JP7490867B1 - Hollow fiber membrane module - Google Patents

Abstract

[Problem] To provide a hollow fiber membrane module that can improve convenience by eliminating the need for sterilization of a liquid separator on the user side. [Solution] A hollow fiber membrane module comprising a housing having at least two ports, a hollow fiber membrane disposed in the housing, and at least two or more sterile connectors that are attached to the ports and connect the housing to a liquid distribution line, eliminating the need for sterilization, the hollow fiber membrane module being sterilized in a state in which the pores of the hollow fiber membrane are held by a membrane pore retaining agent made of an alcohol aqueous solution, and in a sealed state in which the port and the sterile connector are integrated or connected, and the alcohol concentration in the alcohol aqueous solution is 8% by weight or more and 20% by weight or less. [Selected Figure] Figure 1

Description

The present invention relates to a hollow fiber membrane module.

In recent years, there has been remarkable progress in technology that utilizes membranes with selective permeability, and they have been put to practical use in a wide range of fields, including gas and liquid separation filters, hemodialysis machines, hemofilters, and selective blood component separation filters in the medical field.

Polymers such as cellulose-based (regenerated cellulose-based, cellulose acetate-based, chemically modified cellulose-based, etc.), polyacrylonitrile-based, polymethyl methacrylate-based, polysulfone-based, polyvinylidene fluoride-based, polyethylene vinyl alcohol-based, and polyamide-based have been used as materials for the membrane.

Of these, polysulfone-based polymers have attracted attention as semipermeable membrane materials and have been the subject of much research due to their thermal stability, acid resistance, and alkali resistance, as well as the fact that adding a hydrophilizing agent to the membrane-forming solution improves blood compatibility.

Membranes must be sterilized to create modules for manufacturing pharmaceuticals by bonding them together. However, it is known that when porous membranes made of organic polymers, particularly hollow fiber membranes made of hydrophobic polymers such as polysulfone and polyvinylidene fluoride, are sterilized by radiation, the membrane structure changes and the water permeability decreases compared to before sterilization. For this reason, the membranes must always be handled in a wet state or immersed in water.

The conventional method to deal with this problem has been to fill the pores of the hollow fiber membrane before sterilization with a low-volatile organic liquid such as glycerin (see, for example, Patent Document 1). However, low-volatile organic liquids are generally highly viscous, so washing and removing them takes time, and there is a problem in that even if the hollow fiber membrane module is washed by the user after sterilization, small amounts of eluates derived from the low-volatile organic liquid (various derivatives produced by chemical reactions with the low-volatile organic liquid) are found in the liquid filled in the module.

Furthermore, if the membrane is always kept wet before sterilization, or is immersed in water, or the pores in the porous membrane are filled with a low-volatile organic liquid such as glycerin, bacteria will grow during the time until sterilization, making the bacteriostasis undesirable.

As a method for exerting antibacterial performance (bacteriostasis) without using a low-volatile organic liquid, Patent Document 2 shows a method using an aqueous solution of an inorganic salt such as calcium chloride instead of a low-volatile organic liquid, but it is still necessary to wash off the aqueous solution. In addition, there is a concern that even a small amount of remaining inorganic salt may have an adverse effect on the production of pharmaceuticals.

Meanwhile, in virus removers that remove viruses from blood products and blood purifiers that remove unwanted substances from blood during dialysis, etc., liquid separators that pass liquid such as blood products through the liquid and separate specific substances from the liquid have traditionally been used. A liquid separator has, for example, hollow fibers inside a housing, and allows liquid to flow in through a primary port (fluid passage port) formed in the housing, separates specific substances using the hollow fibers, and allows the liquid to flow out from a secondary port.

In general, the liquid separator (hollow fiber membrane module) as described above is sterilized with, for example, a connector or a balloon attached to each port, and then shipped or transported as a kit. Sterilization is performed by high-pressure steam sterilization, in which, for example, the housing is filled with water, the liquid separator is placed in a sterilization bag with each port closed, and exposed to high temperature and high pressure for a predetermined time (see, for example, Patent Document 3). The reason for performing moist heat sterilization in a state filled with water and with each port closed (where pressure changes can be absorbed and gas permeation can be permitted by balloons, etc.) is to prevent the inside of the housing from drying out due to the sterilization process and to maintain a sterile state, and also to maintain the wettability of the hollow fibers until the liquid separator is used, so that the separation performance of the hollow fibers can be fully demonstrated from the start of use. High-pressure steam sterilization is less suitable for mass production of hollow fiber membrane modules than radiation sterilization, and is particularly undesirable for producing large hollow fiber membrane modules with a large membrane area of 3.5 ^m2 or more, since there is no corresponding high-pressure steam sterilization equipment.

JP 2023-036006 A Patent No. 7237656 JP 2003-245329 A

The present invention aims to provide a hollow fiber membrane module that can be immediately used by users who manufacture pharmaceuticals by retaining a membrane pore retaining agent that has excellent bacteriostatic and sterilization resistance and does not affect the safety of pharmaceuticals in the pores of the hollow fiber membrane, eliminating the need for sterilization of the liquid separator on the user side and improving convenience, and by using the membrane pore retaining agent and eliminating the need for sterilization, improving convenience.

As a result of intensive research and repeated experiments to solve the above problems, the inventors discovered that the above problems could be solved by configuring the hollow fiber membrane module in a specific way, and thus completed the present invention.

That is, the present invention is as follows.
[1] A hollow fiber membrane module comprising: a housing having at least two ports; a hollow fiber membrane disposed within the housing; and a sterile connector attached to the port and connecting the housing to a liquid distribution line, the sterile connector eliminating the need for a sterilization process, the hollow fiber membrane module comprising at least two or more sterile connectors, the hollow fiber membrane module being sterilized in a state in which the pores of the hollow fiber membrane are retained by a membrane pore retaining agent made of an alcohol aqueous solution, and in a sealed state in which the port and the sterile connector are integrated or connected, the hollow fiber membrane module having an alcohol concentration of 8% by weight or more and 20% by weight or less.

[2] The hollow fiber membrane module described in [1], wherein the hollow fiber membrane is a precision filtration membrane having a pore size of 0.05 μm or more and 2 μm or less.

[3] The hollow fiber membrane module described in [1], wherein the hollow fiber membrane is a precision filtration membrane having a pore size of 0.3 μm or more and 1 μm or less.

[4] The hollow fiber membrane module described in [1], in which the hollow fiber membrane is made of a polyvinylidene fluoride-based polymer or a polysulfone-based polymer.

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

[6] The hollow fiber membrane module described in [1], in which the pH of the membrane pore retaining agent after sterilization is neutral.

[7] The hollow fiber membrane module described in [1], in which the sterile connector is a sterile connection coupling connector.

[8] The hollow fiber membrane module described in [1], in which the distance between the port and the connector to be connected is 0 mm or more and 100 mm or less.

[9] The hollow fiber membrane module described in [1], in which there are at least two types of sterile connectors integrated with or connected to the port.

[10] The hollow fiber membrane module described in [1], in which the housing, the port, the hollow fiber membrane, and the aseptic connector are sterilizable and alcohol-resistant.

[11] The hollow fiber membrane module described in [1], in which the sterilization is radiation sterilization.

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

[13] The hollow fiber membrane module according to [1], wherein the membrane area of the hollow fiber membrane is 3.5 ^m2 or more.

According to the present invention, a membrane pore retaining agent that has excellent bacteriostatic and sterilization resistance and does not affect the safety of pharmaceuticals is retained in the pores of the hollow fiber membrane, eliminating the need for sterilization of the liquid separator on the user side and improving convenience. Furthermore, by using the membrane pore retaining agent and eliminating the need for sterilization, a hollow fiber membrane module that can be immediately used by users who manufacture pharmaceuticals can be provided.

FIG. 1 is a schematic cross-sectional view of a hollow fiber membrane module according to an embodiment of the present invention.

The following is a detailed description of an embodiment of the present invention. Note that the following is an example for explaining the present invention, and is not intended to limit the present invention to the following content. The present invention can be practiced with appropriate modifications within the scope of its gist.

The hollow fiber membrane module according to an embodiment of the present invention comprises a housing having at least two ports, a hollow fiber membrane disposed within the housing, and at least two or more sterile connectors that are attached to the ports of the housing and connect the housing to a liquid distribution line without the need for sterilization, and is sterilized in a state in which the pores of the hollow fiber membrane are held by a membrane pore retaining agent made of an alcohol aqueous solution, and in a sealed state in which the port and the connector are integrated or connected, and the alcohol concentration in the alcohol aqueous solution is 8% by weight or more and 20% by weight or less.

When the alcohol is ethanol, the alcohol concentration of the aqueous alcohol solution is in the range of 8% by weight to 20% by weight. From the standpoint of bacteriostasis and radiation sterilization resistance, it is not preferable to retain an aqueous alcohol solution with an alcohol concentration outside this range in the pores of the hollow fiber membrane.

[Composition of hollow fiber membrane]
The hollow fiber membrane of this embodiment (hereinafter also simply referred to as "membrane") is mainly composed of a hydrophobic polymer alone, or a hydrophobic polymer and a water-insoluble hydrophilic polymer. Here, "mainly composed of a hydrophobic polymer and a water-insoluble hydrophilic polymer" means that the total of the hydrophobic polymer and the water-insoluble hydrophilic polymer accounts for 80% by mass or more of the material constituting the hollow fiber membrane, preferably 90% by mass or more, more preferably 95% by mass or more, and even more preferably 100% by mass.

[Hydrophobic polymer]
Examples of hydrophobic polymers include polyvinylidene fluoride polymers, polysulfone polymers, polyamides, polyimides, polyetherimides, polyphenylene ethers, polyphenylene sulfides, etc., and among these, polyvinylidene fluoride polymers and aromatic polysulfone polymers are preferred because they have sterilization resistance to gamma ray sterilization and alcohol resistance to ethanol. Examples of aromatic polysulfone polymers used in this embodiment include polymers having repeating units represented by the following general formula (1) or general formula (2). In the formula, Ar represents a disubstituted phenyl group at the para position. The degree of polymerization and molecular weight of the hydrophobic polymer compound are not particularly limited.
--O--Ar--C( _CH3 ) ₂ --Ar--O--Ar--SO2 _-- Ar-- (1)
-O-Ar-SO ₂ -Ar- (2)

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

[Hydrophilic polymer]
In this embodiment, a polymer that forms a contact angle of 90 degrees or less when PBS (a solution of 9.6 g of Dulbecco's PBS (-) powder "Nissui" commercially available from Nissui Pharmaceutical Co., Ltd. dissolved in water to a total volume of 1 L) is brought into contact with a polymer film is called a hydrophilic polymer. In this embodiment, the contact angle of the hydrophilic polymer is preferably 60 degrees or less, and a contact angle of 40 degrees or less is more preferable. When a hydrophilic polymer with a contact angle of 60 degrees or less is contained, the hollow fiber membrane is easily wetted by water, and when a hydrophilic polymer with a contact angle of 40 degrees or less is contained, the tendency to become easily wetted by water is even more pronounced. The contact angle means the angle made by the surface of a water droplet when a water droplet is dropped on the film surface, and is defined in JIS R3257.

In this embodiment, water-insoluble means that when 100 mL of pure water at 25°C is filtered by constant pressure dead-end filtration at 2.0 bar using a membrane assembled to have an effective membrane area of 3.3 ^cm2 , the carbon elution rate from the membrane is 0.1% or less. The elution rate is calculated as follows. The filtrate obtained by filtering 100 mL of pure water at 25°C is recovered and concentrated. The carbon amount is measured using the concentrated liquid obtained with a total organic carbon meter TOC-L (manufactured by Shimadzu Corporation) to calculate the elution rate from the membrane.

[Water-insoluble hydrophilic polymer]
In this embodiment, the water-insoluble hydrophilic polymer is a substance that satisfies the above contact angle and dissolution rate. The water-insoluble hydrophilic polymer includes not only hydrophilic polymers that are water-insoluble themselves, but also hydrophilic polymers that are water-soluble but are made water-insoluble in the manufacturing process. That is, even if the water-soluble hydrophilic polymer is a substance that satisfies the above contact angle, and is made water-insoluble in the manufacturing process, so that the above dissolution rate is satisfied in the constant pressure dead-end filtration after the filter is assembled, it is included in the water-insoluble hydrophilic polymer in this embodiment.

The hollow fiber membrane of this embodiment may contain a water-insoluble hydrophilic polymer. In order to prevent a sudden decrease in filtration rate due to clogging of the membrane caused by protein adsorption, the hollow fiber membrane of this embodiment is hydrophilized by the presence of a water-insoluble hydrophilic polymer on the pore surface of the base membrane containing a hydrophobic polymer. Methods for hydrophilizing the base membrane include coating, grafting reaction, crosslinking reaction, etc., after forming a base membrane made of a hydrophobic polymer. In addition, after forming a blend of a hydrophobic polymer and a hydrophilic polymer, the base membrane may be hydrophilized by coating, grafting reaction, crosslinking reaction, etc.

[Vinyl-based polymer]
Examples of the water-insoluble hydrophilic polymer include vinyl polymers. Examples of the vinyl polymer include homopolymers such as hydroxyethyl methacrylate, hydroxypropyl methacrylate, dihydroxyethyl methacrylate, diethylene glycol methacrylate, triethylene glycol methacrylate, polyethylene glycol methacrylate, vinylpyrrolidone, acrylamide, dimethylacrylamide, glucoxyoxyethyl methacrylate, 3-sulfopropylmethacryloxyethyldimethylammonium betaine, 2-methacryloyloxyethyltubephorylcholine, and 1-carboxydimethylmethacryloyloxyethylmethane ammonium; and homopolymers such as styrene, ethylene, propylene, propyl methacrylate, butyl methacrylate, ethylhexyl methacrylate, and octadecyl methacrylate. Examples of the copolymer include random copolymers, graft copolymers, and block copolymers of hydrophobic monomers such as acrylate, benzyl methacrylate, and methoxyethyl methacrylate, and hydrophilic monomers such as hydroxyethyl methacrylate, hydroxypropyl methacrylate, dihydroxyethyl methacrylate, diethylene glycol methacrylate, triethylene glycol methacrylate, polyethylene glycol methacrylate, vinylpyrrolidone, acrylamide, dimethylacrylamide, glucoxyoxyethyl methacrylate, 3-sulfopropylmethacryloxyethyldimethylammonium betaine, 2-methacryloyloxyethyltubephorylcholine, and 1-carboxydimethylmethacryloyloxyethylmethane ammonium.

Examples of vinyl polymers include copolymers of cationic monomers such as dimethylaminoethyl methacrylate and diethylaminoethyl methacrylate, anionic monomers such as acrylic acid, methacrylic acid, vinylsulfonic acid, sulfopropyl methacrylate and tubufooxyethyl methacrylate, and the above-mentioned hydrophobic monomers. The vinyl polymer may be a polymer that contains equal amounts of anionic monomers and cationic monomers so as to be electrically neutral.

[Electrically neutral]
The water-insoluble hydrophilic polymer is preferably electrically neutral, for example, from the viewpoint of preventing adsorption of a protein, which is a solute. In this embodiment, electrically neutral means that the molecule has no charge or has equal amounts of cations and anions.

Examples of water-insoluble hydrophilic polymers include polysaccharides such as cellulose and its derivatives such as cellulose triacetate. In addition, examples of polysaccharides or their derivatives include polymers in which hydroxyalkyl cellulose or the like has been crosslinked.

The water-insoluble hydrophilic polymer may be polyethylene glycol or a derivative thereof, a block copolymer of ethylene glycol and the above-mentioned hydrophobic monomer, or a random or block copolymer of ethylene glycol and propylene glycol, ethylbenzyl glycol, or the like. In addition, one or both ends of the polyethylene glycol and the above-mentioned copolymer may be substituted with a hydrophobic group to make them water-insoluble.

Examples of compounds in which one or both ends of polyethylene glycol are substituted with a hydrophobic group include α,ω-dibenzylpolyethylene glycol and α,ω-didodecylpolyethylene glycol, and may also be copolymers of polyethylene glycol and hydrophobic monomers such as dichlorodiphenylsulfone having halogen groups at both ends of the molecule.

Examples of water-insoluble hydrophilic polymers include polyethylene terephthalate, polyethersulfone, etc. obtained by condensation polymerization, in which hydrogen atoms in the main chain of the polymer are replaced with hydrophilic groups, and the like are hydrophilized. Hydrophilized polyethylene terephthalate, polyethersulfone, etc. may have hydrogen atoms in the main chain replaced with anionic groups or cationic groups, or may be polymers in which the anionic groups and cationic groups are in equal amounts.

The water-insoluble hydrophilic polymer may be a resin in which the epoxy group of a bisphenol A type or novolac type epoxy resin is ring-opened, or a resin in which a vinyl polymer or polyethylene glycol is introduced into the epoxy group. The water-insoluble hydrophilic polymer may also be a silane-coupled resin. The water-insoluble hydrophilic polymer may be used alone or in a mixture of two or more types.

As the water-insoluble hydrophilic polymer, from the viewpoint of ease of production, homopolymers of hydroxyethyl methacrylate, hydroxypropyl methacrylate, dihydroxyethyl methacrylate; random copolymers of hydrophilic monomers such as 3-sulfopropyl methacryloxyethyl dimethyl ammonium betaine, 2-methacryloyloxyethyl tubefoylcholine, 1-carboxydimethyl methacryloyloxyethyl methane ammonium and hydrophobic monomers such as butyl methacrylate, ethylhexyl methacrylate are preferred, and from the viewpoints of ease of selection of a solvent for the coating liquid when coating the water-insoluble hydrophilic polymer, dispersibility in the coating liquid, and operability, homopolymers of hydroxyethyl methacrylate, hydroxypropyl methacrylate; random copolymers of hydrophilic monomers such as 3-sulfopropyl methacryloxyethyl dimethyl ammonium betaine, 2-methacryloyloxyethyl tubefoylcholine and hydrophobic monomers such as butyl methacrylate, ethylhexyl methacrylate are more preferred.

An example of a water-soluble hydrophilic polymer that has been made water-insoluble during the film manufacturing process is a hydrophilic polymer that has been made water-insoluble by coating a base film of a hydrophobic polymer with a water-soluble hydrophilic polymer obtained by copolymerizing a monomer having an azide group in the side chain with a hydrophilic monomer such as 2-methacryloyloxyethyltubephorylcholine, and then heat-treating the base film to covalently bond the water-soluble hydrophilic polymer to the base film. Alternatively, a hydrophilic monomer such as 2-hydroxyalkyl acrylate may be graft-polymerized onto the base film of a hydrophobic polymer.

As the hollow fiber membrane of this embodiment, or as the base membrane of this embodiment, a membrane formed by blending a hydrophilic polymer and a hydrophobic polymer may be used. The hydrophilic polymer used for blend membrane formation is not particularly limited as long as it is a polymer that is compatible with the hydrophobic polymer in a good solvent, but the hydrophilic polymer is preferably polyvinylpyrrolidone or a copolymer containing vinylpyrrolidone.

Specific examples of polyvinylpyrrolidone include LUVITEC (trade name) K60, K80, K85, and K90, which are commercially available from BASF, with LUVITEC (trade name) K80, K85, and K90 being preferred. As a copolymer containing vinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate is preferred from the standpoint of compatibility with hydrophobic polymers and suppression of interaction of proteins with the membrane surface.

The copolymerization ratio of vinylpyrrolidone and vinyl acetate is preferably 6:4 to 9:1 from the viewpoint of protein adsorption to the membrane surface and interaction with the polysulfone polymer in the membrane. Specific examples of the copolymer of vinylpyrrolidone and vinyl acetate include LUVISKOL (trade name) VA64 and VA73, which are commercially available from BASF. The hydrophilic polymer may be used alone or in a mixture of two or more types.

[Cross-sectional structure of hollow fiber membrane]
The structure of the hollow fiber membrane made of a polysulfone-based polymer of this embodiment is a gradient structure in which the pore size changes continuously from the outer surface of the membrane to the liquid-contacting surface. Examples of the gradient structure include, but are not limited to, a sponge structure in which the pore size decreases continuously from the outer surface of the membrane to the liquid-contacting surface (normal gradient structure), a sponge structure in which the pore size decreases continuously from the outer surface of the membrane to the smallest pore size layer and increases continuously from the smallest pore size layer to the liquid-contacting surface (reverse gradient structure), and a sponge structure in which the pore size increases continuously from the outer surface of the membrane to the liquid-contacting surface (reverse gradient structure).

The cross-sectional structure of the hollow fiber membrane has a gradient structure in which the pore size changes continuously, making it possible to suppress clogging during filtration of a protein solution while efficiently recovering useful components such as antibodies. When using the hollow fiber membrane of this embodiment as a virus separation filtration membrane, a membrane with an inverted gradient structure having a minimum pore size layer (dense layer) at the downstream filtration site of the membrane is preferred.

In this embodiment, the downstream filtration portion refers to the range from the downstream filtration surface corresponding to one membrane surface to 10% of the membrane thickness, and the upstream filtration portion corresponding to the other membrane surface refers to the range from the upstream filtration surface to 10% of the membrane thickness. For example, in a hollow fiber membrane, if liquid is passed through the outer surface side, the range from the inner surface to 10% of the membrane thickness is the downstream filtration portion, and the range from the outer surface to 10% of the membrane thickness is the upstream filtration portion, and if liquid is passed through the inner surface side, the range from the inner surface to 10% of the membrane thickness is the upstream filtration portion, and the range from the outer surface to 10% of the membrane thickness is the downstream filtration portion. The hollow fiber membrane made of a polyvinylidene fluoride polymer of this embodiment preferably has a homogeneous structure in which the difference in pore size is 10 times or less from the outer surface to the center of the membrane cross section and from the center of the membrane cross section to the liquid contact surface.

The average pore diameter is calculated using a method that uses image analysis. Specifically, Image-pro plus manufactured by MediaCybernetics is used to perform binarization of the pores and solid parts. The pores and solid parts are identified based on brightness, and parts that could not be identified and noise are corrected using a freehand tool. The edge parts that form the outline of the pores and the porous structure observed deep inside the pores are identified as pores. After binarization, the area value of each pore is assumed to be a perfect circle, and the pore diameter is calculated. This is performed for all pores, and the average pore diameter is calculated for each range of 1 μm x 2 μm. Note that pores that are interrupted at the edge of the field of view are also counted.

The pore size of the hollow fiber membrane is determined by the location where the average pore size of the pores present in the membrane is the smallest, and determines the membrane's fractionation performance. The pore size (fractionation performance) of the membrane in this embodiment is 0.05 μm or more and 2 μm or less. If the average pore size of the minimum pore size layer is less than 0.05 μm, the membrane's water permeability tends to decrease, and if it exceeds 2 μm, the membrane's ability to remove fine particles and the like tends to decrease. The preferred average pore size of the minimum pore size layer is 0.3 μm or more and 1 μm or less, and more preferably 0.3 μm or more and 0.7 μm or less.

[Pore-retaining agent]
The pore retaining agent in this embodiment is a substance that is filled in the pores in the membrane during the manufacturing process before radiation sterilization in order to prevent performance degradation due to radiation sterilization. In order to manufacture a module for manufacturing pharmaceuticals by bonding membranes, it is necessary to sterilize the membrane. It is known that porous membranes made of organic polymers, especially hollow fiber membranes made of hydrophobic polymers such as polysulfone and polyvinylidene fluoride, have a lower water permeability when sterilized by radiation due to changes in the membrane structure. If the membrane is sterilized by radiation (especially γ-ray sterilization) without retaining a pore retaining agent in the pores in the membrane, the membrane tends to have a lower performance than before radiation sterilization.

By washing and removing the membrane pore retaining agent after radiation sterilization, it is possible to maintain the same performance as the hollow fiber membrane before radiation sterilization, such as water permeability and rejection rate, due to the effect of the membrane pore retaining agent. However, there are reports that various derivatives generated by chemical reactions with the membrane pore retaining agent due to the presence of a small amount of membrane pore retaining agent in the membrane and/or module are problematic. However, since the membrane of this embodiment uses a specific alcohol aqueous solution in a specific concentration range as the membrane pore retaining agent, derivatives are unlikely to be generated. The pH of the membrane pore retaining agent after radiation sterilization is neutral (7±0.5). Since the membrane pore retaining agent is an alcohol aqueous solution that does not affect the safety of pharmaceuticals, it is not necessary to wash and remove the membrane pore retaining agent after radiation sterilization. The hollow fiber membrane module can be immediately used by the user side to manufacture pharmaceuticals while the membrane pore retaining agent is retained in the pores in the membrane, that is, without washing and removing the membrane pore retaining agent.

[Alcohol-water solution]
As the alcohol aqueous solution, it is preferable 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 even more preferably an ethanol aqueous solution having an alcohol concentration of 16% by weight or more and 18% by weight or less. An ethanol aqueous solution having an alcohol concentration of less than 8% by weight tends to have a reduced bacteriostatic effect. An ethanol aqueous solution having an alcohol concentration of more than 20% by weight is treated as a dangerous material, and transportation and storage may be difficult. For example, an ethanol aqueous solution having an alcohol concentration of 18% by weight or less can be transported by air, so an ethanol aqueous solution having an alcohol concentration of 18% by weight or less is preferable in order to quickly transport hollow fiber membrane modules to overseas users.

[Manufacturing method of hollow fiber membrane module]
The manufacture of a hollow fiber membrane module may include the steps of (1) manufacturing the hollow fiber membranes, (2) bundling a plurality of hollow fiber membranes into a hollow fiber membrane bundle, (3) attaching the hollow fiber membrane bundle to a housing having a port to form a modularization step, (4) retaining a membrane pore retaining agent in the pores in the membrane, (5) connecting a connector to the port and sealing the inside of the housing, (6) sterilizing the hollow fiber membrane module with radiation, and (7) packaging the hollow fiber membrane module, followed by (8) use of the hollow fiber membrane module by a user.

[Hollow fiber membrane manufacturing process]
The hollow fiber membrane of this embodiment can be manufactured as follows, although not particularly limited. A hydrophobic polymer (membrane-forming polymer), a solvent for the hydrophobic polymer, and a specific additive are mixed and dissolved, and the degassed solution is used as a membrane-forming stock solution, which is simultaneously discharged from the annular part and center of a double-tube nozzle (spinneret) together with an internal coagulation liquid, and is introduced into a coagulation bath through an idle running part to form a membrane. The obtained membrane is washed with water, wound up, the liquid inside the hollow part is drained, heat-treated, and dried. The membrane can then be hydrophilized.

A wide variety of solvents can be used for the film-forming solution, including N-methyl-2-pyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), dimethyl sulfoxide, and ε-caprolactam, as long as they are good solvents for polysulfone-based polymers. Amide solvents such as NMP, DMF, and DMAc are preferred, with NMP being more preferred.

Specific additives such as polyvinylpyrrolidone or polyethylene glycol are preferably used. Specific additives may be necessary to obtain a microfiltration membrane.

The membrane-forming solution essentially consists of a membrane-forming polymer, specific additives such as polyvinylpyrrolidone, and a solvent for the polymer. It is also possible to add other additives to the membrane-forming solution, such as water and metal salts, which are conventionally known as additives. The membrane-forming polymer concentration in the membrane-forming solution used in this embodiment is not particularly limited as long as it is within a concentration range in which a membrane can be formed from the solution and the resulting membrane has membrane performance, and is 10 to 35% by weight, preferably 10 to 30% by weight. In order to achieve high water permeability or a large molecular weight fraction, the lower the polymer concentration, the more preferable, and 10 to 25% by weight is preferred.

The amount of the specific additive in the film-forming solution is 1 to 30% by weight, preferably 1 to 20% by weight, but 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, and more preferably in the range of 30,000 to 1,500,000.

The film-forming solution is obtained by dissolving the polysulfone polymer, good solvent, and non-solvent at a constant temperature while stirring. The temperature at this time is preferably 30 to 80°C, higher than room temperature. Compounds containing tertiary or lower nitrogen (NMP, DMF, DMAc) are oxidized in air, and heating makes the oxidation more likely to proceed, so it is preferable to prepare the film-forming solution under an inert gas atmosphere. Examples of inert gases include nitrogen and argon, and nitrogen is preferred from the viewpoint of production costs.

It is preferable to remove foreign matter from the membrane-forming solution before it is discharged from the spinneret. Removing foreign matter can prevent thread breakage during spinning and control the structure of the membrane. In order to prevent foreign matter from entering through the packing of the membrane-forming solution tank, it is preferable to install a filter before the membrane-forming solution is discharged from the spinneret. Filters with different pore sizes may be installed in multiple stages, and are not particularly limited. For example, it is preferable to install a mesh filter with a pore size of 30 μm and a mesh filter with a pore size of 10 μm, in that order, from the side closest to the membrane-forming solution tank.

The internal liquid is used to form the hollow portion of the hollow fiber membrane, and is composed of a high-concentration aqueous solution of a good solvent for the membrane-forming polymer. For example, if the membrane-forming polymer is 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 the good solvent. More preferably, the aqueous solution contains 93% by weight or more of the good solvent. If the content of the good solvent is less than 90% by weight, peeling tends to occur near the inner surface of the membrane.

The hollow fiber membrane of this embodiment can be produced using a known tube-in-orifice type double annular nozzle. More specifically, the above-mentioned membrane forming solution and internal liquid are simultaneously discharged from this double annular nozzle, passed through a small air gap, and then immersed in a coagulation bath to coagulate, thereby obtaining the hollow fiber membrane of this embodiment. The air gap here refers to the gap between the nozzle and the coagulation bath. If the air gap is surrounded by a cylindrical tube or the like and gas having a constant temperature and humidity is passed through this air gap at a constant flow rate, the hollow fiber membrane can be produced in a more stable state.

For the coagulation bath, liquids that do not dissolve the polymer, such as water; alcohols such as methanol and ethanol; ethers; and aliphatic hydrocarbons such as n-hexane and n-heptane, are used, but water is preferred. It is also possible to control the coagulation rate by adding a small amount of a solvent that dissolves the polymer to the coagulation bath. To obtain a microfiltration membrane with a hollow fiber membrane pore size of 0.05 μm or more and 2 μm or less, the temperature of the coagulation bath is -30°C or more and 98°C or less, preferably 0°C or more and 90°C or less, and more preferably 0°C or more and 80°C or less. If the temperature of the coagulation bath is higher than 95°C or lower than -30°C, the surface state of the hollow fiber membrane in the coagulation bath tends to be less stable.

To obtain a hollow fiber membrane, which is a precision filtration membrane with a pore size of 0.05 μm or more and 2 μm or less, the spinneret temperature is preferably 10°C or more and 95°C or less. After the membrane-forming solution is discharged from the spinneret, it passes through the free-running section and is introduced into the coagulation bath. The residence time in the free-running section is preferably 0.02 to 0.6 seconds. By setting the residence time to 0.02 seconds or more, sufficient coagulation can be achieved before introduction into the coagulation bath, resulting in an appropriate pore size. By setting the residence time to 0.6 seconds or less, excessive coagulation can be prevented, making it possible to precisely control the membrane structure in the coagulation bath.

The hollow fiber membrane pulled out of the coagulation bath is washed with warm water in a water washing bath, and then wound up on a reel by a winding machine. In the water washing process, it is preferable to completely remove the solvent and the hydrophilic polymer that is not fixed to the membrane. If the hollow fiber membrane is dried while still containing the solvent, the solvent may be concentrated in the membrane during drying, and the polysulfone polymer may dissolve or swell, which may change the membrane structure. If the hydrophilic polymer that is not fixed to the membrane remains, it may 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 that is not fixed to the membrane, and to increase the washing efficiency, the temperature of the warm water is preferably 50°C or higher. In the water washing process, it is preferable to use a Nelson roller. In order to wash thoroughly, 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 aimed at removing unnecessary components, the better, but from the viewpoint of production efficiency, it is appropriate to keep it to 300 seconds or less.

[Bundling process of bundling multiple hollow fiber membranes to form a hollow fiber membrane bundle]
The hollow fiber membranes pulled out of the water washing bath are wound up on a skein by a winding machine to a predetermined number of fibers. The hollow fiber membranes wound up on the skein are cut at both ends to a predetermined length, bundled, and held by a support so as not to slacken. The held hollow fiber membranes are then immersed in hot water and washed. In the hollow part of the hollow fiber membrane wound up on the skein, a cloudy liquid in which nanometer to micrometer sized polysulfone polymer particles are suspended remains. If the hollow fiber membrane is dried without removing the cloudy liquid, the polysulfone polymer particles may block the pores of the hollow fiber membrane, resulting in a decrease in membrane performance, so it is preferable to remove the cloudy liquid in the hollow part. In the hot water treatment step, the inner surface side of the hollow fiber membrane is also washed, so that hydrophilic polymers and the like that were not completely removed in the water washing step and were not fixed to the membrane are efficiently removed. The temperature of the hot water is preferably 50 to 100°C. It is preferable to set the temperature of the hot water to 50°C or higher in order to increase the washing efficiency. The washing time is preferably 30 to 120 minutes. The hot water is preferably exchanged several times during washing.

[Hydrophilicity of the base film]
In order to improve the hydrophilicity of the base membrane (hollow fiber membrane before coating), a coating step is performed.
For example, the coating process in the case of hydrophilization by coating includes a drying process of the wound hollow fiber membrane bundle, a immersion process of the base membrane (hollow fiber membrane bundle that has been subjected to the drying process) in the coating liquid, a dehydration process of the immersed base membrane, and a drying process of the dehydration base membrane. In the immersion process, the base membrane is immersed in a hydrophilic polymer solution. The solvent of the coating liquid is a good solvent for the hydrophilic polymer, and is not particularly limited as long as it is a poor solvent for the polysulfone-based polymer, but alcohol is preferred. The concentration of the water-insoluble hydrophilic polymer in the coating liquid is preferably 1.0% by mass or more in order to sufficiently cover the pore surface of the base membrane with the hydrophilic polymer, and is preferably 10.0% by mass or less in order to cover with an appropriate thickness and prevent the pore size from becoming too small and the flux from decreasing. The immersion time of the base membrane in the coating liquid is preferably 8 to 24 hours.

In the dehydration process, excess coating liquid adhering to the hollow and outer periphery of the base membrane that has been immersed in the coating liquid for a specified time is dehydrated by centrifugation. From the viewpoint of preventing adhesion of the membranes to each other after drying due to remaining hydrophilic polymers, it is preferable to set the centrifugal force during centrifugation to 10 G or more and the centrifugation time to 30 minutes or more.

[Modularization step of bonding a hollow fiber membrane bundle to a housing having ports]
After the drying process of the wound hollow fiber membrane bundle or the drying process of the deliquified base membrane, the hollow fiber membrane bundle is housed in a cylindrical module case (housing) and both end portions are liquid-tightly bonded and fixed with a thermosetting adhesive polymer such as epoxy resin, urethane resin, epoxy acrylate resin, silicone rubber, etc., and then the bonded end portions are cut to open the hollow portions of the hollow fiber membranes, thereby disposing the hollow fiber membrane bundle in the housing. In order to improve the cure shrinkage and strength of the adhesive polymer, the polymer may contain fibrous materials such as glass fiber and carbon fiber, and fine powders such as carbon black, alumina, and silica.

[Housing and port material]
When the hollow fiber membrane of this embodiment is modularized, the material of the module case (housing) and the port is selected from materials that can pass radiation and have sterilization resistance (radiation resistance). For example, the housing and the port are selected from plastics such as polysulfone, polyethersulfone, polyethylene, polypropylene, polybutene, ABS resin, polyvinyl chloride, polyvinylidene fluoride, polytetrafluoroethylene, polycarbonate, polyether ketones, polyphenylene ether, polyphenylene sulfide, and plastics reinforced with glass fiber and carbon fiber. When a distribution plate (rectifier plate, baffle plate, etc.) is used in the housing, the module case and the distribution plate do not necessarily need to be made of the same material. Since this is a module for manufacturing pharmaceuticals, in order to make the housing and the port sterilization-resistant and alcohol-resistant, these materials are preferably aromatic polysulfone, aromatic polyethersulfone, polyethylene, polypropylene, polybutene, ABS resin, glass fiber, etc. The diameter of the housing may be selected from the range of 30 mm to 1500 mm, and the length may be selected from the range of 300 mm to 3000 mm.

[Step of retaining the membrane pore retaining agent in the pores of the membrane]
After immersing the hollow fiber membranes in the module in a liquid pore-retaining agent, the pore-retaining agent (except for the pore-retaining agent retained in the pores in the membrane) is removed from the module, whereby the pore-retaining agent can be filled (retained) in the pores in the membrane. After removing the liquid pore-retaining agent from the module, the inside of the module (housing) can be sealed, whereby the pore-retaining agent can be retained in the pores in the membrane over time. When immersing the hollow fiber membranes in the module in a liquid pore-retaining agent, the liquid pore-retaining agent can 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.

[The process of connecting the connector to the port and sealing the inside of the module (inside the housing)]
The connector is a sterile connector (sterile connection connector). Means for connecting the connector to the port include, but are not limited to, a means for bonding or welding the connector and the port together to form an integrated unit, and a means for connecting the connector and the port to a tube. The tube connection between the connector and the port means fitting (inserting) the connector and the port end (male part) into both ends of a tube (tubular plastic tube) and fixing the connector and the port end fitted into the tube with a tube band or the like. To connect the port to the tube, it is easy to fit (insert) the male part of the reducer into the tube by previously connecting or integrating the port and the reducer. For example, in the case of a ferrule-shaped port, the reducer can be exemplified by a member (adapter) having a ferrule that can be connected to the port by sandwiching a gasket and fixing with a clamp band, and having a male part (protruding part) that is large enough to be fitted (inserted) into the tube (see FIG. 1). By connecting the sterile connector to all ports of the module, it is possible to seal the inside of the module (inside the housing) (isolate it from the outside world).

Figure 1 is a cross-sectional view showing the outline of the configuration of a hollow fiber membrane module. The sterile connector according to this embodiment is configured by attaching a connector 7 or connector 9 to each of ports 14a and 14b, and/or 15a and 15b of this hollow fiber membrane module 1. A reducer 5 or reducer 2 is connected to each port with a clamp band 4 or clamp band 3, sandwiching a gasket. For example, the reducer 5 and connector 7 are inserted into a tube 6, and each is fixed with a tube band 11. The relationship between the other reducers and connectors is similar.

The hollow fiber membrane module 1 has a cylindrical housing 10 with both longitudinal ends closed, as shown in FIG. 1, and a plurality of ports (fluid passages), for example, four ports 14a and 14b, and/or 15a and 15b, provided in the housing 10 for allowing liquid to flow in and out of the housing 10. For example, the ports 14a and 14b are provided at both longitudinal ends of the housing 10, and the ports 15a and 15b are provided on the outer circumferential surface of the body of the housing 10.

A large number of tubular hollow fiber membranes 12 are provided in the housing 10. The hollow fiber membranes 12 are arranged along the longitudinal direction of the housing 10 and extend from near one end to near the other end of the housing 10. Support members 13 that support the hollow fiber membranes 12 are provided near both ends of the longitudinal direction in the housing 10. The support members 13 are formed, for example, in a disk shape that fits the internal shape of the housing 10, and support the ends of the hollow fibers 12 while blocking the space A outside each support member 13 (the space where the ports 14a and 14b open) and the space B inside the two support members 13. Both ends of the hollow fibers 12 open into the space A that leads to the ports 14a and 14b, respectively. Therefore, for example, the liquid that flows in from the port 14a or port 14b passes through the inside of the hollow fiber 12, and the liquid that passes through the side wall of the hollow fiber 12 flows out into the space B between the two support members 13. When passing through the side wall of the hollow fiber 12, a specific substance is separated from the liquid. Connectors 7 are attached to the ports 14a and 14b (see FIG. 1). The connectors 7 may be attached directly to the ports 14a and 14b, or may be attached via a tube or the like.

The ports 15a and 15b are connected to the space B between the two support members 13. Therefore, for example, liquid after separation that has passed through the hollow fibers 12 can be discharged from the ports 15a and 15b. Each port in this embodiment is formed, for example, in a circular tube shape, and a ring-shaped ferrule portion is formed at the open end of the tip. In addition to the ferrule, a flange, a nipple, a screw, etc. can be used. Although not shown in detail in FIG. 1, the ports 15a and 15b in this embodiment have a tapered shape in which the inner diameter gradually decreases as it approaches the body of the housing 10. A connector 9 is attached to the ports 15a and 15b (see FIG. 1). The connector 9 may be attached directly to the ports 15a and 15b, or may be attached via a tube or the like.

As shown in FIG. 1, in a hollow fiber membrane module having a membrane area of ^3.5 m2 or more, the shapes or sizes of the ports 14 and 15 are significantly different, so that at least two types of connectors are required.

As the sterile connector, a sealed, sterile connection, coupleable connector is preferred. To connect a hollow fiber membrane module to a pharmaceutical production line, for example, the connection site with the hollow fiber membrane module needs to be sterilized by flowing high-temperature steam. Since a sealed, sterile connection, coupleable connector does not require such work, it is possible to provide a hollow fiber membrane module that can be immediately used by users who manufacture pharmaceuticals by using a sealed, sterile connection, coupleable connector. Examples of the sealed, sterile connection, coupleable connector include AQG17012HT or AQL17016HT manufactured by Colder Products Company. This connector is sterilization-resistant and alcohol-resistant, and therefore can be preferably used by users who manufacture pharmaceuticals.

The connector is connected to a liquid distribution line. The liquid distribution line is a flow path for supplying the liquid to be filtered to the hollow fiber membrane, and a flow path for recovering the liquid filtered by the hollow fiber membrane.

[Step of sterilizing hollow fiber membrane module by radiation]
The hollow fiber membrane module is packaged in a plastic film (packaging film) made of a resin that is durable against irradiation with sterilizing radiation, packed in a returnable box, and then irradiated with radiation. The packaging is preferably multi-packaged. For the convenience of packing in a returnable box, the distance between the port and the connector connected to the port via a tube or the like is preferably 0 mm or more and 100 mm or less. The package can be transported to a radiation sterilization facility of a sterilization company and the sterilization irradiation can be entrusted to the company. After the irradiation, the package returned can be inspected and tested before being shipped.

In this embodiment, the radiation used may be alpha rays, beta rays, gamma rays, X-rays, ultraviolet rays, or electron beams. In recent years, radiation sterilization methods using gamma rays or electron beams have been widely used due to their low residual toxicity and simplicity. Gamma sterilization is effective at 15 kGy or more. If the radiation dose is 100 kGy or more, three-dimensional crosslinking or collapse of hydrophilic polymers may occur.

[Process for packaging hollow fiber membrane module]
A sterilized hollow fiber membrane module is placed in a bag made of a packaging film, the bag is sealed, and then the bag is placed in a packaging box. In order to seal the bag, a pair of packaging films constituting the bag are overlapped and the packaging films are thermally melted (thermally welded) with a heat sealer or the like. In order to prevent deterioration of the housing, etc. due to oxygen, it is common to perform reduced pressure packaging (sealing) under a pressure lower than atmospheric pressure. The bending stiffness of the packaging film measured by the KES method is preferably 0.1 gf·cm ² /cm or more and 4.0 gf·cm ² /cm or less. If the bending stiffness is less than 0.1 gf·cm ² /cm, there is a tendency for the stretch prevention and handling properties to be inferior. If the bending stiffness exceeds 4.0 gf·cm ² /cm, the packaging film becomes an obstacle, and the packaged hollow fiber membrane module does not smoothly enter the packaging box, or the packaging box tends to be damaged.

The packaging film may be a laminate of multiple resin films of different types. Specifically, the packaging film has an outermost layer, an intermediate layer, and a fusion layer, in that order. The outermost layer and the intermediate layer are bonded to each other, for example, by dry lamination using an adhesive. An adhesive layer may be provided between the intermediate layer and the fusion layer to bond them together.

The intermediate layer is a layer having gas barrier properties and plays a role in preventing the permeation of gases such as oxygen. The intermediate layer is made of, for example, nylon or ethylene-vinyl alcohol copolymer (EVOH). The fusion layer plays a role in sealing the bag made of the packaging film after packaging the membrane product with the packaging film. A pair of packaging films is overlapped, and heat is applied to the packaging films while the fusion layer of one packaging film is in contact with the fusion layer of the other packaging film. This melts the resin that constitutes each fusion layer. The packaging films are then bonded to each other by solidifying the resin. The fusion layer is made of, for example, polyolefin such as polyethylene or polypropylene. Linear low density polyethylene (LLDPE) is suitable as a material for the fusion layer. The thickness of the fusion layer is, for example, in the range of 40% to 70% of the thickness of the packaging film. In one example, the thickness of the fusion layer is 50 μm to 80 μm. The adhesive layer is also made of, for example, polyolefin such as polyethylene or polypropylene.

The present embodiment will be described in detail below with reference to examples, but the present invention is not limited to the following examples. The measurement methods shown in the examples are as follows.

(1) Measurement of inner diameter and membrane thickness The inner diameter of the hollow fiber membrane was measured by photographing the vertical cut surface of the membrane with a stereomicroscope. The outer diameter was measured in the same manner as the inner diameter, and the membrane thickness was calculated by (outer diameter - inner diameter) / 2. The membrane area was calculated from the inner diameter and the effective length of the hollow fiber membrane.

(2) Measurement of pure water permeation rate A filter assembled to have an effective membrane area of 3.3 ^cm2 was used to measure the amount of pure water filtered at 25°C by constant pressure dead-end filtration at 1.0 bar, and the amount of water permeated was calculated from the filtration time.

(3) Bacteriostatic test Staphylococcus aureus strain (NBRC12732) or Escherichia coli strain (NBRC3972) was cultured in a medium at 36±2°C, and the grown colonies were scraped off and suspended in a sterile ion exchanger to prepare a concentration of about 109 CFU/mL, which was used as a test bacterial solution. The housing of the hollow fiber membrane module with all ports connected to sterile connectors (the housing part around the entire circumference between ports 15a and 15b in FIG. 1) was removed, and the test bacterial solution was sprayed uniformly over the entire hollow fiber membrane bundle. The removed housing was set back in place and fixed with adhesive tape. It was confirmed that the inside of the housing was completely sealed at this time. This hollow fiber membrane module was stored at about 25°C. After a predetermined time, the housing of the hollow fiber membrane module (the housing portion between ports 15a and 15b in FIG. 1) was removed, and the hollow fiber membrane was extracted into a 50±2 mm square (test piece), and the square (the thickness of the square is the thickness of one hollow fiber membrane) was fixed with a needle, and the number of attached bacteria was measured at N=5 (one point each at the top, middle, and bottom in the longitudinal direction of the surface of the hollow fiber bundle and two points at the center of the hollow fiber bundle) in the same manner as the method described in JIS Z 2801 (2012), and the average value was calculated. Bacteria reduction rate (increase rate) = viable bacteria count of test piece after a predetermined time has elapsed (cfu) / initial inoculated number of bacteria (cfu)

[Example 1]
[Preparation of polyvinylpyrrolidone solution and filtration of the solution]
600 g of polyvinylpyrrolidone (manufactured by BASF, K value 90, weight average molecular weight 1,200,000) whose moisture content had been adjusted to 0.3% by mass or less by drying at a temperature of 100° C. or less was dissolved in 7,400 g of N-methyl-2-pyrrolidone to obtain a homogeneous solution (polyvinylpyrrolidone solution).

This solution was kept at 70°C and filtered at a filtration flow rate of 2 mL/(min· ^cm2 ) using a stainless steel sintered filter with a pore size of 2 μm (NS-02S2, manufactured by Nippon Seisen Co., Ltd., effective filtration area ²⁰ cm2). During filtration, the sintered filter was immersed in an ultrasonic cleaner, and ultrasonic vibrations of 59 kHz (output 3 kW) were constantly applied to the polyvinylpyrrolidone solution.

[Film formation and removal of residual solvent]
A homogeneous solution (membrane stock solution) was prepared by adding and dissolving 200 g of aromatic polysulfone (P-1700, manufactured by Amoco Engineering Polymers) in 800 g of the above-mentioned filtered solution (polyvinylpyrrolidone solution). In order to remove undissolved polysulfone, the membrane stock solution was filtered using a filter with a pore size of 5 μm (FD-5, manufactured by Fuji Filter Co., Ltd., effective filtration area 40 cm ² ). The mixing ratio of polyvinylpyrrolidone to polysulfone in the membrane stock solution was 27.2% by weight. This membrane-forming stock solution was kept at 60°C, and together with an internal liquid (water content: 95% by weight) consisting of a mixed solution of 95% by weight of N-methyl-2-pyrrolidone and 5% by weight of water, it was extruded from a spinneret (double annular nozzle 0.5 mm-0.7 mm-1.3 mm, nozzle temperature 60°C, temperature of the membrane-forming stock solution at the nozzle 60°C), passed through an air gap of 60 mm, and immersed in a coagulation bath consisting of water at 70±1°C.

At this time, the area from the spinneret to the coagulation bath was enclosed in a cylindrical tube and sealed to prevent outside air from entering. The spinning speed was fixed at 20 m/min. After the wound yarn bundle was cut, the cut surface of the yarn bundle was washed with a hot water shower at 80°C for 2 hours to remove residual solvent in the film.

Observation of the obtained membrane with an electron microscope revealed that the pore size was continuously smaller from the outer surface of the membrane toward the smallest pore size layer and continuously larger from the smallest pore size layer toward the inner surface, that is, a sponge structure (reverse gradient structure), and that the membrane surface with the largest pore size was the inner membrane surface, and that the smallest pore size layer was present near the outer membrane surface. The membrane showed high strength at break of 50 kgf/ ^cm2 or more, and was also found to be a microfiltration membrane with excellent water permeability of 1,000 mL/( ^m2 ·hr·mmHg) or more. Furthermore, even in the internal pressure filtration of latex particles with an average particle size of 0.273 μm, there was no sudden clogging and a stable filtrate volume was maintained for a long time. The outer diameter of the obtained hollow fiber membrane was 1.5 mm, and the membrane thickness was 0.3 mm.

[Manufacture of hollow fiber membrane module]
The bundle of wound hollow fiber membranes was loaded into a polysulfone cylindrical vessel having a port designed so that the effective membrane area (calculated as the inner membrane surface) of the hollow fiber membrane was 3.5 ^m2 , both ends were bonded and fixed with urethane resin, and both ends were cut to form open ends of the hollow fiber membrane. Furthermore, header caps having ports were attached to both ends.

[The membrane pore-retaining agent is retained in the pores of the hollow fiber membrane]
A membrane pore retaining agent consisting of an aqueous alcohol solution with an ethanol concentration of 18% by weight was sealed in the module for 1 hour. The membrane pore retaining agent was removed by dripping off. After removal from the module, a sterile connector was attached to each port to seal the inside of the module (inside the housing). AQL17016HT manufactured by Colder Products Company was attached to 14a and 14b as shown in FIG. 1, and AQG17012HT manufactured by Colder Products Company was attached to 15a and 15b. These sterile connectors are aseptically connectable and couplingable connectors that eliminate the need for sterilization of the liquid separator on the user side.

[Bacteriostatic test results]
The results of the bacteriostatic test of this hollow fiber membrane module are shown in Table 1. It became clear that the membrane pore retaining agent used had excellent bacteriostatic properties.

[Water permeability after gamma ray sterilization]
The results of the water permeability of this hollow fiber membrane module after γ-ray sterilization at 25 kGy are shown in Table 1. It was clear that there was no decrease in water permeability. The pH of the membrane pore retaining agent after sterilization was neutral. It was clear that there is no need for the user to wash and remove the membrane pore retaining agent.

From the above, it has become clear that the hollow fiber membrane module according to the embodiment retains a membrane pore retaining agent, which has excellent bacteriostatic and sterilization resistance and does not affect the safety of pharmaceuticals, in the pores of the hollow fiber membrane, thereby eliminating the need for sterilization of the liquid separator on the user side, thereby improving convenience, and that by using a membrane pore retaining agent and eliminating the need for sterilization, the hollow fiber membrane module can be immediately used by users who manufacture pharmaceuticals.

[Example 2]
The same operation as in Example 1 was carried out, except that the ethanol concentration was 8% by weight. The results of the bacteriostatic test and the water permeability results after γ-ray sterilization of this hollow fiber membrane module are shown in Table 1. It was revealed that the membrane pore retaining agent used had excellent bacteriostatic properties. Furthermore, it was revealed that there was no decrease in water permeability. The pH of the membrane pore retaining agent after sterilization was neutral. Therefore, it was revealed that there is no need for the user to wash and remove the membrane pore retaining agent.

From the above, it has become clear that the hollow fiber membrane module according to the embodiment is a hollow fiber membrane module that can be immediately used by users who manufacture pharmaceuticals by retaining a membrane pore retaining agent in the pores of the hollow fiber membrane, which has excellent bacteriostatic and sterilization resistance and does not affect the safety of pharmaceuticals, thereby eliminating the need for sterilization of the liquid separator on the user side and improving convenience.

[Example 3]
The same operation as in Example 1 was carried out, except that the ethanol concentration was 20% by weight. The results of the bacteriostatic test and the water permeability results after γ-ray sterilization of this hollow fiber membrane module are shown in Table 1. It was revealed that the membrane pore retaining agent used has excellent bacteriostatic properties. Furthermore, it was revealed that there was no decrease in water permeability. The pH of the membrane pore retaining agent after sterilization was neutral. Therefore, it was revealed that there is no need for the user to wash and remove the membrane pore retaining agent.

From the above, it has become clear that the hollow fiber membrane module of the embodiment retains a membrane pore retaining agent, which has excellent bacteriostatic and sterilization resistance and does not affect the safety of pharmaceuticals, in the pores of the hollow fiber membrane, thereby eliminating the need for sterilization of the liquid separator on the user side and improving convenience, and that by using a membrane pore retaining agent and eliminating the need for sterilization, the hollow fiber membrane module can be immediately used by users who manufacture pharmaceuticals.

[Comparative Example 1]
The same procedure as in Example 1 was carried out except that the ethanol concentration was 6% by weight. The results of the bacteriostasis test and the water permeability after γ-ray sterilization of this hollow fiber membrane module are shown in Table 1. It was clear that the membrane pore retaining agent used had poor bacteriostasis. Furthermore, it was clear that the water permeability was greatly reduced.

[Example 4]
The same operations as in Example 1 were carried out, except that a hollow fiber membrane made of polyvinylidene fluoride (PVDF-TP manufactured by Asahi Kasei Chemicals, outer diameter 2 mm, membrane thickness 0.3 mm, average pore size 0.45 μm, membrane cross section has a homogenous structure) was used. The results of the bacteriostasis test and the water permeability performance after γ-ray sterilization of this hollow fiber membrane module are shown in Table 1. It was revealed that the membrane pore retaining agent used had excellent bacteriostasis. Furthermore, it was revealed that there was no decrease in water permeability. The pH of the membrane pore retaining agent after sterilization was neutral. Therefore, it was revealed that there is no need for the user to wash off the membrane pore retaining agent.

From the above, it has become clear that the hollow fiber membrane module of the embodiment retains a membrane pore retaining agent, which has excellent bacteriostatic and sterilization resistance and does not affect the safety of pharmaceuticals, in the pores of the hollow fiber membrane, thereby eliminating the need for sterilization of the liquid separator on the user side and improving convenience, and that by using a membrane pore retaining agent and eliminating the need for sterilization, the hollow fiber membrane module can be immediately used by users who manufacture pharmaceuticals.

[Example 5]
The same operation as in Example 4 was carried out, except that the ethanol concentration was 8% by weight. The results of the bacteriostatic test and the water permeability results after γ-ray sterilization of this hollow fiber membrane module are shown in Table 1. It was revealed that the membrane pore retaining agent used has excellent bacteriostatic properties. Furthermore, it was revealed that there was no decrease in water permeability. The pH of the membrane pore retaining agent after sterilization was neutral. Therefore, it was revealed that there is no need for the user to wash and remove the membrane pore retaining agent.

From the above, it has become clear that the hollow fiber membrane module of the embodiment retains a membrane pore retaining agent, which has excellent bacteriostatic and sterilization resistance and does not affect the safety of pharmaceuticals, in the pores of the hollow fiber membrane, thereby eliminating the need for sterilization of the liquid separator on the user side and improving convenience, and that by using a membrane pore retaining agent and eliminating the need for sterilization, the hollow fiber membrane module can be immediately used by users who manufacture pharmaceuticals.

[Example 6]
The same operation as in Example 4 was carried out, except that the ethanol concentration was 20% by weight. The results of the bacteriostatic test and the water permeability results after γ-ray sterilization of this hollow fiber membrane module are shown in Table 1. It was revealed that the membrane pore retaining agent used has excellent bacteriostatic properties. Furthermore, it was revealed that there was no decrease in water permeability. The pH of the membrane pore retaining agent after sterilization was neutral. Therefore, it was revealed that there is no need for the user to wash and remove the membrane pore retaining agent.

From the above, it has become clear that the hollow fiber membrane module of the embodiment retains a membrane pore retaining agent, which has excellent bacteriostatic and sterilization resistance and does not affect the safety of pharmaceuticals, in the pores of the hollow fiber membrane, thereby eliminating the need for sterilization of the liquid separator on the user side and improving convenience, and that by using a membrane pore retaining agent and eliminating the need for sterilization, the hollow fiber membrane module can be immediately used by users who manufacture pharmaceuticals.

[Comparative Example 2]
The same procedure as in Example 4 was carried out, except that the ethanol concentration was 6% by weight. The results of the bacteriostatic test and the water permeability after γ-ray sterilization of this hollow fiber membrane module are shown in Table 1. It was clear that the membrane pore retaining agent used had poor bacteriostatic properties. Furthermore, it was clear that the water permeability was greatly reduced.

The hollow fiber membrane module according to this embodiment retains a membrane pore retaining agent, which has excellent bacteriostatic and sterilization resistance and does not affect the safety of pharmaceuticals, in the pores of the hollow fiber membrane, eliminating the need for sterilization of the liquid separator on the user side, improving convenience, and further improving convenience by using the membrane pore retaining agent and eliminating the need for sterilization, allowing immediate use by users who manufacture pharmaceuticals, making it suitable for industrial use.

1: Hollow fiber membrane module 2: Reducer 3: Clamp band 4: Clamp 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: Ports 15a, 15b: Ports 16: Tube band 17: Pharmalock tube clamp

Claims (11)

a housing having at least two ports;
A hollow fiber membrane disposed within the housing;
At least two or more aseptic connectors are attached to the port of the housing, and connect the housing to a liquid distribution line, eliminating the need for a sterilization process;
Equipped with
The pores of the hollow fiber membrane are maintained by a membrane pore maintaining agent made of an alcoholic aqueous solution, and the port and the sterile connector are sterilized in a sealed state in which they are integrated or connected together,
The alcohol concentration in the alcohol aqueous solution is 16 % by weight or more and 20% by weight or less,
The hollow fiber membrane is a microfiltration membrane having a pore size of 0.05 μm or more and 2 μm or less,
the alcohol is ethanol,
The hollow fiber membrane is made of a polyvinylidene fluoride-based polymer or a polysulfone-based polymer.
Hollow fiber membrane module. The hollow fiber membrane module according to claim 1, wherein the hollow fiber membrane is a precision filtration membrane having a pore size of 0.3 μm or more and 1 μm or less. The hollow fiber membrane module according to claim 1, wherein the pH of the membrane pore retaining agent after sterilization is neutral. The hollow fiber membrane module according to claim 1, wherein the sterile connector is a sterile connection coupling connector. The hollow fiber membrane module according to claim 1, wherein the distance between the port and the sterile connector to be connected is 0 mm or more and 100 mm or less. The hollow fiber membrane module according to claim 1, wherein there are at least two types of aseptic connectors integrated with or connected to the ports. The hollow fiber membrane module of claim 1, wherein the housing, the port, the hollow fiber membrane, and the aseptic connector are sterilizable and alcohol-resistant. The hollow fiber membrane module according to claim 1, wherein the sterilization is radiation sterilization. The hollow fiber membrane module according to claim 8 , wherein the radiation sterilization is gamma ray sterilization. 2. The hollow fiber membrane module according to claim 1, wherein the membrane area of the hollow fiber membrane is 3.5 ^m2 or more. Water permeability is 1,000 mL/(m ² 2. The hollow fiber membrane module according to claim 1, wherein the thermal expansion coefficient is 1.0 - 1.0 MPa (hr - mmHg) or more.