internal space 11, or conversely, to extract a cell suspension from the internal space 11, while maintaining a closed system.

For example, the injection/exit ports 13a and 13b are made of a tubular member through which the cell suspension can flow, and can be molded into a predetermined shape having a communicating flow path penetrating in the axial direction by injection molding, extrusion molding, or the like using a thermoplastic resin such as polyethylene, polypropylene, vinyl chloride, ethylene-vinyl acetate copolymer, polystyrene-based elastomer, or FEP. The releasable closure configuration of such injection/exit ports 13a and 13b is also not particularly limited, and can be, for example, a separate removable screw cap that closes the communicating flow path of such a tubular member in a liquid-tight manner, or a puncturable elastic material such as rubber that blocks the communicating flow path, or a breakable heat seal film or the like, or other conventionally known port configurations.

The opening dimensions of the infusion/exit ports 13a and 13b may be any dimensions that allow a cellular pharmaceutical preparation containing cells to pass through.
Furthermore, the number of injection/exit ports is not limited to one, but may be multiple, for example, two, three, four, five, six, seven, eight, nine, ten or more.

(Cell filling section: B1)
The cell filling section 20 is connected to the communication section 12 of the cellular pharmaceutical preparation container 10 and forms a flow path for connecting the internal space 11 of the cellular pharmaceutical preparation container 10 with the outside. In addition to the tubular body 22 that forms this flow path, the cell filling section 20 is characterized by having a stopcock 21 (B1) that switches the flow of fluid.

The stopcock 21 is not particularly limited, and may be any that can freely switch between a blocked state and a connected state of the flow path. It may be a two-way stopcock, but is preferably a stopcock with three or more inlet and outlet ports, and is particularly preferably a three-way stopcock. As shown in the figure, the three-way stopcock 21 is, for example, T-shaped, with two branch pipes extending in opposite directions and another branch pipe extending in a direction perpendicular to the two branch pipes, and a manually operable switching valve is provided at the intersection of the three branch pipes.

By having the cell filling section 20 have such a stopcock 21, the cell pharmaceutical preparation container 10 can be connected to an intake means 40 (described later) via the cell filling section 20 to reduce the pressure in the internal space 11, and when a predetermined degree of reduced pressure is reached, the stopcock 21 can be operated to close the flow path, and the reduced pressure in the internal space 11 of the cell pharmaceutical preparation container 10 can be easily maintained while disconnecting it from the intake means 40.

If the stopcock 21 is a three-way stopcock, it is possible to form a flow path separate from the flow path for the pressure reduction operation described above, and supply the cell suspension to the cell pharmaceutical preparation container 10.

In the embodiment shown in Figures 1 and 2, the tubular body 22 of the cell filling section 20 is integrally attached in a liquid-tight manner to the communication section 12 of the cellular pharmaceutical preparation container 10 by heat sealing, but the connection structure between the cellular pharmaceutical preparation container 10 and the cell filling section 20 is not limited to this type of heat sealing method, and it is also possible to adopt, for example, a detachable mechanical connection structure.

The material constituting the tubular body 22 is not particularly limited, but it is preferable that the material has a degree of hardness that does not deform and completely block the flow path when it is connected to the intake means 40 and a decompression process is performed, as described below. In one embodiment, it is preferable that the material has thermoplasticity that allows it to be melt-sealed at any point of the tubular body 22 by hot sealing. Although it is not particularly limited, the tubular body 22 can be made of a material such as polyvinyl chloride, ethylene-vinyl acetate copolymer, etc.

The length of the tubular body 22 depends on the size of the cellular pharmaceutical preparation container 10 to be connected, but if it is longer than necessary, it may reduce the efficiency of the decompression treatment, and if it is too short, it may be difficult to handle the flow path when connected to other members. For example, based on the longitudinal length of the cellular pharmaceutical preparation container 10 to be connected, the length is 1/12 to 17/6 times, for example, 1/12 or more, 1/10 or more, 1/8 or more, 1/6 or more, 1/5 or more, 1/4 or more, 1/3 or more, 2/5 or more, 1/2 or more, 2/3 or more, 7/10 or more, and 17/6 or less, 8/3 or less, 5/2 or less, 7/3 or less, 2 or less, 5/3 or less, 3/2 or less, 4/3 or less, 5/4 or less, 1 or less, 3/4 or less. It is more preferable to set the length to about 1/12 to 3/4 times.

The material from which the stopcock 21 is made is not particularly limited as long as it can reliably close and switch the flow path, and it is possible to use materials made from various synthetic resins such as polyethylene, polypropylene, polyamide (nylon), etc., or materials made from metals such as glass and stainless steel.

(Manifold: C1)
2, the cell-loading system according to the present invention includes a manifold 30 having a branching section 31 connected to the cell-loading section 20. Here, the manifold 30, as is well known, has a structure in which one main line 33 branches into two or more branch lines 34 via the branching section 31.

In the cell filling system according to the present invention, although it is possible to perform the decompression treatment and cell suspension filling treatment on a single cellular pharmaceutical preparation container 10, it is basically premised on performing the decompression treatment from a single suction means 40 common to multiple cellular pharmaceutical preparation containers 10, and therefore has such a manifold 30 for connecting multiple cell filling sections 20 to a single suction means 40.

The number of branching parts 31 or branching pipes 34 of the manifold 30 is not particularly limited, and if there are two or more, it is possible to perform decompression treatment using a common suction means 40 from one system for multiple cell pharmaceutical preparation containers 10. In addition, in order to perform treatment more efficiently, for example, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 100 or less, 90 or less, 80 or less, 70 or less, 65 or less, 60 or less, 50 or less, 40 or less, 30 or less, 25 or less, 20 or less, 19 or less, 18 or less, 17 or less, 16 or less, 15 or less. It is preferable to provide 4 or more and 64 or less, and more preferably 4 or more and 16 or less branching parts 31 or branching pipes 34. Furthermore, although not particularly limited, if at least two or more branching sections 31 are arranged in a straight line in the manifold 30 as shown in Figures 2 and 3, the ease of operation of the connection process is improved when multiple cellular pharmaceutical preparation containers 10 are connected and subjected to decompression treatment.

It is preferable to provide each branching section 31 with a stopcock 32, particularly a three-way stopcock. In this way, by providing each branching section 31 with a stopcock 32 to form a multiple stopcock, it becomes possible to arbitrarily and independently apply decompression treatment to each of the multiple connected cellular pharmaceutical preparation containers 10 in cooperation with the stopcocks 21 in the multiple cell filling sections 20 connected to the multiple cellular pharmaceutical preparation containers 10.

In this way, by providing a three-way stopcock 32 at each branch 31 and configuring the three-way stopcocks 32 so that they can be connected and detached to each other as shown in Figure 2, a manifold 30 of variable length can be created that can flexibly respond to an increase or decrease in the number of cellular pharmaceutical preparation containers 10 to be connected.

(Intake means: D1)
The cell filling system according to the present invention includes an intake means 40 for decompressing the internal space 11 of the cellular pharmaceutical preparation container 10. The intake means 40 is not particularly limited as long as it can decompress the internal space 11 of the cellular pharmaceutical preparation container 10 to a predetermined pressure, and may be, for example, an intake means such as a hydraulic pump, an air pump, or a syringe. As shown in FIG. 2, the intake means 40 is connected to the open end of the main line 33 of the manifold 30, and by operating the intake means 40, it is possible to decompress any of the multiple cellular pharmaceutical preparation containers 10 connected to each branch 31 of the manifold 30. In the embodiment shown in FIG. 3, a syringe is connected to the main line 33 of the manifold 30 as the intake means 40.

As shown in FIG. 2, although not particularly limited, it is preferable to place a separate stopcock 41 between one of the manifold lines 30 to which the suction means 40 is connected, i.e., the main line 33, and the suction means 40. Note that this stopcock 41 only needs to provide communication or blocking between the suction means 40 and the manifold line 30, so even a two-way stopcock will function satisfactorily. By placing the stopcock 41, it is desirable, for example, because the decompression process for each cell pharmaceutical preparation container 10 can be stopped all at once even if the suction means 40 is constantly operating.

In addition, in the cell filling system according to the present invention, a pressure gauge 45 or the like for measuring the degree of pressure reduction can be placed anywhere along the path where the pressure reduction process is performed, as necessary.

(Cell suspension container: E1)
The cell filling system according to the present invention includes a cell suspension container 50 that serves as a supply source for supplying a cell suspension 51 to the internal space 11 of the cellular pharmaceutical preparation container 10. The connection path of this cell suspension container 50 to the cellular pharmaceutical preparation container 10 is not particularly limited, and various paths may be adopted.

For example, it is possible to switch the connection to the suction means 40 and connect the cell suspension container 50, and fill the container 50 through the same flow path that performs the decompression process from the suction means 40 to the manifold 30, each cell filling section 20, and each cell pharmaceutical preparation container 10 as described above.

In this case, it is preferable to place a separate stopcock 52 between the main line 33 of the manifold line 30 connected to the cell suspension container 50 and the cell suspension container 50. The stopcock 52 may be anything that provides communication or blocking between the cell suspension container 50 and the manifold line 30, so even a two-way stopcock will work sufficiently. By placing the stopcock 52, for example, even if the cell suspension container 50 is constantly connected to the manifold line 30, the decompression process can be performed on each cell pharmaceutical preparation container 10 through a common flow path without sending the cell suspension to the manifold line 30 side. Here, it is also possible to place one three-way stopcock instead of the stopcock 41 and the stopcock 52, and use this three-way stopcock to switch between connection to the suction means 40 and connection to the cell suspension container 50.

As another connection path of the cell suspension container 50 to the cellular pharmaceutical preparation container 10, for example, as shown in Figures 1 and 2, if a three-way stopcock is arranged as the stopcock 21 of the cell filling section 20, the cell suspension container 50 can be connected to another flow path that can be switched by this three-way stopcock 21, and the cell suspension 51 can be introduced into the internal space 11 of the cellular pharmaceutical preparation container 10. In other words, the flow path that performs the decompression treatment from the suction means 40 to the manifold 30, each cell filling section 20, and each cellular pharmaceutical preparation container 10 as described above is switched to the flow path connected to the cell suspension container 50 by each three-way stopcock 21, and the supply is performed.

Furthermore, for example, as shown in Figures 1 and 2, if the cellular pharmaceutical preparation container 10 is provided with injection/exit ports 13a and 13b that can each communicate with the internal space 11 in addition to the communication portion 12, it is possible to connect a cell suspension container 50 to one of these injection/exit ports 13a and 13b, and introduce the cell suspension 51 into the internal space 11 of the cellular pharmaceutical preparation container 10 through this route.

In this way, in the cell filling system according to the present invention, the flow path for supplying the cell suspension 51 from the cell suspension container 50 to the internal space 11 of the cellular pharmaceutical preparation container 10 can be a flow path that is almost common to the flow path that performs the decompression treatment, a flow path that is partially common to the flow path, or a completely independent flow path.

(Method of manufacturing a cell medicine)
Next, a method for producing a cell pharmaceutical preparation according to the present invention, which can be carried out using the above-mentioned cell loading system, will be described.

The method for producing a cellular pharmaceutical preparation according to the present invention includes the steps of (a) reducing the pressure in the internal space 11 of a cellular pharmaceutical preparation container 10, which has an internal space 11 and a communication part 12 that connects the internal space, by using an air intake means 40, and (b) filling the reduced pressure internal space 11 of the cellular pharmaceutical preparation container 10 with a cell suspension 51.

In this way, by reducing the pressure inside the cell pharmaceutical preparation container 10 using the suction means 40 before filling the container with the cell suspension 51, the cell suspension can be filled efficiently with almost no gas present inside the container.

Each step in the manufacturing method of the cellular pharmaceutical preparation according to the present invention will be described in more detail below, assuming that the above-mentioned cell filling system is used. Note that the connection and disconnection operations of each member shown below, as well as the stopcock switching operation, are not particularly limited as long as the internal space 11 of the cellular pharmaceutical preparation container 10 can be depressurized and the internal space 11 can be filled with the cell suspension 51, and the order of operations can be changed as appropriate.

(Decompression treatment step)
First, as shown in FIG. 1 , one end of the tubular body 22 of the cell filling section 20 is airtightly attached to the communication section 12 of each cellular pharmaceutical preparation container 10, and a stopcock 21 is placed on a flow path communicating with the internal space 11 of each cellular pharmaceutical preparation container 10.

A single unit is prepared by connecting a cell filling section 20 having a stopcock 21 to the communication section 12 of such a cellular pharmaceutical preparation container 10.

Once multiple units each consisting of a cellular pharmaceutical preparation container 10 and a cell filling section 20 have been prepared, then, as shown in FIG. 2, a port in one flow path direction (direction A in the figure) of the stopcock 21 of each unit is connected to a port in the flow path direction (direction A' in the figure) of the opposing branch pipeline 34 of each branch section 31 of the manifold pipeline 30. In this way, a configuration is formed in which multiple units (cellular pharmaceutical preparation containers 10 and cell filling sections 20) are connected to the manifold pipeline 30.

2, each branch 31 is configured by a three-way stopcock 32, and ports of the three-way stopcock 32 in different flow directions (B' direction in the figure) are linearly connected to form a manifold 30. For this reason, for example, a configuration is possible in which each three-way stopcock 32 is first attached to each unit in which a cell filling section 20 having a stopcock 21 is connected to the communication section 12 of the cellular pharmaceutical preparation container 10 as described above, and then the three-way stopcocks 32 are connected to each other to form a manifold 30 having branch sections 31 according to the number of cellular pharmaceutical preparation containers 10.

Then, once a configuration in which a predetermined number of multiple units (cell pharmaceutical preparation containers 10 and cell filling sections 20) are connected to the manifold 30 has been formed in this manner (see, for example, FIG. 3), an intake means 40 is connected to the open end (the end in the direction B' in the figure) of the main line 33 of the manifold 30. As shown in FIG. 2, a stopcock 41 may be placed between the intake means 40 and the manifold 30, and a pressure gauge 45 may also be attached.

In the above-mentioned connection state, the internal space 11 of the cellular pharmaceutical preparation container 10 is depressurized. At this time, the cell suspension container 50 that supplies the cell suspension 51 to the cellular pharmaceutical preparation container 10 can be connected to the system as long as it does not interfere with the aspiration process in the flow path from the aspiration means 40 through the manifold 30 and each cell filling section 20 to each cellular pharmaceutical preparation container 10, for example, if a stopcock or the like can be provided to stop the inflow. Of course, in the depressurization process step (a), the cell suspension container 50 may not be connected to the system, and may be connected to the system after the depressurization process step (a) is completed.

In the above-mentioned connection state, the decompression process of the internal space 11 of the cellular pharmaceutical preparation container 10 operates the suction means 40 by setting the stopcock 41 between the suction means 40 and the manifold 30 to an "open" state in which they communicate, at least one of the three-way stopcocks 32 on the manifold 30 to an "open" state in which it communicates with the flow path of the cell filling section 20 connected to it, and further setting the stopcock 21 of each cell filling section 20 connected to the three-way stopcock 32 in the "open" state to an "open" state in which it communicates with the internal space 11 of the cellular pharmaceutical preparation container 10.

As described above, the pressure reduction treatment is possible if each of the multiple three-way stopcocks 32 on the manifold 30 and each stopcock 21 on each cell filling section 20 is open to the suction means 40 so as to communicate with the internal space 11 of at least one cellular pharmaceutical preparation container 10. By appropriately opening and closing each of the multiple stopcocks 32 and 21 so as to communicate with the internal spaces 11 of multiple or all of the cellular pharmaceutical preparation containers 10, it is also possible to simultaneously perform pressure reduction treatment of the internal spaces 11 of multiple cellular pharmaceutical preparation containers 10.

That is, for example, in the mode of (1) sequentially depressurizing the internal space of each cellular pharmaceutical preparation container 10, first, the multiple stopcocks 32 and 21 are appropriately opened and closed, respectively, to perform a depressurization process in a state in which only the internal space 11 of one cellular pharmaceutical preparation container 10 is in communication with the suction means 40, and when the degree of depressurization of the internal space 11 of the one cellular pharmaceutical preparation container 10 reaches a predetermined level, the stopcock 21 on the cell filling section 20 communicating with the cellular pharmaceutical preparation container 10 is switched to a "closed" state, releasing the communication state of the internal space of the cellular pharmaceutical preparation container 10 with the suction means 40, and maintaining the depressurized state of the internal space of the cellular pharmaceutical preparation container 10. Then, the multiple stopcocks 32 and 21 are appropriately switched so that only the internal space 11 of another cellular pharmaceutical preparation container 10 is in communication with the suction means 40, and a depressurization process is performed on the internal space 11 of the second cellular pharmaceutical preparation container 10, and such a process is sequentially repeated. For example, even if the suction capacity of the suction means 40 is not very high, such as when a syringe is used as the suction means, by performing such an operation, it is possible to perform continuous and accurate decompression treatment on multiple cell medicine preparation containers 10.

Alternatively, for example, in (2) an aspect in which the internal spaces of multiple cellular pharmaceutical preparation containers 10 are depressurized in parallel, first, the multiple stopcocks 32 and 21 are opened and closed as appropriate to place the internal spaces 11 of the multiple cellular pharmaceutical preparation containers 10 in communication with the suction means 40, and a depressurization process is performed. When the degree of depressurization of the internal space 11 of any one of the multiple cellular pharmaceutical preparation containers 10 being depressurized reaches a predetermined level, the stopcock 21 on the cell filling section 20 that communicates with this cellular pharmaceutical preparation container 10 is individually set to the "closed" state, thereby releasing the communication between the internal space of the cellular pharmaceutical preparation container 10 and the suction means 40, and maintaining the depressurized state of the internal space of this cellular pharmaceutical preparation container 10. In this way, the internal space of the cellular pharmaceutical preparation containers 10 that are being depressurized in parallel all reach a predetermined depressurized state, and the stopcocks 21 on the cell filling sections that communicate with all of the cellular pharmaceutical preparation containers 10 are closed. Once the depressurized state of the internal space of the cellular pharmaceutical preparation container 10 is maintained, the stopcock 32 and the other stopcocks 21 are again opened and closed as appropriate to bring the internal space 11 of the other multiple cellular pharmaceutical preparation containers 10 into communication with the suction means 40, and the same process as above is repeated until the depressurization process is completed for all of the cellular pharmaceutical preparation containers 10 in the system.

The above embodiment (2) of depressurizing the internal spaces of multiple cellular pharmaceutical preparation containers 10 in parallel also includes the embodiment of depressurizing the internal spaces of all cellular pharmaceutical preparation containers 10 in the system in parallel.

The method of reducing the pressure in the internal space of the multiple cellular pharmaceutical preparation containers 10 in the decompression process is not limited to the above-mentioned (1) and (2), and various other methods can be used, such as by changing the method of operating the stopcocks as appropriate. In the present invention, the procedures for opening, closing, and connecting the stopcocks for such reduction in pressure are arbitrary as long as the desired reduction in pressure can be achieved, and any procedure falls within the scope of the present invention.

In addition, in the present invention, in an embodiment in which a three-way stopcock 32 is provided on each branch 31 of the manifold 30 connected to the suction means 40 as described above, by setting the three-way stopcock 32 at each branch 31 to the "closed" state and also setting the stopcock 21 on the unit (the cellular pharmaceutical preparation container 10 and the cell filling unit 20) connected thereto to the "closed" state, it is possible to release the connection between them while maintaining the suction state on the suction means 40 side and the reduced pressure state on the cellular pharmaceutical preparation container 10 side.

For this reason, for units for which decompression processing has been completed (cell pharmaceutical preparation container 10 and cell filling section 20), it is possible to continue decompression processing by the suction means 40 as a whole system, while releasing and removing them individually from the operating system, and to use them for a separate process, for example, to fill them with a cell suspension.

Furthermore, after disconnecting and removing the individual units in this manner, a new unit is connected to the branching section 31, and the three-way stopcock 32 is set to the "open" state. Also, by setting the stopcock 21 on the newly connected unit to the "open" state, the decompression process by the suction means 40 of the entire system can be continued, while the cell pharmaceutical preparation container 10 that has completed the decompression process can be replaced with a new one, and the decompression process can be continued for a new target.

For example, in a case where the cell suspension filling operation is to be performed in parallel for multiple cellular pharmaceutical preparation containers 10 via the manifold 30 after the decompression treatment, the decompression treatment can be terminated by disconnecting the suction means 40 from the manifold 30 after the internal space of the multiple cellular pharmaceutical preparation containers 10 is decompressed without disconnecting the individual cellular pharmaceutical preparation containers 10 that have been decompressed at the branching portion 31 of the manifold 30 as described above, and keeping the multiple cellular pharmaceutical preparation containers 10 that have been decompressed connected to the manifold 30.

Although not particularly limited, such a decompression treatment reduces the pressure inside the cellular pharmaceutical preparation container to 10 KPa or less, 9 KPa or less, 8 KPa or less, 7 KPa or less, 6 KPa or less, 5 KPa or less, 4 KPa or less, 3 KPa or less, 2 KPa or less, 1 KPa or less, or more than 0 KPa. By reducing the pressure inside the cellular pharmaceutical preparation container to preferably 5.7 KPa or less, more preferably 2.8 KPa or less, and even more preferably 1.4 KPa or less, it is desirable to be able to fill the container with the cell suspension efficiently and with almost no gas in the filling operation described below.

(Cell suspension filling process)
As described above, the present invention includes the (a) decompression treatment step followed by the (b) step of filling the decompressed internal space 11 of the cellular pharmaceutical preparation container 10 with the cell suspension 51. This filling step can be easily performed by connecting, for example, a cell suspension container 50 serving as a supply source for the cell suspension 51 to the internal space 11 of the cellular pharmaceutical preparation container 10 maintained in a decompressed state.

As described above, the connection path of the cell suspension container 50 to the cellular pharmaceutical preparation container 10 is not particularly limited, and various paths may be adopted.

2, for example, it is possible to switch the connection to the suction means 40 and connect the cell suspension container 50 to the manifold 30, and fill the container 50 through the same flow path that performs the decompression process from the suction means 40 to the manifold 30, each cell filling section 20, and each cell pharmaceutical preparation container 10 as described above. In this case, the cell suspension 51 is filled into the internal space 11 of the cell pharmaceutical preparation container 10 through the manifold 30 and the cell filling section 20.

Alternatively, the units (the cellular pharmaceutical preparation container 10 and the cell filling section 20) that have undergone the decompression treatment as described above can be disconnected from the manifold 30 while maintaining the decompressed state, and the cell suspension can be filled into each unit. As shown in FIG. 1, the cell suspension container 50 can be connected to another flow path (direction B in the figure) that can be switched by the three-way stopcock 21 of each unit, and the cell suspension 51 can be introduced into the internal space 11 of the cellular pharmaceutical preparation container 10. In this case, the cell suspension 51 is filled into the internal space 11 of the cellular pharmaceutical preparation container 10 via the cell filling section 20. Alternatively, for example, as shown in FIG. 1 and FIG. 2, when the cellular pharmaceutical preparation container 10 is provided with injection/exit ports 13a and 13b that can be communicated with the internal space 11 in addition to the communication section 12, the cell suspension container 50 can be connected to one of these injection/exit ports 13a and 13b, and the cell suspension 51 can be introduced into the internal space 11 of the cellular pharmaceutical preparation container 10 through this route.

In addition, if the units (cell pharmaceutical preparation container 10 and cell filling section 20) that have completed the decompression process are disconnected from the manifold 30 while maintaining the decompressed state, and the cell suspension filling operation is performed on each unit, it becomes possible to divide the work of filling the cell suspension among multiple people, thereby improving work efficiency.

In either embodiment, the internal space 11 of the cellular pharmaceutical preparation container 10 is maintained at a predetermined reduced pressure, allowing for an excellent cell suspension filling operation.

In this manner, a predetermined amount of cell suspension is filled into the internal space of the cellular pharmaceutical preparation container 10, thereby producing a cellular pharmaceutical preparation. After the cell suspension is filled, the cell filling section 20 connected to the cellular pharmaceutical preparation container 10 can maintain a closed system within the container by closing the stopcock 21. To ensure a safer and more reliable closed system, it is also possible to seal the cellular pharmaceutical preparation container by, for example, melt sealing the tubular body 22 of the cell filling section 20 midway by known means such as heat sealing.

The cell pharmaceutical preparation obtained by the manufacturing method according to the present invention is then cryopreserved as necessary, as is well known.

The cell filling system and the method for producing a cell pharmaceutical preparation according to the present invention have been described in detail above based on the embodiments, but the present invention is not limited to the embodiments exemplified above, and it is believed that those skilled in the art will easily understand that various modifications and substitutions can be made within the scope of the concept and essence of the present invention. In particular, the order of connection of each component in the cell filling system and the opening and closing operation of the stopcocks can take a wide variety of forms, but it is clear that all of these are within the scope of the present invention as long as they can perform the same functions and processes as those shown in the above embodiments.

REFERENCE SIGNS LIST 10 Cellular pharmaceutical preparation container 11 Internal space 12 Communication section 13a, 13b Injection/exit port 20 Cell filling section 21 Stopcock (three-way stopcock)
22 Tubular body 30 Manifold 31 Branch 32 Three-way stopcock 33 Main duct 34 Branch duct 40 Suction means 50 Cell suspension container

Claims (16)

A cell filling system for filling a cell suspension into a cell pharmaceutical preparation container, comprising:
(A1) a cellular pharmaceutical preparation container having an internal space and a communication part communicating with the internal space;
(B1) a cell loading section having a stopcock for switching the flow of a fluid and a tubular body connecting the cell pharmaceutical preparation container and the stopcock;
(C1) a manifold having a branch portion connected to the cell loading portion;
(D1) a suction means for reducing the pressure in the internal space of the cell pharmaceutical preparation container;
(E1) a cell suspension container containing a cell suspension;
A cell loading system comprising: The cell filling system according to claim 1, wherein the manifold (C1) has at least two branches. The cell filling system according to claim 2, wherein at least two or more of the branches are arranged in a straight line in the manifold (C1). The cell filling system according to any one of claims 1 to 3, wherein a stopcock is provided at the branch of the manifold (C1). The cell filling system according to any one of claims 1 to 4, wherein the cellular pharmaceutical preparation container (A1) has at least two or more communication parts. The cell filling system according to any one of claims 1 to 5, comprising a stopcock between one of the manifolds and the intake means. The cell loading system according to any one of claims 1 to 6, comprising a stopcock between one of the manifolds and the cell suspension container. A method for producing a cellular pharmaceutical preparation, comprising the steps of: reducing the pressure in the internal space of a cellular pharmaceutical preparation container, which has an internal space and a communication part that communicates with the internal space, by using an air intake means; and filling the reduced pressure internal space of the cellular pharmaceutical preparation container with a cell suspension. The method according to claim 8, wherein the cellular pharmaceutical preparation container has a cell-filling section having a stopcock for switching the flow of fluid and a tubular body for connecting the cellular pharmaceutical preparation container and the stopcock. The method according to claim 9, wherein in the step of reducing the pressure using the suction means, the internal space of the cell pharmaceutical preparation container is reduced in pressure via a manifold having a branch portion connected to the cell filling portion. The method according to any one of claims 8 to 10, wherein in the step of reducing the pressure using the suction means, the internal space of the cellular pharmaceutical preparation container is reduced in pressure via the cell filling section. The method according to any one of claims 8 to 11, wherein the cell pharmaceutical preparation container comprises at least two or more containers. The manufacturing method according to any one of claims 9 to 12, further comprising a step of disconnecting the suction means from the manifold after reducing the pressure in the internal space of the cell pharmaceutical preparation container. The method according to any one of claims 9 to 13, further comprising a step of disconnecting the manifold from the pharmaceutical preparation container after reducing the pressure in the internal space of the cellular pharmaceutical preparation container. The method according to any one of claims 10 to 14, wherein in the step of filling the cell suspension, the cell suspension is filled into the internal space of the cellular pharmaceutical preparation container via the cell filling section. The method according to any one of claims 8 to 15, further comprising a step of sealing the cellular pharmaceutical preparation container after filling the internal space of the cellular pharmaceutical preparation container with the cell suspension.

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