Hollow fiber membrane module

Abstract

The invention provides a hollow fiber membrane module which does not need sterilization operation of a liquid separator of a user side and can improve convenience. A hollow fiber membrane module is provided with: a housing having at least two ports; a hollow fiber membrane disposed in the housing; and two or more sterile connectors which are attached to the ports and which connect the housing and the liquid flow line, and which do not require a sterilization operation, the hollow fiber membrane module being sterilized in a sealed state in which the pores of the hollow fiber membrane are held by a membrane pore holding agent comprising an alcohol aqueous solution and the ports and the sterile connectors are integrated or connected. The alcohol concentration in the aqueous alcohol solution is from 8% by weight to 20% by weight (inclusive).

Description

Technical Field

[0001] The invention relates to a hollow fiber membrane component. Background Art

[0002] In recent years, the technology of utilizing selectively permeable membranes has made remarkable progress and has been put into practical use in a wide range of fields, including gas or liquid separation filters, hemodialyzers in the medical field, blood filters, and blood component selective separation filters.

[0003] Conventionally, polymers such as cellulose (regenerated cellulose, cellulose acetate, chemically modified cellulose, etc.), polyacrylonitrile, polymethyl methacrylate, polysulfone, polyvinylidene fluoride, polyethylene vinyl alcohol, and polyamide have been used as materials for the membrane.

[0004] Among these, polysulfone polymers have not only thermal stability and acid and alkali resistance, but also improved blood compatibility by adding a hydrophilizing agent to the membrane-forming stock solution for membrane formation. Therefore, they have attracted attention as semipermeable membrane materials and research has been advanced.

[0005] On the other hand, in order to produce a component for manufacturing pharmaceutical products by bonding the membrane, the membrane needs to be sterilized, but it is well known that porous membranes made of organic polymers, including hollow fiber membranes of hydrophobic polymers such as polysulfone and polyvinylidene fluoride, will have a lower water permeability than before sterilization due to changes in the membrane structure if sterilized by radiation. Therefore, the membrane needs to be handled in a state of being always wet or immersed in water.

[0006] As a countermeasure, the method adopted in the past is to pre-fill the pores of the hollow fiber membrane before sterilization with a low-volatile organic liquid such as glycerol (for example, see Patent Document 1). However, since the low-volatile organic liquid is generally highly viscous, there are the following problems: it takes time to clean and remove, and even if the user cleans the hollow fiber membrane module after sterilization, a trace amount of dissolved substances from the low-volatile organic liquid (various derivatives generated by chemical reaction with the low-volatile organic liquid) will be observed in the module sealing liquid.

[0007] Furthermore, if the membrane is kept wet or immersed in water before sterilization, or if the porous membrane is treated with a low-volatile organic liquid such as glycerin filled in the pores, bacteria will multiply before sterilization, thus resulting in unsatisfactory antibacterial properties.

[0008] As a method for exerting antibacterial performance (bacteriostatic property) without using low-volatile organic liquid, Patent Document 2 discloses a method of using an aqueous solution containing inorganic salts such as calcium chloride instead of low-volatile organic liquid, but the aqueous solution still needs to be washed and removed. In addition, even in trace amounts, there is a concern that residual inorganic salts may have an adverse effect on the manufacture of pharmaceuticals.

[0009] On the other hand, in virus removers that remove viruses from blood products, blood purifiers that remove unwanted substances from blood during dialysis, etc., liquid separators that allow liquid such as blood products to pass through and separate specified substances from the liquid have been used in the past. The liquid separator is provided with hollow fibers inside a housing, for example, so that liquid flows in from a port (liquid passage) formed on the primary side of the housing, separates specific substances using the hollow fibers, and causes the liquid to flow out from a port on the secondary side.

[0010] Usually, the liquid separator (hollow fiber membrane assembly) as described above is sterilized in a state where, for example, connectors, balloons, etc. are installed at each port, and then shipped, delivered, etc. as a kit. The sterilization treatment is performed, for example, by placing the liquid separator in a sterilization bag with the shell filled with water and each port closed, and exposing it to high-pressure steam sterilization at high temperature and high pressure for a prescribed time (see, for example, Patent Document 3). Moist heat sterilization is performed in a state where the shell is filled with water and each port is closed (however, it is a state where pressure changes can be absorbed by balloons, etc. or gas can pass through) in order to prevent drying of the shell caused by the sterilization treatment and maintain a sterile state, and also to maintain the wettability of the hollow fiber before using the liquid separator and to give full play to the separation performance of the hollow fiber from the beginning of use. Compared with radiation sterilization, high-pressure steam sterilization is not suitable for mass production of hollow fiber membrane assemblies, especially for the production of 3.5m 2 The above large hollow fiber membrane modules with large membrane areas are not ideal because there is no corresponding high-pressure steam sterilization equipment.

[0011] Prior art literature

[0012] Patent Literature

[0013] Patent Document 1: Japanese Patent Application Publication No. 2023-036006

[0014] Patent Document 2: Japanese Patent No. 7237656

[0015] Patent Document 3: Japanese Patent Application Publication No. 2003-245329 Summary of the invention

[0016] Problem that the invention aims to solve

[0017] The object of the present invention is to provide a hollow fiber membrane assembly, which retains a membrane pore retaining agent having excellent antibacterial properties and sterilization resistance and which does not affect the safety of pharmaceuticals in the pores of the hollow fiber membrane, thereby improving convenience by not requiring sterilization of the user's liquid separator, and by using a membrane pore retaining agent and not requiring sterilization, so that it can be directly used by users who manufacture pharmaceuticals.

[0018] Solutions for solving problems

[0019] The present inventors have conducted intensive studies and repeated experiments to solve the above-mentioned problems. As a result, they have found that the above-mentioned problems can be solved by providing a hollow fiber membrane module with a specific structure, thereby completing the present invention.

[0020] That is, the present invention is as follows.

[0021] [1] A hollow fiber membrane assembly, wherein the hollow fiber membrane assembly comprises: a housing having at least two ports; a hollow fiber membrane disposed in the housing; and two or more sterile connectors mounted on the ports of the housing to connect the housing to a liquid flow path, without the need for sterilization, wherein the pores of the hollow fiber membranes are maintained by a membrane pore retaining agent composed of an alcohol aqueous solution and the ports are sterilized in a closed state in which the ports are integrated with or connected to the sterile connectors, and the alcohol concentration in the alcohol aqueous solution is greater than 8% by weight and less than 20% by weight.

[0022] [2] The hollow fiber membrane module according to [1], wherein the hollow fiber membrane is a microfiltration membrane having a pore diameter of 0.05 μm or more and 2 μm or less.

[0023] [3] The hollow fiber membrane module according to [1], wherein the hollow fiber membrane is a microfiltration membrane having a pore diameter of 0.3 μm or more and 1 μm or less.

[0024] [4] The hollow fiber membrane module according to [1], wherein the hollow fiber membrane includes a polyvinylidene fluoride polymer or a polysulfone polymer.

[0025] [5] The hollow fiber membrane module according to [1], wherein the alcohol is ethanol.

[0026] [6] The hollow fiber membrane module according to [1], wherein the pH of the membrane pore retaining agent after sterilization is neutral.

[0027] [7] The hollow fiber membrane module according to [1], wherein the sterile connector is a connector capable of aseptic connection coupling.

[0028] [8] The hollow fiber membrane module according to [1], wherein the distance between the port and the sterile connector connected to the port is greater than or equal to 0 mm and less than or equal to 100 mm.

[0029] [9] The hollow fiber membrane module according to [1], wherein the number of aseptic connectors integrated with or connected to the ports is at least two or more.

[0030]

[10] The hollow fiber membrane module according to [1], wherein the housing, the port, the hollow fiber membrane, and the sterile connector have sterilization resistance and alcohol resistance.

[0031]

[11] The hollow fiber membrane module according to [1], wherein the sterilization is radiation sterilization.

[0032]

[12] The hollow fiber membrane module according to

[11] , wherein the radiation sterilization is gamma-ray sterilization.

[0033]

[13] The hollow fiber membrane module according to [1], wherein the membrane area of ​​the hollow fiber membrane is 3.5 m 2 above.

[0034] Effects of the Invention

[0035] According to the present invention, a hollow fiber membrane assembly can be provided, which retains a membrane pore retaining agent having excellent antibacterial properties and sterilization resistance and which does not affect the safety of pharmaceuticals in the pores of the hollow fiber membrane, thereby improving convenience by eliminating the need for sterilization of the user's liquid separator, and by using a membrane pore retaining agent and eliminating the need for sterilization, thereby enabling direct use by users who manufacture pharmaceuticals. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 It is a schematic cross-sectional view of a hollow fiber membrane module according to an embodiment of the present invention.

[0037] Description of Reference Numerals

[0038] 1. Hollow fiber membrane assembly; 2. Reducer; 3. Clamping band; 4. Clamping band; 5. Reducer; 6. Tube; 7. Sterile connector; 8. Tube; 9. Sterile connector; 10. Housing; 11. Tube band; 12. Hollow fiber membrane; 13. Support member; 14a, 14b, port; 15a, 15b, port; 16. Tube band. DETAILED DESCRIPTION

[0039] The following is a detailed description of the embodiments of the present invention. In addition, the following is an example for explaining the present invention, and is not intended to limit the present invention to the following contents. The present invention can be implemented by appropriately modifying it within the scope of its gist.

[0040] A hollow fiber membrane assembly according to an embodiment of the present invention comprises: a housing having at least two ports; a hollow fiber membrane arranged in the housing; and two or more sterile connectors installed at the ports of the housing to connect the housing to a liquid circulation circuit, without the need for sterilization, wherein the hollow fiber membrane assembly is sterilized in a closed state in which the pores of the hollow fiber membrane are maintained by a membrane pore retaining agent composed of an alcohol aqueous solution and the port and the connector are integrated or connected, and the alcohol concentration in the alcohol aqueous solution is greater than 8 weight % and less than 20 weight %.

[0041] When the alcohol is ethanol, the alcohol concentration of the alcohol aqueous solution is in the range of 8 wt % to 20 wt %. It is not preferable to retain an alcohol aqueous solution having an alcohol concentration outside this range in the pores of the hollow fiber membrane from the viewpoint of antibacterial properties and radiation sterilization resistance.

[0042] [Composition of hollow fiber membrane]

[0043] The hollow fiber membrane of the present embodiment (hereinafter also referred to as "membrane") has a hydrophobic polymer as the main component alone, or has a hydrophobic polymer and a water-insoluble hydrophilic polymer as the main components. Here, "having a hydrophobic polymer and a water-insoluble hydrophilic polymer as the main components" means that the total amount of the hydrophobic polymer and the water-insoluble hydrophilic polymer accounts for more than 80% by mass of the material constituting the hollow fiber membrane, preferably more than 90% by mass, more preferably more than 95% by mass, and further preferably 100% by mass.

[0044] [Hydrophobic polymer]

[0045] As hydrophobic polymers, for example, polyvinylidene fluoride polymers, polysulfone polymers, polyamides, polyimides, polyetherimides, polyphenylene oxides, polyphenylene sulfides, etc. can be listed. Among these, polyvinylidene fluoride polymers and aromatic polysulfone polymers are preferred because they have resistance to sterilization for gamma ray sterilization and alcohol resistance for ethanol. As aromatic polysulfone polymers used in the present embodiment, polymers having repeating units shown in the following general formula (1) or general formula (2) can be listed. Wherein, Ar in the formula represents a phenyl substituted with 2 in the para position. The degree of polymerization and molecular weight of the hydrophobic polymer compound are not particularly limited.

[0046] -O-Ar-C(CH3)2-Ar-O-Ar-SO2-Ar-(1)

[0047] -O-Ar-SO2-Ar-(2)

[0048] The aromatic polysulfone polymer may contain a functional group or a substituent such as an alkyl group in the structure of the general formula (1) or the general formula (2), and the hydrogen atoms of the hydrocarbon skeleton may be substituted by other atoms or substituents such as halogen. The polysulfone polymer may be used alone or in combination of two or more.

[0049] [Hydrophilic polymer]

[0050] In the present embodiment, a polymer having a contact angle of less than 90 degrees when PBS (9.6 g of Dulbecco PBS (-) powder "nissui" commercially available from Nissui Pharmaceutical Co., Ltd. is dissolved in water and the total amount is 1 L of solution) is brought into contact with a polymer film is called a hydrophilic polymer. In the present embodiment, the contact angle of the hydrophilic polymer is preferably less than 60 degrees, and the contact angle is more preferably less than 40 degrees. In the case of a hydrophilic polymer having a contact angle of less than 60 degrees, the hollow fiber membrane is easily wetted by water, and in the case of a hydrophilic polymer having a contact angle of less than 40 degrees, the tendency to be easily wetted by water is more significant. In addition, the contact angle refers to the angle formed by the surface of a water drop when a water drop falls on the surface of a film, and is defined by JIS R3257.

[0051] In this embodiment, water-insoluble means that the effective membrane area is 3.3 cm 2 When 100 mL of pure water at 25°C was filtered through a membrane assembled in a manner of 2.0 bar by dead-end filtration at a constant pressure of 2.0 bar, the dissolution rate of carbon from the membrane was less than 0.1%. The method for calculating the dissolution rate is as follows. The filtrate obtained by filtering 100 mL of pure water at 25°C was recovered and concentrated. Using the obtained concentrated solution, the carbon content was measured using a total organic carbon meter TOC-L (manufactured by Shimadzu Corporation) to calculate the dissolution rate from the membrane.

[0052] [Water-insoluble hydrophilic polymer]

[0053] In the present embodiment, the water-insoluble hydrophilic polymer refers to a substance that satisfies the above-mentioned contact angle and dissolution rate. In addition to the hydrophilic polymer that is itself water-insoluble, the water-insoluble hydrophilic polymer also includes a hydrophilic polymer that is water-soluble but has been made water-insoluble during the manufacturing process. That is, even if it is a water-soluble hydrophilic polymer, if it is a substance that satisfies the above-mentioned contact angle and satisfies the above-mentioned dissolution rate in the constant pressure dead-end filtration after the filter is assembled by being made water-insoluble during the manufacturing process, it is also included in the water-insoluble hydrophilic polymer in the present embodiment.

[0054] The hollow fiber membrane of the present embodiment may contain a water-insoluble hydrophilic polymer. From the viewpoint of preventing the rapid decrease in filtration speed caused by the clogging of the membrane caused by the adsorption of protein, the hollow fiber membrane of the present embodiment is hydrophilized by the presence of a water-insoluble hydrophilic polymer on the surface of the pores of the substrate membrane containing the hydrophobic polymer. As a method for hydrophilizing the substrate membrane, coating, grafting reaction, and cross-linking reaction after the substrate membrane including the hydrophobic polymer is formed can be cited. In addition, the substrate membrane can also be hydrophilized by coating, grafting reaction, and cross-linking reaction after the blend of the hydrophobic polymer and the hydrophilic polymer is formed into a membrane.

[0055] [Vinyl polymer]

[0056] Examples of water-insoluble hydrophilic polymers include vinyl polymers. Examples of vinyl polymers include homopolymers of hydroxyethyl methacrylate, hydroxypropyl methacrylate, dihydroxyethyl methacrylate, diethylene glycol methacrylate, triethylene glycol methacrylate, polyethylene glycol methacrylate, vinyl pyrrolidone, acrylamide, dimethylacrylamide, glucosyloxyethyl methacrylate, 3-sulfopropyl methacryloyloxyethyl dimethylammonium betaine, 2-methacryloyloxyethyl phosphorylcholine, 1-carboxydimethylmethacryloyloxyethylmethanammonium, and the like; homopolymers of styrene, ethylene, propylene, propyl methacrylate, butyl methacrylate, ethylhexyl methacrylate, methyl methacrylate, and the like; Random copolymers, graft copolymers and block copolymers of hydrophobic monomers such as octadecyl acrylate, benzyl methacrylate, methoxyethyl methacrylate and hydroxyethyl methacrylate, hydroxypropyl methacrylate, dihydroxyethyl methacrylate, diethylene glycol methacrylate, triethylene glycol methacrylate, polyethylene glycol methacrylate, vinyl pyrrolidone, acrylamide, dimethylacrylamide, glucosyloxyethyl methacrylate, 3-sulfopropyl methacryloyloxyethyl dimethylammonium betaine, 2-methacryloyloxyethyl phosphorylcholine, 1-carboxydimethylmethacryloyloxyethylmethanammonium and other hydrophilic monomers.

[0057] In addition, as the vinyl polymer, for example, there can be mentioned copolymers of cationic monomers such as dimethylaminoethyl methacrylate and diethylaminoethyl methacrylate, anionic monomers such as acrylic acid, methacrylic acid, vinyl sulfonic acid, sulfopropyl methacrylate, ethylene glycol phosphate methacrylate, and the above-mentioned hydrophobic monomers, etc. The vinyl polymer may also be a polymer containing anionic monomers and cationic monomers in equal amounts in a manner to be electrically neutral.

[0058] [Electroneutrality]

[0059] The water-insoluble hydrophilic polymer is preferably electrically neutral from the viewpoint of preventing adsorption of protein as a solute, for example. In the present embodiment, electrically neutral means that the molecule has no charge or that the cations and anions in the molecule are equal in amount.

[0060] Examples of water-insoluble hydrophilic polymers include polysaccharides such as cellulose and derivatives thereof such as triacetyl cellulose. Polysaccharides and derivatives thereof also include crosslinked polymers such as hydroxyalkyl cellulose.

[0061] As the water-insoluble hydrophilic polymer, polyethylene glycol and its derivatives may be used, or block copolymers of ethylene glycol and the above hydrophobic monomers, random copolymers and block copolymers of ethylene glycol and propylene glycol, ethylbenzyl glycol, etc. In addition, one or both ends of polyethylene glycol and the above copolymers may be substituted with a hydrophobic group to make them water-insoluble.

[0062] Examples of the polyethylene glycol compound having one or both ends substituted with a hydrophobic group include α,ω-dibenzyl polyethylene glycol and α,ω-didodecyl polyethylene glycol. In addition, it may be a copolymer of polyethylene glycol and a hydrophobic monomer such as dichlorodiphenyl sulfone having halogen groups at both ends of the molecule.

[0063] Examples of water-insoluble hydrophilic polymers include polyethylene terephthalate, polyether sulfone, etc. obtained by polycondensation, wherein hydrogen atoms in the main chain are replaced by hydrophilic groups, and polyethylene terephthalate, polyether sulfone, etc. are hydrophilized. Hydrophilized polyethylene terephthalate, polyether sulfone, etc. may have hydrogen atoms in the main chain replaced by anionic groups or cationic groups, or may be a polymer having an equal amount of anionic groups and cationic groups.

[0064] The water-insoluble hydrophilic polymer may be a resin obtained by ring-opening the epoxy group of a bisphenol A type or novolac type epoxy resin, or a resin obtained by introducing a vinyl polymer, polyethylene glycol, etc. into the epoxy group. In addition, the water-insoluble hydrophilic polymer may be a silane-coupled resin. The water-insoluble hydrophilic polymer may be used alone or in combination of two or more.

[0065] As the water-insoluble hydrophilic polymer, random copolymers of hydrophilic monomers such as hydroxyethyl methacrylate, hydroxypropyl methacrylate, and dihydroxyethyl methacrylate, 3-sulfopropyl methacryloyloxyethyl dimethyl ammonium betaine, 2-methacryloyloxyethyl phosphorylcholine, and 1-carboxydimethyl methacryloyloxyethyl methanammonium and hydrophobic monomers such as butyl methacrylate and ethylhexyl methacrylate are preferred from the viewpoint of easy production. Random copolymers of hydrophilic monomers such as hydroxyethyl methacrylate, hydroxypropyl methacrylate, and dihydroxyethyl methacrylate, 3-sulfopropyl methacryloyloxyethyl dimethyl ammonium betaine, 2-methacryloyloxyethyl phosphorylcholine and 1-carboxydimethyl methacryloyloxyethyl methanammonium and hydrophobic monomers such as butyl methacrylate and ethylhexyl methacrylate are more preferred from the viewpoint of ease of selection of a solvent for a coating liquid when applying the water-insoluble hydrophilic polymer, dispersibility in the coating liquid, and handleability.

[0066] As a water-insoluble hydrophilic polymer obtained by making a water-soluble hydrophilic polymer insoluble in water during the film manufacturing process, for example, a water-soluble hydrophilic polymer obtained by copolymerizing a monomer having an azide group in a side chain with a hydrophilic monomer such as 2-methacryloyloxyethylphosphorylcholine may be applied to a hydrophobic polymer substrate film, and then heat-treated to covalently bond the water-soluble hydrophilic polymer to the substrate film, thereby making the water-soluble hydrophilic polymer insoluble in water. Alternatively, a hydrophilic monomer such as 2-hydroxyalkyl acrylate may be graft-polymerized onto a hydrophobic polymer substrate film.

[0067] As the hollow fiber membrane of this embodiment, or as the base membrane of this embodiment, a membrane formed by mixing a hydrophilic polymer and a hydrophobic polymer can also be used. The hydrophilic polymer used for the mixed membrane is not particularly limited as long as it is a polymer compatible with the hydrophobic polymer in a good solvent. As the hydrophilic polymer, a copolymer containing polyvinyl pyrrolidone or vinyl pyrrolidone is preferred.

[0068] As polyvinyl pyrrolidone, specifically, LUVITEC (trade name) K60, K80, K85, K90 etc. commercially available from BASF can be cited, preferably LUVITEC (trade name) K80, K85, K90. As the copolymer containing vinyl pyrrolidone, from the viewpoint of compatibility with hydrophobic polymers and inhibition of interaction between proteins and membrane surfaces, a copolymer of vinyl pyrrolidone and vinyl acetate is preferred.

[0069] From the viewpoint of suppressing the adsorption of proteins on the membrane surface and the interaction between proteins and polysulfone polymers in the membrane, the copolymerization ratio of vinyl pyrrolidone to vinyl acetate is preferably 6:4 to 9:1. Specific examples of copolymers of vinyl pyrrolidone and vinyl acetate include LUVISKOL (trade name) VA64 and VA73 commercially available from BASF. The hydrophilic polymer may be used alone or in combination of two or more.

[0070] [Cross-sectional structure of hollow fiber membrane]

[0071] The structure of the hollow fiber membrane including the polysulfone polymer of the present embodiment is an inclined structure in which the pore size changes continuously from the outer surface of the membrane toward the liquid contact surface. The inclined structure can be, for example, a sponge structure in which the pore size continuously decreases from the outer surface of the membrane toward the liquid contact surface (positive inclined structure), a sponge structure in which the pore size continuously decreases from the outer surface of the membrane toward the minimum pore size layer and the pore size continuously increases from the minimum pore size layer toward the liquid contact surface (reverse inclined structure), and a sponge structure in which the pore size continuously increases from the outer surface of the membrane toward the liquid contact surface (reverse inclined structure), but is not limited thereto.

[0072] By setting the cross-sectional structure of the hollow fiber membrane to a tilted structure in which the pore size changes continuously, clogging during the filtration of the protein solution can be suppressed, and useful components such as antibodies can be efficiently recovered. When the hollow fiber membrane of the present embodiment is used as a virus separation filtration membrane, it is preferably a membrane with a reverse tilted structure having a minimum pore size layer (dense layer) at the downstream portion of the membrane filtration.

[0073] In the present embodiment, the downstream filtering part refers to the range from the downstream filtering surface corresponding to one membrane surface to 10% of the membrane thickness, and the upstream filtering part corresponding to the other membrane surface refers to the range from the upstream filtering surface to 10% of the membrane thickness. For example, in a hollow fiber membrane, if liquid is passed to the outer surface side, the range from the inner surface to 10% of the membrane thickness is the downstream filtering part, and the range from the outer surface to 10% of the membrane thickness is the upstream filtering part. If liquid is passed to the inner surface side, the range from the inner surface to 10% of the membrane thickness is the upstream filtering part, and the range from the outer surface to 10% of the membrane thickness is the downstream filtering part. The hollow fiber membrane comprising a polyvinylidene fluoride polymer of the present embodiment is preferably a homogeneous structure in which the pore size difference from the outer surface of the membrane to the central part of the membrane cross section and from the central part of the membrane cross section to the liquid contact surface is less than 10 times.

[0074] The average pore size is calculated by using an image analysis method. Specifically, Image-pro plus manufactured by MediaCybernetics is used to perform binarization processing on the pore portion and the real part. The pore portion and the real part are identified based on brightness, and the unrecognizable parts and noise are corrected with a hand-drawn tool. The edge portion that will become the outline of the pore portion and the porous structure observed inside the pore portion are identified as pore portions. After the binarization process, the pore / 1 area value is assumed to be a perfect circle, and the pore size is calculated. This is performed for each of the pores, and the average pore size is calculated for each 1μm×2μm range. In addition, the pore portions that are interrupted at the end of the field of view are also counted.

[0075] Regarding the pore size of the hollow fiber membrane, the location where the average pore size of the pores present in the membrane is the smallest determines the retention performance of the membrane. The pore size (retention performance) of the membrane of the present embodiment is greater than 0.05 μm and less than 2 μm. If the average pore size of the minimum pore size layer is less than 0.05 μm, there is a tendency for the water permeability of the membrane to decrease, and if it exceeds 2 μm, there is a tendency for the removal performance of fine particles, etc. to decrease. The average pore size of the preferred minimum pore size layer is greater than 0.3 μm and less than 1 μm, and more preferably greater than 0.3 μm and less than 0.7 μm.

[0076] [Membrane pore retaining agent]

[0077] The membrane pore retainer in this embodiment is a substance that is pre-filled in the pores of the membrane during the manufacturing process before radiation sterilization in order to prevent the performance degradation caused by radiation sterilization. In order to make a component for manufacturing pharmaceuticals by bonding the membrane, it is necessary to sterilize the membrane, but it is well known that if a porous membrane made of organic polymers, including a hollow fiber membrane of hydrophobic polymers such as polysulfone and polyvinylidene fluoride, is subjected to radiation sterilization, the water permeability will be reduced compared to before sterilization due to changes in the membrane structure. If radiation sterilization (especially gamma ray sterilization) is performed without maintaining the membrane pore retainer in the pores of the membrane, there is a tendency to become a low-performance membrane different from that before radiation sterilization.

[0078] By cleaning and removing the membrane pore retainer after radiation sterilization, the effect of the membrane pore retainer can be used to maintain the same water permeability, blocking rate and other properties as the hollow fiber membrane before radiation sterilization. However, there is a report that the membrane pore retainer is present in trace amounts in the membrane and / or in the assembly, and thus, various derivatives generated by chemical reactions with the membrane pore retainer are considered to be a problem. However, the membrane of the present embodiment is not easy to produce derivatives because it uses a specific alcohol aqueous solution within a specific concentration range as a membrane pore retainer. The pH of the membrane pore retainer after radiation sterilization is neutral (7±0.5). Since an alcohol aqueous solution that does not affect the safety of pharmaceuticals is used, i.e., a membrane pore retainer, it is not necessary to clean and remove the membrane pore retainer after radiation sterilization. The hollow fiber membrane assembly can be directly used by the user side of the manufacturing pharmaceuticals while the membrane pore retainer is maintained in the empty hole portion of the membrane, that is, without cleaning and removing the membrane pore retainer.

[0079] [Alcohol aqueous solution]

[0080] As the alcohol aqueous solution, it is preferred to use an ethanol aqueous solution having an alcohol concentration of 8% by weight or more and 20% by weight or less, more preferably an ethanol aqueous solution having an alcohol concentration of 16% by weight or more and 19% by weight or less, and further preferably an ethanol aqueous solution having an alcohol concentration of 16% by weight or more and 18% by weight or less. In an ethanol aqueous solution having an alcohol concentration of less than 8% by weight, there is a tendency for the antibacterial effect to decrease. In an ethanol aqueous solution having an alcohol concentration exceeding 20% ​​by weight, it will be regarded as a dangerous substance, and transportation and storage become difficult. For example, an ethanol aqueous solution having an alcohol concentration of less than 18% by weight can be transported by air, and therefore, in order to quickly transport the hollow fiber membrane assembly to overseas users, an ethanol aqueous solution having an alcohol concentration of less than 18% by weight is preferred.

[0081] [Method for manufacturing hollow fiber membrane module]

[0082] The manufacture of the hollow fiber membrane module may include the following steps: (1) a manufacturing step of the hollow fiber membrane; (2) a bundling step of bundling a plurality of hollow fiber membranes to form a hollow fiber membrane bundle; (3) a module step of bonding the hollow fiber membrane bundle to a housing having a port; (4) a step of retaining a membrane pore retaining agent in the pores of the membrane; (5) a step of connecting a connector to the port to seal the inside of the housing; (6) a step of sterilizing the hollow fiber membrane module with radiation; (7) a step of packaging the hollow fiber membrane module. Then, (8) the user uses the hollow fiber membrane module.

[0083] [Hollow Fiber Membrane Manufacturing Process]

[0084] The hollow fiber membrane of the present embodiment is not particularly limited and can be manufactured as follows. A hydrophobic polymer (membrane-forming polymer), a solvent for the hydrophobic polymer, and a specific additive are mixed and dissolved, and the deaerated solution is used as a membrane-making stock solution, and is ejected from the annular portion and the central portion of a double tube nozzle (spinning port) together with an internal coagulation liquid, and is guided to a coagulation bath after passing through an empty walk portion to form a membrane. The obtained membrane is washed with water, wound, the liquid in the hollow portion is discharged, heat treated, and dried. Afterwards, the membrane can also be hydrophilized.

[0085] The solvent used in the membrane-forming stock solution can be widely used if it is a good solvent for polysulfone polymers such as N-methyl-2-pyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide, ε-caprolactam, etc., but amide solvents such as NMP, DMF, DMAc are preferred, and NMP is more preferred.

[0086] As the specific additive, polyvinyl pyrrolidone, polyethylene glycol, etc. are preferably used. In order to obtain a microfiltration membrane, a specific additive is required.

[0087] The film-forming stock solution essentially includes a film-forming polymer, specific additives such as polyvinyl pyrrolidone, and a solvent for the polymer. Other additives such as water and metal salts known as existing additives may also be added to the film-forming stock solution. The concentration of the film-forming polymer in the film-forming stock solution used in the present embodiment is not particularly limited as long as it is a concentration range in which the film can be formed from the stock solution and the obtained film has the performance as a film, and is 10 to 35% by weight, preferably 10 to 30% by weight. In order to achieve higher water permeability or a larger molecular weight cutoff, the polymer concentration is preferably lower, preferably 10 to 25% by weight.

[0088] The amount of the specific additive in the membrane stock solution is 1 to 30% by weight, preferably 1 to 20% by weight, and the optimal concentration is determined by the molecular weight used. The weight average molecular weight of the specific additive used is preferably in the range of 2,900 to 2,000,000, more preferably in the range of 30,000 to 1,500,000.

[0089] The film-forming stock solution is obtained by dissolving a polysulfone polymer, a good solvent, and a non-solvent while stirring at a certain temperature. The temperature at this time is preferably higher than 30 to 80°C at room temperature. Compounds containing nitrogen of level 3 or less (NMP, DMF, DMAc) are oxidized in the air and are easily further oxidized when heated. Therefore, the preparation of the film-forming stock solution is preferably carried out under an inert gas atmosphere. As the inert gas, nitrogen, argon, etc. can be cited. From the viewpoint of production cost, nitrogen is preferred.

[0090] It is preferred that foreign matter is removed from the film-forming stock solution before it is ejected from the spinning nozzle. By removing foreign matter, it is possible to prevent wire breakage during the spinning process and to control the structure of the membrane. In order to prevent foreign matter from being mixed in from the sealing gasket of the film-forming stock solution tank, it is preferred to set a filter before the film-forming stock solution is ejected from the spinning nozzle. It is also possible to set filters with different pore sizes in multiple stages, which is not particularly limited. For example, it is preferred to set a mesh filter with a pore size of 30 μm and a mesh filter with a pore size of 10 μm in sequence from the side closer to the film-forming stock solution tank.

[0091] The internal liquid is used to form the hollow part of the hollow fiber membrane, and is composed of a high-concentration aqueous solution of a good solvent relative to the membrane-forming polymer. For example, if the membrane-forming polymer is a bisphenol A-type aromatic polysulfone, the good solvent is a solvent selected from the group consisting of N-methyl-2-pyrrolidone and N,N-dimethylformamide. The high-concentration aqueous solution is preferably an aqueous solution containing 90% by weight or more of a good solvent. More preferably, it is an aqueous solution containing 93% by weight or more of a good solvent. If the content of the good solvent is less than 90% by weight, there is a tendency for peeling to occur near the inner surface of the membrane.

[0092] The hollow fiber membrane of the present embodiment can be produced using a known double annular nozzle of a tube-in-hole type. More specifically, the aforementioned membrane-making stock solution and the internal liquid are ejected simultaneously from the double annular nozzle, and after passing through a number of air gaps, they are immersed in a coagulation bath for coagulation, thereby obtaining the hollow fiber membrane of the present embodiment. The air gap referred to here refers to the gap between the nozzle and the coagulation bath. If the air gap is surrounded by a cylindrical tube, etc., and a gas with a certain temperature and humidity is made to flow into the air gap at a certain flow rate, the hollow fiber membrane can be manufactured in a more stable state.

[0093] As the coagulation bath, for example, water; alcohols such as methanol and ethanol; ethers; aliphatic hydrocarbons such as n-hexane and n-heptane, etc., which are liquids that do not dissolve the polymer, are used, but water is preferably used. In addition, the coagulation rate can also be controlled by slightly adding a solvent that dissolves the polymer to the coagulation bath. In order to obtain a precision filtration membrane with a pore size of 0.05 μm or more and 2 μm or less of the hollow fiber membrane, the temperature of the coagulation bath is from -30°C to 98°C, preferably from 0°C to 90°C, and more preferably from 0°C to 80°C. If the temperature of the coagulation bath exceeds 95°C or is lower than -30°C, there is a tendency that the state of the surface of the hollow fiber membrane in the coagulation bath is difficult to stabilize.

[0094] In order to obtain a precision filtration membrane, i.e., a hollow fiber membrane, having a pore size of 0.05 μm or more and 2 μm or less, the spinning nozzle temperature is preferably 10°C or more and 95°C or less. After the membrane stock solution is ejected from the spinning nozzle, it is introduced into the coagulation bath via the air run section. The residence time of the air run section is preferably 0.02 to 0.6 seconds. By setting the residence time to 0.02 seconds or more, the coagulation before introduction into the coagulation bath can be sufficient to form an appropriate pore size. By setting the residence time to 0.6 seconds or less, excessive coagulation can be prevented, and precise membrane structure control can be performed in the coagulation bath.

[0095] The hollow fiber membrane lifted from the coagulation bath is washed with warm water in a water washing bath and then wound into a ball with a winder. In the water washing process, it is preferred to reliably remove the solvent and the hydrophilic polymer not fixed to the membrane. If the hollow fiber membrane is dried in a state containing a solvent, the solvent is concentrated in the membrane during the drying process, and the polysulfone polymer dissolves or swells, which may change the membrane structure. If there are hydrophilic polymers that are not fixed to the membrane, it is possible to block the pores and reduce the permeability of the membrane. In order to increase the diffusion rate of the solvent / non-solvent to be removed and the hydrophilic polymer not fixed to the membrane and improve the water washing efficiency, the temperature of the warm water is preferably above 50°C. Nelson rollers are preferably used in the water washing process. In order to fully wash with water, the residence time of the hollow fiber membrane in the water washing bath is preferably 80 to 300 seconds. The longer the water washing process for the purpose of removing unwanted components, the better, but from the perspective of production efficiency, it is appropriate to set it to 300 seconds or less.

[0096] [Bundling step of bundling a plurality of hollow fiber membranes to form a hollow fiber membrane bundle]

[0097] The hollow fiber membrane lifted from the water washing bath is wound into a ball by a winder with a specified number of roots. The wound hollow fiber membrane is cut at both ends in a manner of a specified length to form a bundle, and is held by a support to prevent loosening. Then, the held hollow fiber membrane is immersed in hot water and washed. In the hollow part of the hollow fiber membrane wound into a ball, there remains a turbid liquid in which fine particles of polysulfone polymers ranging from nanometers to micrometers are floating. If the hollow fiber membrane is dried without removing the turbid liquid, sometimes the fine particles of the polysulfone polymer block the pores of the hollow fiber membrane and cause the membrane performance to decrease, so it is preferred to remove the turbid liquid in the hollow part. In the hot water treatment process, since the inner surface side of the hollow fiber membrane is also cleaned, the hydrophilic polymers that are not completely removed in the water washing process and are not fixed to the membrane can be efficiently removed. The temperature of the hot water is preferably 50 to 100°C. From the perspective of improving the cleaning efficiency, it is preferred to set the temperature of the hot water to 50°C or above. The cleaning time is preferably 30 to 120 minutes. It is preferred to replace the hot water several times during the cleaning process.

[0098] [Hydrophilicization of substrate film]

[0099] In the case of improving the hydrophilicity of the substrate membrane (hollow fiber membrane before coating), a coating process is performed. For example, the coating process when the hydrophilic treatment is performed by coating includes a drying process of the wound hollow fiber membrane bundle, an impregnation process of the substrate membrane (hollow fiber membrane bundle that has undergone a drying process) in the coating liquid, a dehydration process of the impregnated substrate membrane, and a drying process of the substrate membrane after dehydration. In the impregnation process, the substrate membrane is immersed in a hydrophilic polymer solution. The solvent of the coating liquid is a good solvent for the hydrophilic polymer. If it is a poor solvent for a polysulfone polymer, there is no particular restriction, but alcohol is preferably used. In order to fully cover the pore surface of the substrate membrane with a hydrophilic polymer, the concentration of the water-insoluble hydrophilic polymer in the coating liquid is preferably 1.0% by mass or more, and from the viewpoint of covering with an appropriate thickness and preventing the pore size from becoming too small and causing a decrease in Flux, it is preferably 10.0% by mass or less. The immersion time of the substrate membrane in the coating liquid is preferably 8 to 24 hours.

[0100] In the dehydration process, the base film immersed in the coating liquid for a predetermined time is dehydrated by centrifugation to remove the excess coating liquid attached to the hollow part and the periphery of the film. From the viewpoint of preventing the films after drying from being fixed to each other due to the remaining hydrophilic polymer, the centrifugal force during the centrifugation is preferably set to 10G or more, and the centrifugation time is preferably set to 30 minutes or more.

[0101] [Assembly step of bonding the hollow fiber membrane bundle to the housing having the port]

[0102] After the drying process of the wound hollow fiber membrane bundle or the drying process of the substrate membrane after dehydration, the hollow fiber membrane bundle is stored in a cylindrical component shell (housing), and the two ends are fixed in a liquid-tight manner using a thermosetting adhesive polymer such as epoxy resin, polyurethane resin, epoxy acrylate resin, silicone rubber, etc., and then the adhesive ends are cut to open the hollow part of the hollow fiber membrane, thereby arranging the hollow fiber membrane bundle in the housing. In order to improve the curing shrinkage and strength of the adhesive polymer, the polymer may also contain fibrous materials such as glass fiber and carbon fiber, carbon black, alumina, silica and other fine powders.

[0103] [Material of housing and port]

[0104] As the material of the assembly housing (housing) and the port when the hollow fiber membrane of the present embodiment is assembled, a material that can pass through radiation and has sterilization resistance (radiation resistance) is selected. For example, the shell and port of plastics such as polysulfone, polyethersulfone, polyethylene, polypropylene, polybutene, ABS resin, polyvinyl chloride, polyvinylidene fluoride, polytetrafluoroethylene, polycarbonate, polyetherketone, polyphenylene ether, polyphenylene sulfide, glass fiber, and plastics reinforced by carbon fiber are selected. In the case where the shell uses a distribution plate (rectifier, baffle, etc.), the assembly housing and the distribution plate do not have to be the same material. Since it is a component for manufacturing pharmaceuticals, in order to form a shell and a port with sterilization resistance and alcohol resistance, these materials are preferably aromatic polysulfone, aromatic polyethersulfone, polyethylene, polypropylene, polybutene, ABS resin, glass fiber, etc. It can also be that the diameter of the shell is selected from the range of more than 30mm and less than 1500mm, and the length is selected from the range of more than 300mm and less than 3000mm.

[0105] [Step of holding a membrane pore retaining agent in the pores of the membrane]

[0106] After the hollow fiber membrane in the assembly is immersed in the liquid membrane pore retaining agent, the membrane pore retaining agent (except for the membrane pore retaining agent retained in the empty pore portion of the membrane) is removed from the assembly, thereby enabling the empty pore portion in the membrane to be filled (retained) with the membrane pore retaining agent. By sealing the assembly (inside the housing) after removing the liquid membrane pore retaining agent from the assembly, the membrane pore retaining agent can be continuously retained in the empty pore portion of the membrane over time. When the hollow fiber membrane in the assembly is immersed in the liquid membrane pore retaining agent, the liquid membrane pore retaining agent can also be passed from the outer surface of the membrane to the inner surface, or from the inner surface of the membrane to the outer surface.

[0107] [Process of connecting the connector to the port and sealing the inside of the assembly (inside the housing)]

[0108] The connector is a sterile connector (sterile connection interface). Methods for connecting the connector to the port include a method of integrating the connector and the port by bonding or welding, a method of connecting the connector and the port by tube, etc., but are not limited to these. The tube connection between the connector and the port refers to embedding (inserting) the connector and the port end (convex portion) at both ends of the tube (tubular plastic tube), and fixing the connector and the port end embedded in the tube with a tube band or the like. When connecting the port to the tube, it is easier to embed (insert) the convex portion of the reducer into the tube by pre-connecting or integrating the port and a component such as a reducer. As the reducer, for example, if it is a nozzle-shaped port, a component (adapter) having a nozzle and a convex portion (protruding portion) can be exemplified, the nozzle being fixed by a clamping band via a gasket so as to be connectable to the port, and the convex portion having a size that can be embedded (inserted) into the tube (refer to Figure 1 ). By connecting the sterile connector to all the ports of the component, the inside of the component (inside the housing) can be sealed (isolated from the outside world).

[0109] Figure 1 It is a schematic cross-sectional view showing the structure of the hollow fiber membrane assembly. The aseptic connector of this embodiment is formed by installing a connector 7 or a connector 9 corresponding to each port 14a and 14b, and / or 15a and 15b of the hollow fiber membrane assembly 1. The reducing tube 5 or the reducing tube 2 is connected to each port via a gasket using a clamping band 4 or a clamping band 3. For example, the reducing tube 5 and the connector 7 are inserted into the tube 6 and fixed respectively using a tube band 11. The relationship between other reducing tubes and connectors is also the same.

[0110] The hollow fiber membrane module 1 is, for example, Figure 1 As shown, there is a cylindrical housing 10 with both ends in the longitudinal direction closed, and a plurality of, for example, four ports (liquid passages) 14a and 14b, and / or 15a and 15b provided on the housing 10 and used to allow liquid to flow into or out of the housing 10. For example, the ports 14a and 14b are provided at both ends in the longitudinal direction of the housing 10, and the ports 15a and 15b are provided on the outer peripheral surface of the main body of the housing 10.

[0111] A plurality of hollow fiber membranes 12 in a tubular shape are provided in the housing 10. The hollow fiber membranes 12 are arranged along the longitudinal direction of the housing 10, extending from near one end of the housing 10 to near the other end. Support members 13 for supporting the hollow fiber membranes 12 are provided near both ends in the longitudinal direction of the housing 10. The support members 13 are formed, for example, in a disc shape suitable for the internal shape of the housing 10, support the ends of the hollow fiber membranes 12, and separate the space A (the space where the ports 14a and 14b are opened) outside each support member 13 from the space B inside the two support members 13. Both ends of the hollow fiber membrane 12 are opened to the space A communicating with the ports 14a and 14b, respectively. Therefore, for example, the liquid flowing in from the port 14a or the port 14b passes through the tube of the hollow fiber membrane 12, and the liquid passing through the side wall of the hollow fiber membrane 12 flows out to the space B between the two support members 13. When passing through the side wall of the hollow fiber membrane 12, a predetermined substance is separated from the liquid. In addition, connectors 7 (see Figure 1 ) The connector 7 may be directly mounted on the ports 14a and 14b or may be mounted via a tube or the like.

[0112] Ports 15a and 15b are connected to the space B between the two support members 13. Therefore, for example, the liquid separated by the hollow fiber membrane 12 can be discharged from ports 15a and 15b. Each port of the present embodiment is formed into a circular tube, for example, and a ring-shaped nozzle is formed at the opening end of the top. In addition to the nozzle, a flange, a threaded pipe, a thread, etc. can also be used. Although Figure 1 Although not shown in detail, the ports 15a and 15b of this embodiment have a tapered shape whose inner diameter gradually decreases as it approaches the main body of the housing 10. The connector 9 (see Figure 1 ) The connector 9 may be directly mounted on the ports 15a and 15b or may be mounted via a tube or the like.

[0113] like Figure 1 As shown, the membrane area is 3.5m 2 In the above hollow fiber membrane modules, the shapes or sizes of the ports 14 and 15 are greatly different, and therefore at least two types of connectors are required.

[0114] As a sterile connector, a connector capable of performing a sealed aseptic connection coupling is preferred. In order to connect a hollow fiber membrane assembly on a pharmaceutical production line, it is necessary to sterilize by, for example, flowing high-temperature steam through a portion connected to the hollow fiber membrane assembly. Such an operation is not required in a connector capable of performing a sealed aseptic connection coupling. Therefore, by using a connector capable of performing a sealed aseptic connection coupling, a hollow fiber membrane assembly that can be directly used by a user who manufactures pharmaceuticals can be provided. As a connector capable of performing a sealed aseptic connection coupling, for example, AQG17012HT or AQL17016HT manufactured by Colder Products Company can be exemplified. Since this connector has sterilization resistance and alcohol resistance, it can be preferably used by a user who manufactures pharmaceuticals.

[0115] The connector is connected to a liquid flow path. The liquid flow path refers to a flow path for supplying liquid filtered by the hollow fiber membrane and a flow path for recovering the liquid filtered by the hollow fiber membrane.

[0116] [Process of sterilizing hollow fiber membrane modules with radiation]

[0117] The hollow fiber membrane assembly is packaged with a plastic film (wrapping film) formed of a resin having durability for sterilization radiation exposure, and then irradiated with radiation after being packed into a turnover box. The packaging is preferably multiple packaging. From the convenience of packing into the turnover box, the distance between the port and the connector connected to the port via a tube or the like is preferably greater than 0 mm and less than 100 mm. The above-mentioned package is transported to the radiation sterilization facility of the sterilization operator, and the radiation irradiation for sterilization can be entrusted to the operator, and the package returned after the radiation irradiation can be checked, inspected and shipped.

[0118] The radiation mentioned in this embodiment uses α rays, β rays, γ rays, X rays, ultraviolet rays, electron rays, etc. In recent years, from the viewpoint of less residual toxicity and simplicity, radiation sterilization using γ rays and electron rays is often used. In order to sterilize with γ rays, 15kGy or more is effective. If the irradiation dose is more than 100kGy, it may cause three-dimensional crosslinking and disintegration of hydrophilic polymers.

[0119] [Packaging process of hollow fiber membrane modules]

[0120] A sterilized hollow fiber membrane assembly is placed in a bag made of a packaging film, and the bag is sealed and stored in a packaging box. In order to seal, a pair of packaging films constituting the bag are overlapped, and the packaging films are heat-melted (thermally welded) using a heat sealer or the like. In order to prevent the deterioration of the outer shell, etc. caused by oxygen, reduced pressure packaging (sealing) is usually performed at a pressure lower than atmospheric pressure. The bending rigidity of the packaging film measured by the KES method is preferably 0.1 gf·cm 2 / cm or more and 4.0gf·cm 2 / cm or less. If the bending rigidity is less than 0.1gf·cm 2 / cm, there is a tendency to resist stretching and poor workability. If the bending rigidity exceeds 4.0 gf·cm 2 / cm, there is a tendency that the packaging film becomes an obstacle and the packaged hollow fiber membrane module cannot be smoothly placed in the packaging box, or the packaging box is damaged.

[0121] The packaging film can be a laminate of multiple resin films of different types. Specifically, the packaging film has an outermost layer, an intermediate layer, and a welding layer in sequence. The outermost layer and the intermediate layer are bonded to each other by dry lamination using an adhesive, for example. An adhesive layer for bonding the intermediate layer and the welding layer may also be provided between the intermediate layer and the welding layer.

[0122] The middle layer is a gas barrier layer that prevents the permeation of gases such as oxygen. The middle layer is composed of, for example, nylon or ethylene-vinyl alcohol copolymer (EVOH). The welding layer seals the bag composed of the packaging film after the film product is packaged with the packaging film. A pair of packaging films are overlapped and the welding layer of one packaging film is in contact with the welding layer of another packaging film. The packaging films are heated. As a result, the resins constituting each welding layer are melted. Then, the packaging films are bonded to each other by solidifying the resin. The welding layer is composed of, for example, polyolefins such as polyethylene and polypropylene. Linear low-density polyethylene (LLDPE) is suitable as a material for the welding layer. The thickness of the welding layer is, for example, in the range of more than 40% and less than 70% of the thickness of the packaging film. In one example, the thickness of the welding layer is more than 50 μm and less than 80 μm. The adhesive layer is also composed of, for example, polyolefins such as polyethylene and polypropylene.

[0123] Example

[0124] Hereinafter, the present embodiment will be described in detail by way of examples, but the present invention is not limited to the following examples. The measurement methods described in the examples are as follows.

[0125] (1) Measurement of inner diameter and film thickness

[0126] The inner diameter of the hollow fiber membrane was obtained by photographing a vertical cross section of the membrane using a stereo microscope. The outer diameter was obtained in the same way as the inner diameter, and the membrane thickness was obtained by (outer diameter - inner diameter) / 2. The membrane area was calculated based on the inner diameter and the effective length of the hollow fiber membrane.

[0127] (2) Measurement of pure water permeation rate

[0128] Measure pure water at 25°C in an assembled membrane with an effective membrane area of ​​3.3 cm 2 The filtration volume is obtained by dead-end filtration at a constant pressure of 1.0 bar in the filter, and the water permeability is calculated based on the filtration time.

[0129] (3) Antibacterial test

[0130] Staphylococcus aureus strain (NBRC12732) or Escherichia coli strain (NBRC3972) was cultured in a culture medium at 36±2°C, and the grown colonies were scraped and sterilized for ion exchange suspension to prepare about 109 CFU / mL, which was used as the test bacterial solution. Remove the outer shell of the hollow fiber membrane module with sterile connectors connected to all ports (located at Figure 1Remove the outer shell (the entire outer shell between port 15a and port 15b) and spray the test bacterial solution evenly over the entire hollow fiber membrane bundle. Set the removed outer shell in its original form and fix it with adhesive tape. At this time, confirm that the inside of the outer shell is completely sealed. Store the hollow fiber membrane assembly at about 25°C. After the specified time, remove the outer shell of the hollow fiber membrane assembly (located at Figure 1 The hollow fiber membrane was extracted from the outer shell between port 15a and port 15b of the hollow fiber bundle) to form a square (test piece) of 50±2 mm, and the square was fixed with a needle (the thickness of the square was one hollow fiber membrane). The number of attached bacteria was measured by the same method as described in JIS Z 2801 (2012) with N=5 (1 point each at the top, middle, and bottom in the length direction of the surface of the hollow fiber bundle, and 2 points in the center of the hollow fiber bundle) and the average value was obtained. Bacteria reduction rate (increase rate) = number of viable bacteria in the test piece after a specified time (cfu) / number of inoculated bacteria at the beginning (cfu)

[0131] [Example 1]

[0132] [Preparation of polyvinyl pyrrolidone solution and filtration of the solution]

[0133] 600 g of polyvinyl pyrrolidone (manufactured by BASF, K value 90, weight average molecular weight 1,200,000) dried at a temperature of 100° C. or less to a water content of 0.3% by mass or less was dissolved in 7,400 g of N-methyl-2-pyrrolidone to prepare a uniform solution (polyvinyl pyrrolidone solution).

[0134] The solution was kept at 70°C and filtered using a stainless steel sintered filter with a pore size of 2 μm (NS-0S02 manufactured by Nippon Seisen Co., Ltd., effective filtration area 20 cm 2 ), with a filtration flow rate of 2 mL / (min·cm 2 During the filtration process, the sintered filter was immersed in an ultrasonic cleaning machine, and ultrasonic vibration of 59 kHz (power 3 kW) was always applied to the polyvinyl pyrrolidone solution.

[0135] [Film formation and removal of residual solvent]

[0136] 200 g of aromatic polysulfone (P-1700 manufactured by Amoco Engineering Polymers Co., Ltd.) was added to 800 g of the solution (polyvinyl pyrrolidone solution) after filtration through the filter to prepare a uniform solution (membrane stock solution). In order to remove the undissolved matter of polysulfone, a filter with a pore size of 5 μm (manufactured by Fuji Filter Co., Ltd., FD-5, effective filtration area 40 cm2) was used. 2) The film-forming stock solution was filtered. Here, the mixing ratio of polyvinyl pyrrolidone to polysulfone in the film-forming stock solution was 27.2 wt %. The film-forming stock solution was kept at 60°C, ejected from a spinning nozzle (double annular nozzle 0.5 mm-0.7 mm-1.3 mm, nozzle temperature 60°C, temperature of the film-forming stock solution at the nozzle portion 60°C) together with an internal liquid (water content 5 wt %) consisting of a mixed solution of 95 wt % N-methyl-2-pyrrolidone and 5 wt % water, passed through an air gap of 60 mm, and immersed in a coagulation bath consisting of water at 70±1°C.

[0137] At this time, the area from the spinning nozzle to the coagulation bath is surrounded by a cylindrical tube, which is sealed so that the outside air cannot enter. The spinning speed is fixed at 20 m / min. After the wound fiber bundle is cut, 80°C hot water is sprayed from above the cut surface of the fiber bundle for 2 hours for cleaning, thereby removing the residual solvent in the membrane.

[0138] The obtained membrane was observed with an electron microscope, and it was confirmed that it was a sponge structure (reverse tilt structure) in which the pore size continuously decreased from the outer surface of the membrane to the minimum pore size layer, and the pore size continuously increased from the minimum pore size layer to the inner surface. The membrane surface with the largest pore size was the inner surface of the membrane, and the minimum pore size layer existed near the outer surface of the membrane. It was confirmed that the breaking strength of the membrane was as high as 50kgf / cm 2 More than 1000mL / (m 2 ·hr·mmHg) or more. Moreover, there was no sudden clogging during the internal pressure filtration of latex particles with an average particle size of 0.273μm, and the filtrate volume was maintained for a long time. The outer diameter of the obtained hollow fiber membrane was 1.5mm and the membrane thickness was 0.3mm.

[0139] [Manufacturing of hollow fiber membrane modules]

[0140] The bundle of wound hollow fiber membranes was loaded onto the hollow fiber membrane so that the effective membrane area (converted into the membrane inner surface) of the hollow fiber membrane was 3.5 m 2 In a polysulfone cylindrical container having a port, both ends are bonded and fixed with polyurethane resin, and both end faces are cut to form the open ends of the hollow fiber membrane. Furthermore, head caps having ports are installed at both ends.

[0141] [Maintaining the membrane pore retaining agent in the pores of the hollow fiber membrane]

[0142] A membrane pore retainer consisting of an alcohol aqueous solution with an ethanol concentration of 18% by weight is sealed in the component for 1 hour. The membrane pore retainer is removed by dripping. After being removed from the component, a sterile connector is installed at each port, thereby sealing the inside of the component (inside the housing). Figure 1Reference numerals 14a and 14b are provided with AQL17016HT manufactured by Colder Products Company, and reference numerals 15a and 15b are provided with AQG17012HT manufactured by Colder Products Company. These aseptic connectors are connectors capable of aseptic connection and coupling without requiring sterilization of a liquid separator at the user's side.

[0143] [Antibacterial test results]

[0144] The antibacterial test results of the hollow fiber membrane module are shown in Table 1. It was found that the membrane pore retaining agent used had excellent antibacterial properties.

[0145] Table 1

[0146]

[0147] [Water permeability after γ-ray sterilization]

[0148] Table 1 shows the water permeability results of the hollow fiber membrane module after γ-ray sterilization at 25 kGy. It is clear that there is no decrease in water permeability. The pH of the membrane pore retaining agent after sterilization is neutral. It is clear that the user does not need to wash and remove the membrane pore retaining agent.

[0149] From the above, it is clear that the hollow fiber membrane component of the embodiment is a hollow fiber membrane component as follows: by retaining a membrane pore retaining agent with excellent antibacterial properties and sterilization resistance that does not affect the safety of the medicine in the pores of the hollow fiber membrane, the convenience is improved by not requiring the user's liquid separator to be sterilized, and the convenience is improved by using a membrane pore retaining agent and not requiring sterilization, so that it can be directly used by users who manufacture medicines.

[0150] [Example 2]

[0151] The same operation as in Example 1 was performed except that the ethanol concentration was 8% by weight. Table 1 shows the antibacterial test results of the hollow fiber membrane module and the water permeability results after γ-ray sterilization. It is clear that the membrane pore retaining agent used has excellent antibacterial properties. In addition, it is clear that there is no reduction in water permeability. The pH of the membrane pore retaining agent after sterilization is neutral. Therefore, it is clear that the user does not need to clean and remove the membrane pore retaining agent.

[0152] From the above, it is clear that the hollow fiber membrane component of the embodiment is a hollow fiber membrane component as follows: by retaining a membrane pore retaining agent with excellent antibacterial properties and sterilization resistance that does not affect the safety of the medicine in the pores of the hollow fiber membrane, the convenience is improved by not requiring the user's liquid separator to be sterilized, and the convenience is improved by using a membrane pore retaining agent and not requiring sterilization, so that it can be directly used by users who manufacture medicines.

[0153] [Example 3]

[0154] The same operation as in Example 1 was performed except that the ethanol concentration was 20% by weight. Table 1 shows the antibacterial test results of the hollow fiber membrane module and the water permeability results after γ-ray sterilization. It is clear that the membrane pore retaining agent used has excellent antibacterial properties. In addition, it is clear that there is no reduction in water permeability. The pH of the membrane pore retaining agent after sterilization is neutral. Therefore, it is clear that the user does not need to clean and remove the membrane pore retaining agent.

[0155] From the above, it is clear that the hollow fiber membrane component of the embodiment is a hollow fiber membrane component as follows: by retaining a membrane pore retaining agent with excellent antibacterial properties and sterilization resistance that does not affect the safety of the medicine in the pores of the hollow fiber membrane, the convenience is improved by not requiring the user's liquid separator to be sterilized, and the convenience is improved by using a membrane pore retaining agent and not requiring sterilization, so that it can be directly used by users who manufacture medicines.

[0156] [Comparative Example 1]

[0157] The same operation as in Example 1 was performed except that the ethanol concentration was 6 wt%. Table 1 shows the antibacterial test results of the hollow fiber membrane module and the water permeability results after γ-ray sterilization. It was clear that the membrane pore retaining agent used had poor antibacterial properties. In addition, it was clear that the water permeability was greatly reduced.

[0158] [Example 4]

[0159] A hollow fiber membrane including polyvinylidene fluoride (PVDF-TP manufactured by Asahi Kasei Chemicals, outer diameter 2 mm, membrane thickness 0.3 mm, average pore diameter 0.45 μm, and a homogeneous membrane cross-section) was used, and the same operation as in Example 1 was performed except that. Table 1 shows the antibacterial test results of the hollow fiber membrane assembly and the water permeability results after gamma-ray sterilization. It is clear that the membrane pore retaining agent used has excellent antibacterial properties. In addition, it is clear that there is no reduction in water permeability. The pH of the membrane pore retaining agent after sterilization is neutral. Therefore, it is clear that the user does not need to clean and remove the membrane pore retaining agent.

[0160] From the above, it is clear that the hollow fiber membrane component of the embodiment is a hollow fiber membrane component as follows: by retaining a membrane pore retaining agent with excellent antibacterial properties and sterilization resistance that does not affect the safety of the medicine in the pores of the hollow fiber membrane, the convenience is improved by not requiring the user's liquid separator to be sterilized, and the convenience is improved by using a membrane pore retaining agent and not requiring sterilization, so that it can be directly used by users who manufacture medicines.

[0161] [Example 5]

[0162] The same operation as in Example 4 was performed except that the ethanol concentration was 8% by weight. Table 1 shows the antibacterial test results of the hollow fiber membrane module and the water permeability results after γ-ray sterilization. It is clear that the membrane pore retaining agent used has excellent antibacterial properties. In addition, it is clear that there is no reduction in water permeability. The pH of the membrane pore retaining agent after sterilization is neutral. Therefore, it is clear that the user does not need to clean and remove the membrane pore retaining agent.

[0163] From the above, it is clear that the hollow fiber membrane component of the embodiment is a hollow fiber membrane component as follows: by retaining a membrane pore retaining agent with excellent antibacterial properties and sterilization resistance that does not affect the safety of the medicine in the pores of the hollow fiber membrane, the convenience is improved by not requiring the user's liquid separator to be sterilized, and the convenience is improved by using a membrane pore retaining agent and not requiring sterilization, so that it can be directly used by users who manufacture medicines.

[0164] [Example 6]

[0165] The same operation as in Example 4 was performed except that the ethanol concentration was set to 20% by weight. Table 1 shows the antibacterial test results of the hollow fiber membrane module and the water permeability results after γ-ray sterilization. It is clear that the membrane pore retaining agent used has excellent antibacterial properties. In addition, it is clear that there is no reduction in water permeability. The pH of the membrane pore retaining agent after sterilization is neutral. Therefore, it is clear that the user does not need to clean and remove the membrane pore retaining agent.

[0166] From the above, it is clear that the hollow fiber membrane component of the embodiment is a hollow fiber membrane component as follows: by retaining a membrane pore retaining agent with excellent antibacterial properties and sterilization resistance that does not affect the safety of the medicine in the pores of the hollow fiber membrane, the convenience is improved by not requiring the user's liquid separator to be sterilized, and the convenience is improved by using a membrane pore retaining agent and not requiring sterilization, so that it can be directly used by users who manufacture medicines.

[0167] [Comparative Example 2]

[0168] The same operation as in Example 4 was performed except that the ethanol concentration was 6 wt%. Table 1 shows the antibacterial test results of the hollow fiber membrane module and the water permeability results after γ-ray sterilization. It was clear that the antibacterial property of the membrane pore retaining agent used was poor. In addition, it was clear that the water permeability was greatly reduced.

[0169] Industrial Applicability

[0170] The hollow fiber membrane component of this embodiment improves convenience by retaining a membrane pore retaining agent with excellent antibacterial properties and sterilization resistance that does not affect the safety of pharmaceuticals in the pores of the hollow fiber membrane, thereby eliminating the need for sterilization of the user's liquid separator. By using a membrane pore retaining agent and eliminating the need for sterilization, the component can be directly used by users who manufacture pharmaceuticals, and is therefore suitable for use in industry.

Claims

1. A hollow fiber membrane module, wherein: The hollow fiber membrane module has: a housing having at least two ports; a hollow fiber membrane disposed in the housing; and Two or more sterile connectors are mounted on the ports of the housing to connect the housing to the liquid flow line without sterilization. The hollow fiber membrane module is sterilized in a sealed state in which the pores of the hollow fiber membrane are maintained by a membrane pore retaining agent composed of an alcohol aqueous solution and the port is integrated with or connected to the sterile connector. The alcohol concentration in the alcohol aqueous solution is 8% by weight or more and 20% by weight or less.

2. The hollow fiber membrane module according to claim 1, wherein: The hollow fiber membrane is a microfiltration membrane having a pore size of 0.05 μm or more and 2 μm or less.

3. The hollow fiber membrane module according to claim 1, wherein: The hollow fiber membrane is a microfiltration membrane having a pore diameter of 0.3 μm or more and 1 μm or less.

4. The hollow fiber membrane module according to claim 1, wherein: The hollow fiber membrane includes a polyvinylidene fluoride polymer or a polysulfone polymer.

5. The hollow fiber membrane module according to claim 1, wherein: The alcohol is ethanol.

6. The hollow fiber membrane module according to claim 1, wherein: The pH of the membrane pore retaining agent after sterilization is neutral.

7. The hollow fiber membrane module according to claim 1, wherein: The aseptic connector is a connector capable of aseptic connection coupling.

8. The hollow fiber membrane module according to claim 1, wherein: The distance between the port and the sterile connector connected to the port is greater than or equal to 0 mm and less than or equal to 100 mm.

9. The hollow fiber membrane module according to claim 1, wherein: The number of the aseptic connectors integrated with or connected to the port is at least two or more.

10. The hollow fiber membrane module according to claim 1, wherein: The housing, the port, the hollow fiber membrane, and the sterile connector are sterilization-resistant and alcohol-resistant.

11. The hollow fiber membrane module according to claim 1, wherein: The sterilization is radiation sterilization.

12. The hollow fiber membrane module according to claim 11, wherein: The radiation sterilization is gamma ray sterilization.

13. The hollow fiber membrane module according to claim 1, wherein: The membrane area of ​​the hollow fiber membrane is 3.5m 2 above.

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