Porous hollow fiber membrane

Abstract

This application relates to porous hollow fiber membranes. The present invention provides a porous hollow fiber membrane primarily composed of polysulfone-based polymers. This membrane has an asymmetric structure with a dense inner surface and a porous outer surface. The average short diameter of the pores on the inner surface is 20 nm or more and 40 nm or less, and the porosity of the inner surface is 10% or more and 30% or less. Furthermore, at least one side of the outer or inner surface is supported by a polymer containing monocarboxylic acid vinyl ester units. This invention provides a porous hollow fiber membrane that exhibits excellent removal performance for target substances such as viruses and can be used as a separation membrane with high permeability even under low pressure.

Description

[0001] This application is a divisional application of Chinese invention patent application No. 201980030075.5 (PCT application number PCT / JP2019 / 020597), filed on May 24, 2019, entitled "Porous Hollow Fiber Membrane". Technical Field

[0002] This invention relates to porous hollow fiber membranes for separating biological components. Background Technology

[0003] In recent years, biopharmaceuticals, especially antibodies such as immunoglobulins, have been widely used due to their high therapeutic efficacy and few side effects. Antibodies are produced by organisms such as animal cells; therefore, for use as pharmaceuticals, they need to be separated and purified from many impurities. In a typical separation and purification process, after separating the cells used to produce antibodies by centrifugation, separation and purification are performed using a chromatographic column that specifically adsorbs antibodies (such as a protein A column), and finally, virus removal is performed.

[0004] As a method for virus removal, separation based on sieving effect through membrane filtration using a separation membrane is effective because it has minimal impact on active ingredients such as antibodies and can remove viruses resistant to energy and chemicals. The separation membrane used for virus removal needs to have high separation performance, prevent virus leakage, and also require a high recovery rate of the active ingredient, namely antibodies.

[0005] Hollow fiber membranes are increasingly used as virus removal membranes, and are widely applied in industrial applications such as microfiltration and ultrafiltration, as well as medical applications such as hemodialysis. Patent Document 1 discloses a hollow fiber membrane for treating protein-containing solutions, comprising a blend of polysulfone polymers and polyvinylpyrrolidone (PVP). Patent Document 2 discloses a porous hollow fiber membrane comprising two components: a polysulfone polymer and a vinylpyrrolidone-vinyl acetate copolymer, with a dense outer layer. Patent Document 3 discloses a porous hollow fiber membrane comprising a polysulfone polymer and a hydrophilic polymer, with controlled dense layer thickness and pore size.

[0006] Existing technical documents Patent documents Patent Document 1: International Publication No. 2011 / 111679 Patent Document 2: International Publication No. 2013 / 012024 Patent document 3: International Publication No. 2016 / 113964. Summary of the Invention

[0007] The problem that the invention aims to solve However, the hollow fiber membrane described in Patent Document 1 has a substantially uniform structure, and its permeability to pure water tends to be low.

[0008] The hollow fiber membranes described in Patent Documents 2 and 3 suppress blockage caused by protein adhesion by containing a copolymer of vinylpyrrolidone and vinyl acetate, but their permeability is low, so they need to be processed under high pressure.

[0009] The purpose of this invention is to provide a porous hollow fiber membrane that exhibits excellent removal performance for isolated substances such as viruses and can be used as a separation membrane with high permeability even under low pressure.

[0010] Methods for solving problems To address the aforementioned issues, the present invention provides a porous hollow fiber membrane with polysulfone polymer as the main component. The porous hollow fiber membrane has an asymmetric structure with a dense inner surface and a loose outer surface. The average short diameter of the pores on the inner surface is 20 nm or more and 40 nm or less, and the porosity of the inner surface is 5% or more and 30% or less. Furthermore, at least one side of the outer or inner surface is supported by a polymer containing monocarboxylic acid vinyl ester units.

[0011] More specifically, the present invention relates to the following: <1> A porous hollow fiber membrane, which is mainly composed of polysulfone polymer, has an asymmetric structure with a dense inner surface and a loose outer surface. The average short diameter of the pores on the inner surface is 20 nm or more and 40 nm or less, and the porosity of the inner surface is 5% or more and 30% or less. Furthermore, a polymer containing monocarboxylic acid vinyl ester units is supported on at least one side of the outer or inner surface.

[0012] <2> ,according to <1> The porous hollow fiber membrane, wherein the thickness of the dense layer on the inner surface side, which does not contain pores with a diameter greater than 130 nm, is less than 1 μm.

[0013] <3> ,according to <1> or <2> The porous hollow fiber membrane wherein the ratio of the major axis to the minor axis of the pores on the inner surface is 2 or more and 6 or less.

[0014] <4> ,according to <1> ~ <3> The porous hollow fiber membrane according to any one of the following methods, wherein the membrane thickness of the porous hollow fiber membrane is more than 20 μm and less than 100 μm.

[0015] <5> ,according to <1> ~ <4> The porous hollow fiber membrane according to any one of the following, wherein the monocarboxylic acid vinyl ester unit is a unit represented by "-CH(OCO-R)-CH2-" (R is an aliphatic hydrocarbon group or an aromatic hydrocarbon group).

[0016] <6> ,according to <5> The porous hollow fiber membrane, wherein R is an aliphatic hydrocarbon group with 1 to 20 carbon atoms.

[0017] <7> ,according to <6> The porous hollow fiber membrane wherein the monocarboxylic acid vinyl ester unit is selected from the group consisting of vinyl acetate unit, vinyl propionate unit, vinyl butyrate unit, vinyl valerate unit, neovalerate unit, and vinyl hexanoate unit.

[0018] <8> ,according to <1> ~ <7> The porous hollow fiber membrane according to any one of the following methods, wherein the polymer containing monocarboxylic acid vinyl ester units is a copolymer comprising hydrophilic units and hydrophobic units containing monocarboxylic acid vinyl ester units.

[0019] <9> ,according to <8> The porous hollow fiber membrane, wherein the hydrophilic unit is a vinylpyrrolidone unit.

[0020] <10> ,according to <9> The porous hollow fiber membrane, wherein the polymer containing monocarboxylic acid vinyl ester units is a copolymer comprising monocarboxylic acid vinyl ester units and vinylpyrrolidone units.

[0021] <11> ,according to <1> ~ <10> The porous hollow fiber membrane according to any one of the following methods, wherein when at least one of the outer or inner surfaces of the porous hollow fiber membrane is measured by X-ray photoelectron spectroscopy, and the total peak area originating from carbon is taken as 100 (atomic percentage), the area percentage of carbon peaks originating from ester groups is 0.1 (atomic percentage) or more and 25 (atomic percentage) or less.

[0022] <12> ,according to <1> ~ <11> The porous hollow fiber membrane described in any one of the following methods, wherein, when at least one of the outer or inner surfaces of the porous hollow fiber membrane is measured using micro-infrared spectroscopy, the peak area (A) of the infrared absorption spectrum originating from the ester groups is... COO The peak area of ​​the infrared absorption spectrum of the benzene ring derived from polysulfone polymers (A) CC The ratio of (A) COO ) / (A CC The average value is above 0.01 and below 1.

[0023] <13> ,according to <1> ~ <12> The porous hollow fiber membrane according to any one of the following methods, wherein the number average molecular weight of the polymer containing the monocarboxylic acid vinyl ester unit is 1,000 or more and 1,000,000 or less.

[0024] <14> A porous hollow fiber membrane module, which houses a series of porous hollow fiber membranes within a housing. <1> ~ <13> The porous hollow fiber membrane described in any one of the following statements.

[0025] <15> , <1> ~ <13> The porous hollow fiber membrane or any one of the above. <14> The porous hollow fiber membrane module is used in the virus removal process.

[0026] <16> , <1> ~ <13> The porous hollow fiber membrane or any one of the above. <14> The porous hollow fiber membrane assembly is used in the process of separating antibodies from antibody-producing cells.

[0027] <17> , <1> ~ <13> The porous hollow fiber membrane or any one of the above. <14> The porous hollow fiber membrane assembly is used in the process of separating antibody agglutination from antibodies.

[0028] <18> A purification system for obtaining desired cells or proteins from a solution containing cells and proteins, the purification system having... <1> ~ <13> The porous hollow fiber membrane and the separation membrane according to any one of the following, wherein the separation membrane has pores with a smaller pore size than the hollow fiber membrane, and the porous hollow fiber membrane and the separation membrane are configured such that the solution is continuously processed by the porous hollow fiber membrane and the separation membrane.

[0029] Invention Effects The porous hollow fiber membrane of the present invention enables the separation of biological components, particularly proteins such as antibodies and viruses, at low pressure and in a short time. Attached Figure Description

[0030] [ Figure 1 [Image] is an SEM image obtained by taking a cross-section of the porous hollow fiber membrane prepared in Example 1 at 10,000x magnification.

[0031] [ Figure 2 ] is Figure 1 The image is obtained by binarizing the image.

[0032] [ Figure 3 ] is to Figure 2 The image is obtained by extracting only the pores larger than 130nm from a portion of the image.

[0033] [ Figure 4 The image is an SEM image obtained by taking a picture of the inner surface of the hollow fiber membrane at 50,000x magnification.

[0034] [ Figure 5 The image is a SEM image obtained by taking a 3000x magnification image of the outer surface of the hollow fiber membrane.

[0035] [ Figure 6 This is an example of a preferred method for hollow fiber membrane modules.

[0036] [ Figure 7 This is an example of a preferred method for hollow fiber membrane modules. Detailed Implementation

[0037] The present invention will now be described in detail. It should be noted that in this specification, "~" indicates a range of values ​​including both the lower and upper limits.

[0038] <Porous Hollow Fiber Membrane> The porous hollow fiber membrane of the present invention (hereinafter, sometimes simply referred to as "hollow fiber membrane"; in addition, for ease of explanation, the state before loading the coated polymer described later is sometimes also referred to as "hollow fiber membrane") uses polysulfone-based polymers as the main component.

[0039] The so-called polysulfone polymer in this invention refers to a polymer having an aromatic ring, a sulfonyl group and an ether group on its main chain. Specifically, examples include polysulfone, polyethersulfone, and polyallyl ethersulfone. As the polysulfone polymer used in this invention, a polymer having repeating units selected from the repeating units represented by the following formulas (1) and (2) is preferred.

[0040] [Chemical Formula 1] In addition to having the repeating units represented by formula (1) or (2) above, polysulfone polymers may also have other repeating units within a range that does not impair the effects of the present invention. In this case, the content of other repeating units is preferably less than 10% by mass of the polysulfone polymer. Furthermore, the hydrogen atoms of the hydrocarbon skeleton of the polysulfone polymer may be replaced by other atoms such as alkyl groups, functional groups, and halogens, or it may be a modified body.

[0041] In this invention, it is particularly preferred to use polysulfone polymers represented by formula (3) or (4) that contain only repeating units represented by formula (1) or (2) above, but are not limited to them.

[0042] [Chemical Formula 2] In equations (3) and (4), n represents an integer greater than 50, preferably an integer between 50 and 200.

[0043] Specific examples of such polysulfone polymers include Udel (registered trademark) P-1700, P-3500 (made by Solvay), Ultrason (registered trademark) S3010, S6010 (made by BASF), etc.

[0044] The above-mentioned polysulfone polymers can be used alone or in combination of two or more.

[0045] It should be noted that "using polysulfone-based polymers as the main component" means that in the components constituting the hollow fiber membrane, polysulfone-based polymers account for more than 50% of the total mass. The content of polysulfone-based polymers is preferably more than 75% of the components constituting the hollow fiber membrane, and more preferably more than 90%.

[0046] According to a preferred embodiment, the hollow fiber membrane of the present invention further contains a hydrophilic polymer. That is, the hollow fiber membrane of the present invention is preferably composed of a mixed resin of the aforementioned polysulfone-based polymer and a hydrophilic polymer. The hydrophilic polymer functions as a pore-forming agent when forming porous hollow fiber membranes using polysulfone-based polymers, and also adjusts the viscosity of the membrane-forming solution and imparts an inhibitory effect on protein adhesion. It should be noted that the so-called hydrophilic polymer in the present invention refers to a polymer soluble in water or ethanol, preferably a polymer dissolved in them at a concentration of 0.1 g / mL or higher.

[0047] As a hydrophilic polymer, a hydrophilic polymer that is a good solvent for polysulfone-based polymers and is miscible with polysulfone-based polymers is preferred. Examples of such hydrophilic polymers include polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, and copolymers thereof. Examples of copolymers include copolymers of vinylpyrrolidone with components selected from vinyl acetate, vinyl propionate, and vinyl butyrate, etc., but there are no particular limitations. Among these, from the viewpoint of compatibility with polysulfone-based polymers, polyvinylpyrrolidone or copolymers thereof are preferred.

[0048] From the viewpoint of its role as a pore-forming agent and its effect in inhibiting protein adhesion, the content of hydrophilic polymer in the hollow fiber membrane is preferably 0.5% by weight or more, and more preferably 1.0% by weight or more. On the other hand, if the content of hydrophilic polymer is too high, membrane formation may become difficult and there is a possibility of dissolution from the hollow fiber membrane. Therefore, the content of hydrophilic polymer is preferably 10% by weight or less, and more preferably 8% by weight or less.

[0049] Typically, hollow fiber membranes include so-called symmetrical membranes with a symmetrical structure where the pore size remains largely unchanged along the thickness direction, and so-called asymmetrical membranes with an asymmetrical structure where the pore size varies along the thickness direction. The porous hollow fiber membrane of this invention is an asymmetrical membrane with a dense inner surface and a porous outer surface. In other words, it has a structure with small pores on the inner surface and large pores on the outer surface. Such an asymmetrical membrane has the advantage of easily controlling the pore size of the dense layer (which is important for substance separation). Furthermore, in an asymmetrical membrane, by having regions with small pores that facilitate the separation of target substances such as viruses and regions with large pores that reduce water permeation resistance, it is easy to simultaneously achieve separation performance and water permeability.

[0050] According to a preferred embodiment, the thickness of the layer (hereinafter referred to as the dense layer) on the inner surface side of the hollow fiber membrane of the present invention, which does not have pores with a diameter of 130 nm or more, is 1 μm or less. The thickness of the dense layer can be determined by observing a cross-section of the hollow fiber membrane perpendicular to the axis using a scanning electron microscope (SEM) at 10,000x magnification, and analyzing the captured image using image processing software. Specifically, firstly, for the captured image, a threshold is determined such that the structural portion is high brightness and other portions are low brightness, and then binarization is performed. Then, in the hollow fiber membrane, the region where the low brightness portion is not observed is designated as the dense layer, and the average thickness of the dense layer in the above cross-section is calculated, wherein the low brightness portion is an area of ​​1.3 × 10⁻⁶ with a diameter of 130 nm, assuming a perfect circular shape. 4 (nm) 2 The part above. More specifically, the thickness of the dense layer is the value measured by the method described in "(6) Determination of the thickness of the dense layer" below.

[0051] In the hollow fiber membrane of the present invention, the separation of substances is mainly achieved through the dense layer. When the dense layer is too thick, the resistance to the permeation of treatment liquids such as water increases. To obtain high permeability, the thickness of the dense layer is preferably 1 μm or less, more preferably 0.8 μm or less, even more preferably 0.5 μm or less, and even more preferably 0.2 μm or less. On the other hand, when the thickness of the dense layer is extremely thin, the separation performance may decrease depending on the processing conditions. Therefore, the thickness of the dense layer is preferably 0.05 μm or more, more preferably 0.1 μm or more.

[0052] The size of the target substance to be separated in the hollow fiber membrane of the present invention depends on the shape of the pores on the inner surface. The pores on the inner surface of the hollow fiber membrane are mostly elliptical rather than circular. The shorter diameter (minor axis) of the elliptical pores is beneficial for substance separation; therefore, controlling the minor axis of the pores on the inner surface is important in the present invention. For example, in the manufacture of biopharmaceuticals, it is necessary to separate antibodies (approximately 8-10 nm), which are useful substances, from their polymers, and to separate antibodies from various viruses (approximately 30-100 nm). From the viewpoint of the permeability of antibodies, which are useful substances, the average value of the minor axis of the pores on the inner surface is preferably 20 nm or more, more preferably 22 nm or more, and even more preferably 25 nm or more. On the other hand, from the viewpoint of separation performance, the average value of the minor axis of the pores on the inner surface is preferably 40 nm or less, more preferably 38 nm or less, and even more preferably 35 nm or less. Furthermore, when the longer diameter (major axis) of the elliptical pores is increased, the porosity of the membrane surface can be improved, which is therefore preferred. The ratio of the major axis to the minor axis (major axis / minor axis) of the pores on the inner surface is preferably 2 or more, and more preferably 2.5 or more. On the other hand, if the ratio of the major axis to the minor axis is too large, the strength of the film may decrease. Therefore, the ratio of major axis to minor axis is preferably 6 or less, and more preferably 5 or less. It should be noted that the minor axis and major axis of the pores in the dense layer referred to here are average values, specifically, values ​​measured by the method described later in "(4) Measurement of Surface Pore Diameter".

[0053] The porosity of the inner surface has a significant impact on the permeability of hollow fiber membranes. A lower porosity reduces the flow path for substances to pass through, thus increasing the permeation resistance. Therefore, in the hollow fiber membrane of the present invention, the porosity of the inner surface is 5% or more, preferably 10% or more, and more preferably 15% or more. On the other hand, increasing the porosity of the inner surface makes pore size control difficult and easily causes changes in the pore structure when pressure is applied; therefore, the porosity of the inner surface is 30% or less, preferably 25% or less. It should be noted that the porosity of the inner surface of the hollow fiber membrane is a value measured by the method described later in "(5) Determination of Porosity".

[0054] In this specification, the layers existing outside the dense layer of the hollow fiber membrane of the present invention, that is, the layers other than the dense layer on the outer surface side of the hollow fiber membrane, are referred to as the porous layer. To minimize the permeation resistance of the porous layer, the porous layer preferably has a structure in which the pore size gradually increases from the dense layer side to the outer surface side. Furthermore, from the viewpoint of the strength of the hollow fiber membrane, it is preferable that no macropores are observed in the porous layer; macropores are void regions in which the solid portion of the membrane is missing in an elliptical or droplet shape.

[0055] From the viewpoint of permeability, the average minor diameter of the pores on the outer surface of the hollow fiber membrane, i.e., the outer surface of the porous layer, is preferably 0.2 μm or more, more preferably 0.3 μm or more. On the other hand, from the viewpoint of the strength of the hollow fiber membrane, the average minor diameter of the pores on the outer surface is preferably 2 μm or less, more preferably 1.5 μm or less. Furthermore, from the viewpoint of permeability, the porosity of the outer surface is preferably 1% or more, more preferably 3% or more, and even more preferably 5% or more. On the other hand, from the viewpoint of strength, the porosity of the outer surface is preferably 20% or less, more preferably 15% or less.

[0056] The susceptibility of hollow fiber membranes to breakage is related to their thickness and inner diameter. A thinner membrane reduces the boundary membrane mass transfer coefficient, thus improving material removal performance. Conversely, excessively thin membranes are prone to fiber breakage and drying cracking, potentially causing manufacturing problems. Therefore, the thickness of the hollow fiber membrane is preferably 20 μm or more, more preferably 30 μm or more. Furthermore, the thickness is preferably 100 μm or less, more preferably 80 μm or less, and even more preferably 60 μm or less. Additionally, the inner diameter of the hollow fiber membrane is preferably 150 μm or more, more preferably 200 μm or more, and even more preferably 220 μm or more; and preferably 500 μm or less, more preferably 400 μm or less, and even more preferably 300 μm or less. The inner diameter of a hollow fiber membrane refers to the value obtained by measuring the membrane thickness of the hollow fiber membrane using a 1000x microscope, such as MICROWATCHER (e.g., VH-Z100; KEYENCE Co., Ltd.), and calculating it using the following formula.

[0057] Hollow fiber membrane inner diameter = hollow fiber membrane outer diameter - (membrane thickness × 2) The outer diameter of a hollow fiber membrane refers to the value obtained by measuring the outer diameter of the hollow fiber membrane using a laser displacement meter (e.g., LS5040T; KEYENCE Co., Ltd.).

[0058] Regarding the porous hollow fiber membrane of the present invention, a polymer containing monocarboxylic acid vinyl ester units (hereinafter, sometimes referred to as "coated polymer") is supported on at least one side of the outer and inner surfaces of the hollow fiber membrane. The coated polymer is particularly preferably supported on at least the inner surface initially contacted by the treated liquid, and more preferably on both the inner and outer surfaces. Furthermore, it is even more preferable that the coated polymer is also supported inside the porous layer of the hollow fiber membrane (the collective term for the aforementioned dense and loose layers). By supporting the coated polymer on the inner surface, outer surface, and inside the porous layer, the adhesion of proteins and the like can be effectively suppressed.

[0059] A monocarboxylic acid is a compound formed by a carboxyl group and a hydrocarbon group bonded to the carbon atom of that carboxyl group, i.e., a compound represented by "R-COOH" (where R is a hydrocarbon group). The hydrocarbon group R can be any aliphatic or aromatic hydrocarbon group, but from the viewpoint of ease of synthesis, an aliphatic hydrocarbon group is preferred, and particularly a saturated aliphatic hydrocarbon group. Furthermore, from the viewpoint of the manufacturing cost of carboxylic acids, a saturated aliphatic hydrocarbon group is preferred to have a straight-chain or branched structure, and more preferably a straight-chain structure. Examples of monocarboxylic acids where R is an aromatic hydrocarbon group include benzoic acid and its derivatives. Examples of monocarboxylic acids where R is a saturated aliphatic hydrocarbon group include acetic acid, propionic acid, and butyric acid.

[0060] Saturated aliphatic hydrocarbon groups can be not only straight-chain structures such as ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl, but also branched structures such as isopropyl and tert-butyl, and cyclic structures such as cyclopropyl and cyclobutyl. Furthermore, ether bonds and ester bonds can be included in the aliphatic chain. It should be noted that the hydrogen atom in the hydrocarbon group R can be replaced by any substituent, but when the terminal hydrogen atom is replaced by anionic functional groups such as sulfonic acid groups, it will make the protein structure unstable and may cause adhesion to the surface of hollow fiber membranes. Therefore, it is preferable that the terminal hydrogen atom is not replaced by anionic functional groups.

[0061] When the hydrocarbon group R has a small number of carbon atoms, it is preferable for reducing the hydrophobicity of monocarboxylic acids, minimizing hydrophobic interactions with proteins, and preventing adhesion. Therefore, when R is an aliphatic or aromatic hydrocarbon group, the number of carbon atoms is preferably 1 to 20, more preferably 1 to 9, and even more preferably 2 to 5. It should be noted that when R is a saturated aliphatic hydrocarbon group, the compound with 1 carbon atom is acetic acid, and the compound with 2 carbon atoms is propionic acid.

[0062] Furthermore, the term "unit" as used in this specification refers to a repeating unit in a homopolymer or copolymer obtained by monomer polymerization, and the term "vinyl carboxylic acid ester unit" refers to a repeating unit obtained by polymerizing vinyl carboxylic acid ester monomers, that is, a repeating unit represented by "-CH(OCO-R)-CH2-" (R being an aliphatic hydrocarbon group or an aromatic hydrocarbon group). R is the same as described above for monocarboxylic acids, and preferred examples, etc., are also based on the above description.

[0063] Specific examples of vinyl ester monocarboxylic acids where R is a saturated aliphatic unit include vinyl propionate, vinyl pentanoate, vinyl decanoate, and vinyl methoxyacetate. From the perspective of avoiding excessive hydrophobicity, preferred examples include vinyl acetate (R: CH3), vinyl propionate (R: CH2CH3), vinyl butyrate (R: CH2CH2CH3), vinyl pentanoate (R: CH2CH2CH2CH3), vinyl pentanoate (R: C(CH3)3), and vinyl hexanoate (R: CH2CH2CH2CH2CH3). Specific examples of vinyl ester monocarboxylic acids where R is an aromatic unit include vinyl benzoate and its substitutes.

[0064] The presence of polymers containing monocarboxylic acid vinyl ester units on the outer or inner surface of hollow fiber membranes can be confirmed by combining compositional analysis using a TOF-SIMS device with measurements using X-ray photoelectron spectroscopy (XPS). Specifically, firstly, the peaks of carboxylic acid ions originating from the aforementioned monocarboxylic acid vinyl ester units can be detected by compositional analysis using a TOF-SIMS device; therefore, the structure of the monocarboxylic acid is determined by analyzing its mass (m / z).

[0065] In compositional analysis using a TOF-SIMS device, the sample surface is irradiated with pulsed ions (primary ions) in an ultra-high vacuum. Ions escaping from the sample surface (secondary ions) acquire constant kinetic energy and are introduced into a time-of-flight mass analyzer. The secondary ions, accelerated with the same energy, each pass through the analyzer at a velocity corresponding to their mass. However, since the distance to the detector is constant, the time to reach the detector (time of flight) becomes a function of mass. By precisely measuring the distribution of this time of flight, the mass distribution of the secondary ions, i.e., the mass spectrum, is obtained. For example, Bi3 is used as the primary ion species. ＋＋ When detecting negative ions twice, the peak at m / z = 59.02 corresponds to C2H3O2. - This refers to acetic acid (aliphatic chain with 1 carbon atom). Furthermore, the peak at m / z = 73.04 corresponds to C3H5O2. - Propionic acid (aliphatic chain with 2 carbon atoms).

[0066] The conditions for component analysis using a TOF-SIMS device are as follows. The measurement area is set to 200 μm × 200 μm, the first-order ion acceleration voltage is set to 30 kV, and the pulse width is set to 5.9 nm. The detection depth in this analytical method is less than a few nm. At this time, if the carboxylic acid ion intensity is less than 0.4% relative to the total secondary ion intensity, it is judged as noise and determined that carboxylic acid ions are not present. More specifically, it is set to the value measured according to "(7) TOF-SIMS determination" described later.

[0067] Furthermore, during XPS analysis, the peak originating from the carbon atom of the ester group (COO) was observed to be located at CH... x The main peak of C4 (around 285 eV) appears from +4.0 to +4.2 eV, indicating that the aforementioned carboxylic acid forms an ester bond. The XPS measurement angle is the value obtained at 90°. When measuring at 90°, the region from the surface to a depth of approximately 10 nm is detected. If the peak area originating from the ester group is less than 0.4% relative to the total peak area originating from carbon, it is considered noise and is considered as the absence of ester groups. More specifically, the value is assumed to be obtained according to "(8) X-ray Electron Spectroscopy (XPS) Measurement" described later.

[0068] Based on the above two test results, it can be determined whether there are polymers containing monocarboxylic acid vinyl ester units on the surface of porous hollow fiber membranes.

[0069] Furthermore, the amount of coated polymer present on the surface of the porous hollow fiber membrane or inside the porous layer can be determined by measuring the amount of carbon derived from ester groups using XPS.

[0070] The peaks originating from the ester group (COO) can be determined by peak segmentation from the main peak originating from CH and CC at C1s to the peaks appearing in the range of +4.0–4.2 eV. The amount of carbon originating from the ester group (atomic percentage) is calculated by determining the proportion of the peak area originating from the ester group relative to the total peak area originating from the carbon group. More specifically, the C1s peaks are mainly derived from CH... x The components of CC, C=C and CS, the components mainly derived from CO and CN, and the components derived from π-π The peak is composed of five components: satellite peak components, components originating from C=O, components originating from COO, and components derived from CH. The peak is divided into these five components. The component originating from COO is derived from CH... x The peaks appear from the main peak of CC (around 285 eV) to +4.0 to 4.2 eV. The peak areas of each component are calculated by rounding to the second decimal place.

[0071] To exert an inhibitory effect on protein adhesion, when measuring at least one of the outer or inner surfaces using XPS, the percentage of carbon peak area originating from ester groups, when the total peak area originating from carbon is taken as 100 (atomic percentage), is 0.1 (atomic percentage) or more, more preferably 1.0 (atomic percentage) or more, and even more preferably 1.5 (atomic percentage) or more. On the other hand, to prevent a decrease in the permeability of the hollow fiber membrane, it is preferable that the amount of polymer containing monocarboxylic acid vinyl ester units supported on the outer or inner surface is not excessive. From the viewpoint of preventing a decrease in permeability, this percentage of carbon peak area originating from ester groups is preferably 25 (atomic percentage) or less, more preferably 20 (atomic percentage) or less, and even more preferably 10 (atomic percentage) or less.

[0072] It should be noted that during XPS measurements, measurements were taken at two locations on the porous hollow fiber membrane, and the average value of these two values ​​was used.

[0073] Furthermore, the amount of ester groups relative to polysulfone polymers on the surface of the porous hollow fiber membrane can be determined by total reflectance infrared spectroscopy (ATR). Specifically, the measurement range at one location is set to 3 μm × 3 μm, and the cumulative number of measurements is more than 30. Infrared absorption spectra are measured at 25 points on the surface of the porous hollow fiber membrane. The infrared absorption spectra are concentrated in the range of 1711–1759 cm⁻¹. -1 Draw a baseline, and take the area enclosed by this baseline and the positive portion of the spectrum as the peak area originating from the ester group (A). COO Similarly, in the range of 1549–1620 cm -1 Draw a baseline, and take the area enclosed by this baseline and the positive portion of the spectrum as the peak area (A) of the benzene ring C=C originating from the polysulfone polymer. CC ). Calculate the ratio of the two (A). COO ) / (A CC The average value at 25 locations was calculated. Furthermore, the above average value was calculated at three different locations near both ends and the center of a hollow fiber membrane along its length. This average value at these three locations was taken as the average value of (A) in the hollow fiber membrane being measured. COO ) / (A CC The average value of the hollow fiber membrane. More specifically, it is set as the value measured according to the "(9) Micro ATR method" described later. COO ) / (A CC The average value of (A) is preferably 0.01 or more, more preferably 0.03 or more, and even more preferably 0.05 or more. On the other hand, when the proportion of ester groups is too high, the surface hydrophobicity increases, and the inhibitory effect on protein adhesion may decrease. Therefore, (A) COO ) / (A CCThe average value of () is preferably 1 or less, more preferably 0.5 or less, and even more preferably 0.3 or less.

[0074] In the above-mentioned measurements, for example, when testing the inner surface of the hollow fiber membrane, the hollow fiber membrane is cut into a semi-cylindrical shape with a single blade to prepare a sample that exposes the inner surface of the hollow fiber membrane, and the inner surface is measured. When testing the outer surface of the hollow fiber membrane, the same sample as the inner surface is used for measurement. When measuring the interior of the hollow fiber membrane, the hollow fiber membrane is immersed in water for 5 minutes to wet it, then frozen with liquid nitrogen and quickly broken. The cross-section of the freeze-dried hollow fiber membrane is measured, or the thickness portion of the hollow fiber membrane is cut with a single blade, and the exposed interior portion of the hollow fiber membrane is measured.

[0075] From the viewpoint of sufficiently inhibiting protein adhesion, the number average molecular weight of the coated polymer is preferably 1,000 or more, more preferably 5,000 or more. On the other hand, there is no particular upper limit on the number average molecular weight of the polymer, but from the viewpoint of avoiding a decrease in the efficiency of introduction into the hollow fiber membrane, it is preferably 1,000,000 or less, more preferably 500,000 or less, and even more preferably 100,000 or less. It should be noted that the number average molecular weight of the homopolymer or copolymer can be determined by gel permeation chromatography (GPC).

[0076] The preferred coating polymer is a copolymer containing both hydrophilic and hydrophobic units (hereinafter, sometimes simply referred to as "copolymer"). When hydrophilic polymers such as polyethylene glycol and polyvinyl alcohol are used to coat the surface of hollow fiber membranes, it has been found that the inhibition effect on the adhesion of proteins is insufficient. This is believed to be because when the hydrophilicity of the hollow fiber membrane surface is too strong, the protein structure becomes unstable, thus failing to adequately inhibit protein adhesion. In recent years, in particular, the water surrounding the polymer has received attention. For highly hydrophilic polymers, the interaction between the polymer and water is strong, reducing the mobility of water around the polymer. On the other hand, it is believed that the structure of proteins is stabilized by water, known as adsorbed water. Therefore, it is believed that if the mobility of the adsorbed water of the protein is close to that of the water surrounding the polymer, the protein structure becomes unstable, thus inhibiting protein adhesion to the hollow fiber membrane surface. Regarding copolymers containing both hydrophilic and hydrophobic units, it is believed that the mobility of water around the polymer can be controlled by controlling the hydrophilic groups, hydrophobic groups, and copolymerization ratio used. Here, the term "hydrophilic unit" refers to a unit in which the monomer constituting the unit, when used alone to manufacture a polymer, is soluble in water, provided that the polymer has a weight-average molecular weight of 10,000 to 1,000,000. "Soluble" means that the solubility in 100g of water at 20°C exceeds 0.1g.

[0077] The monomer constituting the hydrophilic unit is more preferably a monomer with a solubility exceeding 10 g. Examples of such monomers include vinyl alcohol monomers, acryloylmorpholine monomers, vinylpyridine monomers, vinylimidazolium monomers, and vinylpyrrolidone monomers. Among these, monomers having amide, ether, or ester bonds are preferred from the perspective of not being overly hydrophilic compared to monomers having carboxyl or sulfonic acid groups, and easily achieving a balance with hydrophobic monomers. Vinylacetamide monomers, vinylpyrrolidone monomers, and vinylcaprolactam monomers having amide bonds are particularly preferred. Among these, vinylpyrrolidone monomers are further preferred from the perspective of low polymer toxicity. Therefore, according to a preferred embodiment of the present invention, the coating polymer contains vinylpyrrolidone units as hydrophilic units.

[0078] As a monomer constituting the hydrophobic unit, it contains at least a vinyl monocarboxylic acid ester, but may also contain units selected from acrylates, methacrylates, vinyl-ε-caprolactam, etc.

[0079] From the viewpoint of inhibiting protein adhesion, the molar fraction of hydrophobic units in the copolymer containing both hydrophilic and hydrophobic units is preferably 10% or more and 90% or less, more preferably 20% or more and 80% or less, and even more preferably 30% or more and 70% or less. In this case, the hydrophobic unit may be only a monocarboxylic acid vinyl ester unit, or it may further include other hydrophobic units. Setting the molar fraction of hydrophobic units below the above-mentioned upper limit is preferable in terms of inhibiting the increase in the overall hydrophobicity of the copolymer and preventing protein adhesion. Furthermore, setting the molar fraction of hydrophobic units above the above-mentioned lower limit is preferable in terms of inhibiting the increase in the overall hydrophilicity of the copolymer, preventing the instability and modification of the protein structure, and thus preventing protein adhesion. It should be noted that the above molar fraction can be calculated, for example, by performing nuclear magnetic resonance (NMR) measurement, based on the peak area ratio corresponding to each component. When the above molar fraction cannot be calculated using NMR measurement due to reasons such as peak overlap, the above molar fraction can also be calculated by elemental analysis.

[0080] As a coating polymer, copolymers comprising vinyl carboxylic acid units and vinyl pyrrolidone units are particularly preferred. In this case, the molar ratio of vinyl pyrrolidone units to vinyl carboxylic acid units is preferably 30:70 to 90:10, more preferably 40:60 to 80:20, and even more preferably 50:50 to 70:30.

[0081] Examples of arrangements of units in the aforementioned copolymers include block copolymers, alternating copolymers, and random copolymers. Among these, alternating copolymers or random copolymers are preferred from the viewpoint of minimizing the uneven distribution of hydrophilic and hydrophobic units throughout the copolymer. Random copolymers are more preferred from the viewpoint of ease of synthesis.

[0082] It should be noted that, although not mandatory, from the viewpoint of avoiding leaching of the coated polymer during use, it is preferable to fix the coated polymer onto the hollow fiber membrane via chemical bonds. The fixation method will be described later.

[0083] From the viewpoint of shortening processing time and miniaturizing hollow fiber membrane modules and auxiliary equipment, high water permeability is preferred for the porous hollow fiber membrane of the present invention. Preferably, the water permeability is 1 L / (hr·kPa·m). 2 ) or more, preferably 3L / (hr·kPa·m 2 ) or above, more preferably 10 L / (hr·kPa·m 2 On the other hand, if the permeability is too high, the hollow fiber membrane comes into contact with the protein faster, which may lead to protein modification. Therefore, the preferred permeability is 50 L / (hr·kPa·m). 2 )the following.

[0084] In the manufacturing process of biopharmaceuticals, the required virus clearance rate for the entire process is 99.9999999% or higher (LRV = 9). Furthermore, it is preferable to study the inactivation and removal processes for two or more different viruses. Therefore, the virus clearance rate of such porous hollow fiber membranes is preferably at least 99.99% or higher (LRV = 4).

[0085] In biopharmaceuticals, antibodies are expensive. During the manufacturing process, various separations and purifications are performed, thus requiring vigorous efforts to minimize antibody loss. This is especially true for separation membranes, which, due to their large surface area, are easily adsorbed by antibodies, leading to a decrease in recovery rate. Particularly when multiple separation membranes are used consecutively, the reduction in antibody recovery rate due to membrane adhesion becomes a significant problem. Therefore, an antibody recovery rate of 80% or higher is preferred, more preferably 85% or higher, and even more preferably 90% or higher.

[0086] Furthermore, when antibodies and target proteins adhere to the hollow fiber membrane, the volume of the treatment solution decreases over time, leading to prolonged treatment time and reduced antibody recovery rate. Therefore, it is preferable to prevent the volume of the treatment solution from decreasing over time. For example, when treating the solution at a low pressure of 20–50 kPa, the ratio of the volume of treatment solution recovered in 25–30 minutes or 55–60 minutes to the volume recovered in the initial 0–5 minutes is preferably 0.7 or more, more preferably 0.8 or more, and even more preferably 0.9 or more. Additionally, when treating the solution at a low pressure of 20–50 kPa, the antibody permeability maintenance rate (calculated as the antibody permeability in 25–30 minutes relative to the antibody permeability in the initial 0–5 minutes) is preferably 80% or more, more preferably 85% or more, and even more preferably 90% or more.

[0087] Sometimes, during the manufacturing process, antibodies may produce agglomerates composed of bound antibodies. Such agglomerates are considered ineffective impurities and therefore need to be removed during manufacturing. The content of antibody agglomerates relative to the antibody monomer is preferably 2% or less, more preferably 1% or less, and even more preferably 0%. The content of antibody agglomerates can be analyzed by light scattering, size exclusion chromatography, or similar methods.

[0088] The typical manufacturing process for biopharmaceuticals includes culturing antibody-producing cells, separating the cells from the antibodies, recovering and purifying the antibodies, inactivating viruses, and removing viruses. In the cell-antibody separation process, centrifugation and deep filtration can be used. For antibody recovery, a protein A column immobilized with protein A that specifically adsorbs antibodies is primarily used. Additionally, in the purification process, cation exchange columns and anion exchange columns are used to remove host cell proteins used for antibody production. The virus inactivation process typically involves low pH treatment below pH 4.

[0089] As described above, the hollow fiber membrane of the present invention exhibits excellent antibody permeability, thus enabling its application in the process of separating antibodies from antibody-producing cells after the cell culture process. The size of cells used to produce antibodies is generally 8–20 μm, making separation possible using the porous hollow fiber membrane of the present invention. Furthermore, it can be used to remove antibody agglomerates and the like, which are difficult to remove using protein A chromatography columns, during antibody recovery. While protein A chromatography columns, which use specific interactions with antibodies for separation, struggle to remove antibody agglomerates (approximately 40–80 nm), the porous hollow fiber membrane of the present invention allows for separation of antibodies from antibody agglomerates based on size differences. Additionally, the hollow fiber membrane or hollow fiber membrane assembly of the present invention can be applied to the process of separating antibodies from antibody agglomerates during antibody purification.

[0090] Furthermore, in the final stage of the manufacturing process of the aforementioned biopharmaceuticals, the hollow fiber membrane of the present invention is preferably used as the virus removal membrane. Moreover, after using separation membranes of various pore sizes to perform cell separation, antibody recovery, purification, and other processes according to the size of the target substance to be removed in each stage of the aforementioned manufacturing process, the hollow fiber membrane of the present invention can also be used as the virus removal membrane.

[0091] Especially in the current manufacturing processes of biopharmaceuticals, inefficiency arises due to the batch processing of each step. This problem can be solved by using the porous hollow fiber membrane or hollow fiber membrane module of the present invention as a purification system. Specifically, it is a purification system for obtaining desired cells or proteins from a solution containing cells and proteins. This purification system has the hollow fiber membrane and separation membrane of the present invention, wherein the separation membrane has pores with a diameter smaller than that of the hollow fiber membrane of the present invention. The porous hollow fiber membrane and the separation membrane are configured such that the solution is subjected to the porous hollow fiber membrane and the separation membrane of the present invention. even Continuous processing. When using the above purification system, by continuously configuring separation membranes with different pore sizes, solutions containing cells and proteins can be continuously processed to purify and recover the desired cells or proteins, thus resulting in high productivity and making it preferred.

[0092] In addition to its use in the manufacturing process of biopharmaceuticals, the hollow fiber membrane of the present invention can also be used in the virus removal process of blood products.

[0093] <Manufacturing Method of Porous Hollow Fiber Membranes> The preferred method for forming the porous hollow fiber membrane of the present invention is a phase separation method. As a phase separation method, methods such as the so-called non-solvent-induced phase separation method, which utilizes a poor solvent to induce phase separation, and the so-called thermally induced phase separation method, which induces phase separation by cooling a high-temperature membrane-forming solution using a solvent with relatively low solubility, can be used. Of these, the method of forming the membrane by utilizing a poor solvent to induce phase separation is particularly preferred.

[0094] In the aforementioned membrane formation process, phase separation occurs through contact between the membrane-forming solution and the undesirable solvent, thus determining the structure of the porous hollow fiber membrane. Specifically, when the core liquid containing the undesirable solvent is discharged from the inside of the dual-tube spinneret, and the membrane-forming solution flows on the outside during membrane formation, phase separation begins from the inner surface (inner surface) of the hollow fiber membrane where the membrane-forming solution and the undesirable solvent are in contact. Then, the undesirable solvent diffuses along the membrane thickness direction, and phase separation continues. At this point, the porous hollow fiber membrane with the highest concentration of undesirable solvent has the smallest pore size on its inner surface, forming a dense structure, which becomes a loose structure with larger pores towards the outer surface. The pore size of the inner surface and the thickness of the dense layer can be adjusted by controlling the phase separation rate. Specifically, this can be achieved by adjusting the concentration of the undesirable solvent in the core liquid, the discharge temperature of the membrane-forming solution, and the concentration of polysulfone polymers in the membrane-forming solution. In particular, changing the concentration of the undesirable solvent in the core liquid is effective for adjusting the pore size and the dense layer. By adjusting the concentration and diffusion rate of the undesirable solvent in the core solution, the pore size and thickness of the dense layer on the surface of the hollow fiber membrane can be controlled. Furthermore, by increasing the concentration of polysulfone-based polymers in the membrane-forming solution, the polysulfone-based polymers, which are the main components of the hollow fiber membrane, are densely distributed, thus increasing the thickness of the dense layer.

[0095] As a polysulfone polymer used in the film-forming solution, the above-mentioned polymers can be used, either one or a mixture of two or more.

[0096] Increasing the concentration of polysulfone-based polymers in the film-forming solution can improve the mechanical strength of the hollow fiber membrane. However, excessively high concentrations of polysulfone-based polymers may lead to problems such as poor drainage due to decreased solubility and increased viscosity of the film-forming solution. Furthermore, the concentration of polysulfone-based polymers can regulate water permeability and molecular weight cutoff. Excessively high concentrations of polysulfone-based polymers increase the density of this polymer on the inner surface of the hollow fiber membrane, thus reducing water permeability and molecular weight cutoff. Based on the above, the concentration of polysulfone-based polymers in the film-forming solution is preferably 30% by mass or less. On the other hand, a lower limit for the concentration of polysulfone-based polymers in the film-forming solution is preferably 10% by mass or more.

[0097] When dissolving polysulfone polymers in a solvent, it is preferable to dissolve them at a high temperature to improve solubility. However, there is a possibility that heat may cause polymer modification or solvent evaporation, thereby altering the composition. Therefore, the preferred dissolution temperature is above 30°C and below 120°C. However, depending on the type of polysulfone polymer and additives, their optimal range may sometimes vary.

[0098] Furthermore, by incorporating a hydrophilic polymer into the membrane-forming solution, the following effects can be expected: the effect of improving water permeability as a pore-forming agent as described above, and the effect of inhibiting protein adhesion by increasing hydrophilicity. In addition, by incorporating a hydrophilic polymer, the viscosity of the membrane-forming solution can be adjusted, and the formation of macropores, which is a major cause of membrane strength reduction, can be suppressed. However, if the amount of hydrophilic polymer in the membrane-forming solution is too high, it may sometimes cause decreased solubility and poor drainage due to increased viscosity of the membrane-forming solution. Furthermore, due to the large amount of hydrophilic polymer remaining in the hollow fiber membrane, water permeability may decrease due to increased permeation resistance. The above-mentioned materials can be used as hydrophilic polymers; one type can be used alone, or two or more types can be mixed. The optimal amount of hydrophilic polymer added to the membrane-forming solution varies depending on its type and target performance, but it is preferably 1% by mass or more and 20% by mass or less relative to the total amount of the membrane-forming solution.

[0099] It should be noted that using hydrophilic polymers with lower molecular weights (weight average molecular weight 1000–200000) enhances pore-forming properties, thus improving the permeability of hollow fiber membranes. Conversely, using hydrophilic polymers with higher molecular weights (weight average molecular weight 200000–1200000) results in longer molecular chains and increased interactions with polysulfone-based polymers, making them more likely to remain within the hollow fiber membrane and contributing to improved hydrophilicity. Therefore, blending low- and high-molecular-weight hydrophilic polymers is more preferable.

[0100] The solution (core solution) discharged from the inner tube of the double-tube spinneret is a mixture of a good solvent and a poor solvent for polysulfone-based polymers. The water permeability and molecular weight cutoff (pore size) of the hollow fiber membrane can be adjusted according to this mixture. There are no particular limitations on the poor solvent; water, ethanol, isopropanol, and other alcohol-based solvents can be used, with water being the most preferred. There are no particular limitations on the good solvent, but N-methylpyrrolidone and N,N-dimethylacetamide are preferred.

[0101] By contacting the aforementioned film-forming stock solution with the core solution, phase separation of the film-forming stock solution is induced due to the action of the undesirable solvent, thereby coagulation occurs. Excessively increasing the ratio of undesirable solvent in the core solution reduces the membrane's water permeability and molecular weight cutoff. On the other hand, if the ratio of undesirable solvent is too low, it may drip directly in a liquid state, thus failing to obtain a hollow fiber membrane. The appropriate ratio of good solvent to undesirable solvent in the core solution varies depending on the types of both, but it is preferable that the undesirable solvent in the mixture is 10% by mass or more and 80% by mass or less.

[0102] The temperature of the double-tube spinneret at discharge affects the viscosity of the film-forming solution, phase separation behavior, and the diffusion rate of the core liquid into the film-forming solution. Generally, the higher the temperature of the double-tube spinneret, the faster the diffusion rate of undesirable solvents, thus facilitating phase separation and increasing the water permeability and molecular weight cutoff of the resulting hollow fiber membrane. However, if the temperature of the double-tube spinneret is too high, the discharge becomes unstable due to the decreased viscosity and coagulation of the film-forming solution, thereby reducing spinnability. On the other hand, if the temperature of the double-tube spinneret is too low, condensation may sometimes cause moisture to adhere to the double-tube spinneret. Therefore, the temperature of the double-tube spinneret is preferably above 20°C and below 90°C.

[0103] As described above, separation performance depends on the short axis of the pores present on the inner surface of the hollow fiber membrane. Therefore, by making the pores elliptical and increasing the porosity, both high separation performance and high water permeability can be achieved. Methods for making the pores on the inner surface of the hollow fiber membrane elliptical include a stretching method where the porous membrane is stretched after curing, and a method of increasing the draw ratio and stretching the porous membrane before curing. The method of increasing the draw ratio is preferred because it is not limited by the manufacturing method or raw materials of the porous membrane and can be widely applied. The draw ratio is a value obtained by dividing the traction speed of the porous membrane by the discharge linear velocity from the slit that discharges the membrane-forming solution. The discharge linear velocity is a value obtained by dividing the discharge amount by the cross-sectional area of ​​the slit (the portion of the spinneret from which the solution is discharged). Therefore, to increase the draw ratio, the traction speed can be increased, or the cross-sectional area of ​​the discharge portion of the slit can be increased. The method of increasing the cross-sectional area of ​​the slit is preferred because it easily increases the draw ratio without changing the shape of the porous membrane.

[0104] Preferably, the film-forming solution travels in the air within a defined zone called the dry section after exiting the dual-tube spinneret and before entering the coagulation bath. In the dry section, the outer surface of the discharged film-forming solution comes into contact with the air and absorbs moisture from the air, which becomes a poor solvent, thus causing phase separation. Therefore, by controlling the dew point of the dry section, the porosity of the outer surface of the resulting hollow fiber membrane can be adjusted. When the dew point of the dry section is low, phase separation may not occur sufficiently, the porosity of the outer surface decreases, the friction of the hollow fiber membrane increases, and the spinnability deteriorates. On the other hand, when the dew point of the dry section is too high, the outer surface may solidify, thus reducing the porosity. The dew point of the dry section is preferably 60°C or lower and 10°C or higher.

[0105] When the distance of the dry section (dry length) is too short, solidification occurs before phase separation is fully completed, resulting in reduced water permeability and retention performance. Therefore, the dry length is preferably 50 mm or more, and more preferably 100 mm or more. On the other hand, when the dry length is too long, spinning stability may be reduced due to filament shaking, etc. Therefore, the dry length is preferably 600 mm or less.

[0106] After passing through the dry section, the film-forming solution is supplied to a coagulation bath with a poor solvent, primarily composed of polysulfone-based polymers. Water is preferably used as the poor solvent in the coagulation bath. Upon entering the coagulation bath, the film-forming solution coagulates due to the large amount of poor solvent present, thus fixing the film structure. Alternatively, a good solvent may be added to the coagulation bath as needed. Higher temperatures in the coagulation bath, or higher concentrations of good solvent, further inhibit coagulation and promote phase separation, thereby increasing water permeability and molecular weight cutoff.

[0107] Hollow fiber membranes obtained by coagulation in a coagulation bath contain excess hydrophilic polymers derived from the solvent and the original solution, therefore further washing is preferable. As a washing method, a method of passing the membrane in a solvent that dissolves the excess hydrophilic polymer but not the polysulfone polymer component is preferred. Examples of such solvents include alcohols such as ethanol, aqueous solutions containing a good solvent to a degree that does not dissolve the polysulfone polymer, or water. From an operability point of view, water is preferred. Furthermore, increasing the temperature of the solvent used for washing can improve washing efficiency; therefore, a washing temperature of 50–100°C is preferred.

[0108] Methods for loading and coating polymers onto the surface of such porous hollow fiber membranes include adding the coating polymer to the stock solution or core solution during membrane formation; and contacting the surface with the coating polymer solution after membrane formation. Among these methods, contacting the hollow fiber membrane with the coating polymer solution after membrane formation is preferred from the perspective of not affecting the membrane formation conditions. Examples of such methods include immersing the hollow fiber membrane in the coating polymer solution, passing the coating polymer solution through the hollow fiber membrane, or spraying the coating polymer solution onto the hollow fiber membrane, etc. Since the coating polymer can be applied from the inside of the hollow fiber membrane to the outer surface, passing the coating polymer solution through the hollow fiber membrane is preferred.

[0109] When the coating polymer solution is passed through a hollow fiber membrane, if the concentration of the polymer in the solution is too low, a sufficient amount of polymer cannot be introduced onto the surface. Therefore, the concentration of the coating polymer in the coating polymer solution is preferably 10 ppm or more, more preferably 100 ppm or more, and even more preferably 300 ppm or more. However, if the concentration is too high, there is a possibility of increased leaching from the component and changes in pore size. Therefore, the concentration of the coating polymer in the aqueous solution is preferably 100,000 ppm or less, more preferably 10,000 ppm or less.

[0110] Water is preferably used as the solvent in the preparation of the coating polymer solution. However, if the coating polymer has low solubility in water, it may be dissolved in an organic solvent that does not dissolve the hollow fiber membrane, or in a mixture of an organic solvent that is miscible with water and does not dissolve the hollow fiber membrane and water. Examples of organic solvents that can be used as the above-mentioned organic solvents or mixed solvents include, but are not limited to, alcohol-based solvents such as methanol, ethanol, or propanol.

[0111] Regarding the direction in which the coated polymer solution passes through the hollow fiber membrane, it can be either from the inside to the outside or from the outside to the inside of the hollow fiber membrane. However, if the size of the coated polymer used is larger than the pore size of the inner surface of the hollow fiber membrane, when the liquid is passed from the inside, the coated polymer cannot pass through the pores and is concentrated on the inner surface side, thus making it impossible to load the coated polymer on the inside and outer surface of the hollow fiber membrane. In this case, the coated polymer solution can be flowed separately on the outside of the hollow fiber membrane to load the coated polymer onto the entire hollow fiber membrane. The molecular weight cutoff of the hollow fiber membrane is determined based on the measurement results of "(11) Determination of Molecular Weight Cutoff Using Dextran" described later. Based on the results, the molecular weight of the coated polymer can be set so that the size of the coated polymer is smaller than the pore size of the inner surface of the hollow fiber membrane.

[0112] Furthermore, as described above, it is preferable that the coated polymer is fixed to the hollow fiber membrane via chemical bonds. There are no particular limitations on the method for fixing the coated polymer via chemical bonds; examples include irradiating the hollow fiber membrane with radiation after contact with the coated polymer, and introducing reactive groups such as amino and carboxyl groups onto the surfaces of both the coated polymer and the hollow fiber membrane to be fixed, thereby causing a reaction between them.

[0113] Examples of methods for introducing reactive groups onto the surface of hollow fiber membranes include methods such as polymerizing monomers with reactive groups to obtain a substrate with reactive groups on its surface; methods for introducing reactive groups after polymerization by ozone treatment or plasma treatment; and so on.

[0114] Alternatively, when using irradiation, the radiation source can be alpha rays, beta rays, gamma rays, X-rays, ultraviolet rays, or electron beams. Irradiation is performed under the following conditions: the hollow fiber membrane within the hollow fiber membrane module is in contact with a solution containing a coated polymer; the coated polymer is introduced onto the surface of the hollow fiber membrane, and the solution within the hollow fiber membrane module is removed; or the hollow fiber membrane has been dried. Using this method, sterilization of the hollow fiber membrane module can be achieved simultaneously with fixing the coated polymer, which is therefore preferable. In this case, the radiation dose is preferably 15 kGy or more, more preferably 25 kGy or more. On the other hand, excessively high radiation doses promote the deterioration and decomposition of the polymer; therefore, the radiation dose is preferably 100 kGy or less.

[0115] Additionally, antioxidants can be used to inhibit the cross-linking reaction of coated polymers caused by radiation exposure. Antioxidants are substances that readily donate electrons to other molecules. Examples include water-soluble vitamins such as vitamin C, polyphenols, and alcohol solvents such as methanol, ethanol, or propanol, but these are not limited to these. These antioxidants can be used alone or in combination of two or more. When safety is a concern, antioxidants with low toxicity, such as ethanol and propanol, are preferred.

[0116] The hollow fiber membrane module of the present invention is obtained by embedding the hollow fiber membrane of the present invention within a housing. As a preferred embodiment, such as... Figure 6 As shown, a bundle of hollow fiber membranes 2 cut to the required length is housed in a cylindrical housing 1. Preferably, both ends of the hollow fiber membrane are fixed to the ends of the cylindrical housing 1 using a potting material 6 or similar. Preferably, both ends of the hollow fiber membrane are open. Furthermore, the hollow fiber membrane assembly preferably has water collection pipes (headers) 3A and 3B at both ends of the housing 1. Preferably, the water collection pipes 3A and 3B have liquid-permeable inlets 4A and 4B. Furthermore, as... Figure 6 As shown, the hollow fiber membrane module preferably has nozzles 5A and 5B on the side of the housing.

[0117] The liquid to be treated is introduced through inlet 4A or 4B, permeates from the inner surface of the hollow fiber membrane to the outer surface, and then exits through nozzle 5A or 5B. In this case, the liquid can flow in from both sides of inlet 4A and 4B, or only from one side. Alternatively, the liquid to be treated can be introduced through nozzle 5A or 5B, permeates from the outer surface of the hollow fiber membrane to the inner surface, and then exits through inlet 4A or 4B. In this case, the liquid can flow in from both sides of nozzle 5A and 5B, or only from one side.

[0118] As other preferred embodiments of hollow fiber membrane modules, such as Figure 7 As shown, the hollow fiber membrane 2, which is made into a U-shape, can be housed within a cylindrical shell 7. In this case, the end of the hollow fiber membrane is fixed to one side of the cylindrical shell by a potting material 6 or the like. The liquid to be treated can flow in through the opening 8 of the hollow fiber membrane as an inlet or flow out through it as an outlet.

[0119] As a method for manufacturing an assembly from the porous hollow fiber membrane of the present invention, examples include: a method of centrifuging the hollow fiber membrane while fixing it to a housing, and a method of forming the hollow fiber membrane into a U-shape and fixing only the open portion of the hollow fiber membrane to the housing. Although not particularly limited, one example is given below. First, the hollow fiber membrane is cut to the desired length, and the required number of strands are bundled and placed into a cylindrical housing. Then, temporary caps are placed at both ends, and potting material is injected into both ends of the hollow fiber membrane. At this time, it is preferable to inject the potting material while rotating the assembly using a centrifuge, as this allows for uniform filling of the potting material. After the potting material cures, the two ends of the hollow fiber membrane are cut off, leaving the two ends open. By installing inlet ports (collection pipes) for the treated liquid at both ends of the housing and capping the collection pipes and the nozzle portion of the housing, a hollow fiber membrane assembly is obtained.

[0120] Example (1) Fabrication of hollow fiber membrane modules Twenty hollow fiber membranes are filled into a shell with a diameter of approximately 5 mm and a length of approximately 17 cm. After sealing both ends with "QUICK MENDER" (registered trademark), an epoxy resin-based reactive adhesive manufactured by Konishi Co., Ltd., the shell is cut to create an opening, thus producing a hollow fiber membrane assembly.

[0121] (2) Determination of permeability Regarding the hollow fiber membrane module produced by (1), as described in the various examples and comparative examples, a copolymer coating was applied to the hollow fiber membrane. The water permeability of the coated hollow fiber membrane module was evaluated. The inner and outer sides of the hollow fiber membrane of the hollow fiber membrane module were washed with distilled water for 30 minutes. A water pressure of 16 kPa was applied to the inner side of the hollow fiber membrane, and the filtration rate of water flowing out from the outer side of the hollow fiber membrane per unit time was measured. The water permeability (UFR) was calculated using the following formula, using the value rounded to the first decimal place. At this time, the length of the portion of the hollow fiber membrane filled in the shell without adhesive was measured for use in calculating the membrane area.

[0122] UFR (L / hr / kPa / m) 2 = Qw / (P×T×A) Here, Qw: filtration volume (L), T: outflow time (hr), P: pressure (kPa), A: membrane area (m²) 2 ).

[0123] (3) Determination of virus removal performance The components used in the evaluation of (2) were evaluated. They were prepared in distilled water or phosphate buffer at approximately 1.0 × 10⁻⁶. 6The viral stock solution was prepared using a method containing bacteriophage MS-2 (ATCC 15597-B1) with a size of approximately 27 nm at a concentration of PFU / ml. Here, distilled water or phosphate buffer was used as the solution after autoclaving at 121°C for 20 minutes. The viral stock solution was fed from the inner surface to the outer surface of the hollow fiber membrane, or from the outer surface to the inner surface, at approximately 20°C and a pressure of 50 kPa, and filtered through a full-volume filtration method to obtain the filtrate. The first 10 ml of filtrate was discarded, and then 10 ml of the filtrate for assay was collected. Based on the Overlay agar assay, Standard Method 9211-D (APHA, 1998, Standard methods for the examination of water and wastewater, 18th ed.), the concentration of bacteriophage MS-2 is determined by inoculating 1 ml of filtrate, appropriately diluted with distilled water as needed, onto a test petri dish and counting the plaques. A plaque refers to a group of bacteria infected with the virus and killed, which can be counted as punctate plaques. Virus removal performance is expressed by the logarithmic removal rate (LRV). For example, LRV2 means -log10x = 2, or 0.01, indicating that the concentration of virus in the permeate is 1 / 100th (removal rate 99%) relative to the concentration of virus in the stock solution. Furthermore, if no plaques can be measured in the permeate, it is considered that LRV > 6.0.

[0124] (4) Determination of surface pore size Hollow fiber membranes were immersed in water for 5 minutes to moisten them, then frozen with liquid nitrogen. The freeze-dried hollow fiber membranes were used as test samples. The hollow fiber membranes were cut into semi-cylindrical shapes, exposing the inner surface. The inner surface of the hollow fiber membrane was observed using a scanning electron microscope (SEM) (S-5500, Hitachi High-Technologies Corporation) at 50,000x magnification, and the images were imported into a computer. The imported image size was 640 pixels × 480 pixels. For pores in a 1μm × 1μm range on the inner surface of the hollow fiber membrane, image processing software (ImageJ, developed by the National Institutes of Health) was used to fit each pore to an ellipse shape, and the minor and major axes were measured. Measurements were repeatedly taken in the 1μm × 1μm range, and data were added until the total number of measured pores reached more than 50. When observing pores in a double-layered manner in the depth direction, the exposed portion of the deeper pores was measured. Pores that were partially outside the measurement range were excluded. The SEM image is binarized to obtain an image where the holes are black and the structural parts are white. When it's impossible to clearly binarize the holes and structural parts due to contrast differences within the image, the holes are first painted black before image processing. The holes are fitted into elliptical shapes, and the minor and major axes of each hole are measured. The average value of the minor axis is calculated. The value, rounded to two decimal places, is used as the hole diameter. Holes with an area of ​​5 pixels or less in consecutive pixels are removed from the data to eliminate noise. The ratio of the major to minor axis is calculated based on the average value of each hole, rounded to two decimal places.

[0125] Regarding the surface pore size of the hollow fiber membrane, the observation was performed at a magnification of 1500x, as described above, and the data was imported into a computer. For pores in the range of 50μm×50μm, the short and long diameters were measured in the same manner.

[0126] (5) Determination of open area ratio Similar to (4), the surface of the sample was observed using a SEM (S-5500, manufactured by Hitachi High-Technologies Corporation) at a magnification of 50,000, and the image was imported into the computer. The size of the imported image was 640 pixels × 480 pixels. For the SEM image, a 1 μm × 1 μm area was cropped, and image analysis was performed using image processing software. The threshold was determined by binarizing the structural parts to make them high-brightness and the rest to make them low-brightness, resulting in an image where the high-brightness parts were white and the low-brightness parts were black. If the structural parts could not be separated from the rest due to the contrast difference within the image, the image was cropped at the parts with the same contrast, binarized separately, and then stitched together as initially to recover a single image. Alternatively, the area outside the structural parts could be painted black for image analysis. Low-brightness parts in the image containing noise and with fewer than 5 consecutive pixels were treated as high-brightness parts because the noise and holes could not be distinguished. As a method to eliminate noise, low-brightness regions with five or fewer consecutive pixels are excluded during pixel count measurement. Alternatively, noisy regions can be painted white. The number of pixels in the low-brightness regions is measured, and the percentage of pixels in the low-brightness regions relative to the total number of pixels in the analyzed image is calculated as the aperture ratio. The same measurement is performed on five images, and the average value is calculated and rounded to two decimal places.

[0127] For the surface pore size of the hollow fiber membrane, the same observation was performed at a magnification of 1500x as described above. The data was then imported into a computer, and the porosity was calculated for a range of 50μm×50μm.

[0128] (6) Determination of the thickness of the dense layer Hollow fiber membranes were immersed in water for 5 minutes to moisten them, then frozen with liquid nitrogen and rapidly broken. The freeze-dried hollow fiber membranes were used as observation samples. The cross-section of the hollow fiber membrane was observed using a SEM (S-5500, manufactured by Hitachi High-Technologies Corporation) at 10,000x magnification, and the images were imported into a computer. The imported image size was 640 pixels × 480 pixels. When the pores in the cross-section were found to be blocked during SEM observation, the sample was remade. Pore blockage is sometimes caused by deformation of the hollow fiber membrane in the stress direction during the cutting process.

[0129] SEM images were cropped at a distance of 1 μm parallel to the surface of the porous membrane and at any length along the membrane thickness direction. Image processing software was used for image analysis. The length of the membrane direction in the analysis range only needs to include the dense layer. If the dense layer cannot be included in the field of view for magnification measurement, two or more SEM images were combined to include the dense layer. A threshold was determined by binarizing the structural parts to make them high-brightness and other parts low-brightness, resulting in an image where high-brightness parts are white and low-brightness parts are black. If the structural parts cannot be separated from other parts due to contrast differences within the image, the image was cropped at the parts with the same contrast, binarized separately, and then stitched together as initially to reconstruct a single image. Alternatively, the area outside the structural parts can be blacked out for image analysis. When pores are observed twice in the depth direction, shallower pores are measured. If part of a pore is outside the measurement range, that pore is excluded. For low-brightness areas in an image containing noise and with fewer than 5 consecutive pixels, since it's impossible to distinguish noise from holes, they are treated as high-brightness areas and treated as structures. As a noise reduction method, low-brightness areas with fewer than 5 consecutive pixels are excluded during pixel count measurement. Alternatively, the noisy areas can be painted white. The number of pixels displaying a scale bar of known length within the image is measured, and the length of each pixel is calculated. The number of pixels for a hole is measured, and the hole area is calculated by multiplying the number of holes by the square of the length of each pixel. The diameter of a circle equivalent to the hole area is calculated using the following formula, and this is taken as the hole diameter. The area of ​​a hole with a diameter of 130 nm is 1.3 × 10⁻⁶. 4 (nm) 2 ).

[0130] Aperture = (Aperture area ÷ Pi) 1 / 2 ×2 Apertures with a diameter of 130 nm or larger were selected. The layer where these pores were not observable was designated as the dense layer. The thickness of the dense layer was measured in a direction perpendicular to the inner surface of the hollow fiber membrane. A perpendicular line was drawn from the surface, and the shortest distance from the surface along this line to the nearest pore with a diameter of 130 nm or larger (i.e., the distance between the nearest pore with a diameter of 130 nm or larger to the surface) was determined. Measurements were taken at five locations within the same image. Then, the same measurements were performed on five images, and the average of a total of 25 sets of measurement data was calculated. The value, rounded to three decimal places, was taken as the thickness of the dense layer.

[0131] (7) TOF-SIMS measurement The hollow fiber membrane was cut into a semi-cylindrical shape using a single-edged blade, and measurements were taken at three different locations on the inner or outer surface of the membrane. The sample was rinsed with ultrapure water and dried at room temperature and 0.5 Torr for 10 hours before being used for measurement. The measuring apparatus and conditions are described below.

[0132] Measurement device: TOF.SIMS 5 (manufactured by ION-TOF) Primary ion: Bi3 ＋＋ First ion acceleration voltage: 30kV Pulse width: 5.9ns Secondary ion polarity: negative Number of scans: 64 scans / cycle Cycle time: 140μs Measurement range: 200×200μm 2 Mass range (m / z): 0~1500.

[0133] The presence of carboxylic acid ions on the surface of the hollow fiber membrane was confirmed by the obtained mass m / z spectrum. However, if the carboxylic acid ion intensity relative to the total secondary ion intensity was less than 0.4%, it was judged as noise and therefore not carboxylic acid was considered to be absent.

[0134] (8) X-ray electron spectroscopy (XPS) determination The hollow fiber membrane was cut into a semi-cylindrical shape using a single-edged blade, and measurements were taken at two different locations on either the inner or outer surface of the membrane. The sample was rinsed with ultrapure water and then dried at room temperature and 0.5 Torr for 10 hours before being used for measurement. The measuring apparatus and conditions are described below.

[0135] Measuring apparatus: ESCALAB220iXL (manufactured by VG Corporation) Excitation X-rays: Monochromatic Al Kα1,2 rays (1486.6 eV) X-ray diameter: 0.15mm Photoelectron escape angle: 90° (the tilt of the detector relative to the sample surface).

[0136] The C1s peak is composed mainly of components originating from CHx, CC, C=C, and CS, components mainly originating from CO and CN, and components originating from π-π The sample consists of five components: satellite peaks, C=O-derived components, and COO-derived components. Peak segmentation is performed on these five components. The COO-derived components appear from the main peaks of CHx and CC (around 285 eV) to +4.0~4.2 eV. The peak area ratio of each component is rounded to two decimal places to calculate the percentage of carbon peak area derived from the ester group, where the total peak area derived from carbon is taken as 100 (atomic percentage). It should be noted that if the peak area percentage is below 0.4%, it is considered below the detection limit.

[0137] (9) Microscopic ATR method Hollow fiber membranes were cut into semi-cylindrical shapes using a single-edged blade, rinsed with ultrapure water, and dried at room temperature and 0.5 Torr for 10 hours to prepare samples for surface measurement. The surfaces of the dried hollow fiber membranes were measured using a JASCO IRT-3000 microscope via micro-ATR. During the measurement, the field of view (aperture) was set to 100 μm × 100 μm, the measurement range was 3 μm × 3 μm, the integration was performed 30 times, and a total of 25 measurements were taken at 5 locations in each direction. The obtained spectra were analyzed within the wavelength range of 1549–1620 cm⁻¹. -1 Draw a baseline within the spectrum, and use the area enclosed by this baseline and the positive portion of the spectrum as the peak area (A) of the benzene ring C=C originating from polysulfone. CC Similarly, at wavelengths of 1711–1759 cm⁻¹ -1 Draw a baseline, and take the area enclosed by this baseline and the positive portion of the spectrum as the peak area originating from the ester group (A). COO The above operation was performed at three different locations within the same hollow fiber to determine (A). COO ) / (A CC The average value of (A) was then used. Furthermore, the same measurements were performed on three different hollow fibers, and the average value of each hollow fiber membrane was calculated. COO ) / (A CC The average value of (A) is calculated. COO ) / (A CC The average value of () is the value after rounding to the third decimal place.

[0138] (10) Antibody recovery test A Tris-buffer solution containing 2.0 g / L of IgG (derived from human serum, Oriental Yeast Co., Ltd.) was prepared as the stock solution. For hollow fiber membrane modules prepared by (1) above and coated with copolymers as described in the examples and comparative examples, 10 mL of the above stock solution was allowed to flow from the inner surface to the outer surface of the hollow fiber, or from the outer surface to the inner surface of the hollow fiber membrane, under an applied pressure of 50 kPa, and the filtrate was recovered, and the volume was measured. Then, 5 mL of the Tris-buffer solution was allowed to flow from the inner surface to the outer surface of the hollow fiber, or from the outer surface to the inner surface of the hollow fiber membrane, under an applied pressure of 50 kPa, and the washing liquid was recovered, and the volume was measured. The IgG recovery rate (antibody recovery rate) was calculated by (total weight of IgG contained in the filtrate and washing liquid) / (weight of IgG contained in the stock solution) × 100%. The weight of IgG was determined using an ELISA kit (manufactured by Funakoshi Corporation), and the IgG concentration was calculated by multiplying the IgG concentration by the volume of the solution. The value was rounded to two decimal places.

[0139] (11) Determination of molecular weight cutoff using dextran For the hollow fiber membrane module made by (1), the inner and outer sides of the hollow fiber membrane were washed with distilled water for 30 minutes before determination. Dextran (product numbers: No. 31394, No. 31388, No. 31387, No. 31389, No. 31397, No. 31398, No. 95771) manufactured by SIGMA-Aldrich and Dextran T500 manufactured by PHARMACOSMOS were dissolved in distilled water at a concentration of 0.5 m / mL (total solute concentration of 4.0 mg / mL) to prepare a dextran aqueous solution (stock solution).

[0140] The stock solution was allowed to flow into the inner side of the hollow fiber membrane and filtered outwards. The stock solution temperature was maintained at 37°C, and the flow rate was adjusted to 1.8 mL / min for the stock solution and 0.36 mL / min for the filtration. The inlet solution, outlet solution, and filtrate of the hollow fiber membrane module were collected 15 to 23 minutes after the stock solution was introduced. All samples were filtered through a 0.45 μm filter, and the filtrate was used as the assay sample for GPC analysis to determine the concentration of dextran. GPC analysis was performed under the following conditions: GPC was performed using a Tosoh TSK-gel-GMPW column. XLThe chromatographic column temperature was 40℃, and distilled water for liquid chromatography was used as the mobile phase. A GPC system (Tosoh HLC-8220GPC) was used, with a sample flow rate of 1 mL / min, a reference flow rate of 0.5 mL / min, and a sample injection volume of 0.00 μL. Differential refractive index was used as the detector. Before sample analysis, a calibration curve for the weight-average molecular weight of dextran was prepared using monodisperse dextran (SIGMA-Aldrich dextran standards No. 31416, No. 31417, No. 31418, No. 31420, No. 31422, No. 31424, and No. 49297). Using this calibration curve, the above measurements were performed, and the weight-average molecular weight and concentration distribution curves of dextran were determined for the inlet solution, outlet solution, and filtrate. The sieve factor (SC) of weight-average molecular weight is calculated from the dextran concentration (Ci) of the inlet solution, the dextran concentration (Co) of the outlet solution, and the dextran concentration (Cf) of the filtrate using the following formula.

[0141] SC = 2Cf / (Ci + Co) The weight-average molecular weight when SC is 0.5 is taken as the cut-off molecular weight, and the numbers below the hundreds place are discarded.

[0142] (12) Determination of antibody permeability maintenance rate A phosphate buffer solution of IgG (derived from human serum, Oriental Yeast Co., Ltd.) with a concentration of 2.0 g / L was prepared as the stock solution. For the hollow fiber membrane module prepared by (1) above and coated with copolymer as described in the examples and comparative examples, 30 mL of the stock solution was flowed from the inner surface of the hollow fiber to the outer surface, or from the outer surface of the hollow fiber membrane to the inner surface, under an applied pressure of 50 kPa. At this time, the filtrate was sampled every 5 mL, and the absorbance of light at a wavelength of 280 nm in the antibody stock solution, the initial 0-5 mL of filtrate, and the last 25-30 mL of filtrate was measured by UV-Vis spectroscopy. The retention rate of antibody permeability was calculated by the following formula, with the absorbance of the antibody stock solution as Abs (stock solution), the absorbance of the initial 0-5 mL of filtrate as Abs (5 mL), and the absorbance of the last 25-30 mL of filtrate as Abs (30 mL).

[0143] Antibody permeability maintenance rate (%) = [Abs (30mL) / Abs (stock solution)] / [Abs (5mL) / Abs (stock solution)] × 100.

[0144] (13) Determination of the number-average molecular weight of polymers A 0.1N LiNO3 solution of water / methanol (50 / 50, v / v) was prepared as the GPC developing solution. 2 mg of the copolymer was dissolved in 2 mL of this solution. 100 μL of this copolymer solution was injected into a Tosoh GMPW column. XL In GPC, the determination was performed at a flow rate of 0.5 mL / min. The determination time was 30 minutes. Detection was performed using a differential refractive index (RI) detector, and the number-average molecular weight was calculated from the peak originating from the copolymer that appeared around the 15-minute dissolution time. The number-average molecular weight was rounded to the nearest hundred. For the preparation of the standard curve, Agilent Technologies' polyethylene oxide standard samples (0.1 kD~1258 kD) were used.

[0145] [Example 1] 18 parts by weight of polysulfone (SOLVAY Udel (registered trademark) P-3500), 6 parts by weight of polyvinylpyrrolidone (ASHLAND LCC Povidone (PLASDONE) K29 / K32), and 3 parts by weight of polyvinylpyrrolidone (ASHLAND LCC Povidone (PLASDONE) K90) were added to a solvent containing 72 parts by weight of N,N-dimethylacetamide and 1 part by weight of water. The solution was heated at 90°C for 14 hours to obtain the membrane-forming solution. This membrane-forming solution was discharged from an orifice-type double cylindrical spinneret adjusted to 40°C. Simultaneously, a solution containing 72% by weight of N,N-dimethylacetamide and 28% by weight of water, serving as the core liquid, was discharged from the inner tube. After passing the discharged membrane-forming solution through a dry space of 350 mm, it was introduced into a coagulation bath containing water at 50°C to obtain a hollow fiber membrane. The resulting hollow fiber membrane has an inner diameter of 281 μm and a thickness of 52 μm, exhibiting an asymmetric structure with a dense inner surface and a porous outer surface. A hollow fiber membrane module was fabricated using the method described in (1) above, and the molecular weight cutoff of dextran was determined using the method described in (11) above. Based on the results, a vinylpyrrolidone / vinyl propionate random copolymer (with a molar fraction of 40% vinyl propionate units and a number-average molecular weight of 16,500) with a size smaller than the pore size of the inner surface of the hollow fiber membrane was selected. An aqueous solution containing 50 ppm of this copolymer and 200 ppm of ethanol was passed through the hollow fiber membrane from the inside to the outside to coat the entire membrane. Subsequently, the membrane was irradiated with 25 kGy of γ-rays to obtain hollow fiber membrane module 1.

[0146] [Example 2] Hollow fiber membrane module 2 was obtained by the same procedure as in Example 1, except that the concentration of the vinylpyrrolidone / vinyl propionate random copolymer (vinyl propionate unit molar fraction of 40% and number average molecular weight of 16,500) was 200 ppm.

[0147] [Example 3] Except that the polymer used in the coating solution is a vinylpyrrolidone / vinyl acetate random copolymer (BASF "KOLLIDON" (registered trademark) VA64), the hollow fiber membrane module 3 was obtained by the same operation as in Example 1.

[0148] [Example 4] Except for discharging the membrane-forming solution from a double-cylinder spinneret that has been adjusted to 45°C, a hollow fiber membrane was obtained through the same procedures as in Example 1. The resulting hollow fiber membrane has an inner diameter of 278 μm and a thickness of 50 μm, exhibiting an asymmetric structure with a dense inner surface and a porous outer surface. Hollow fiber membrane module 4 was obtained through the same procedures as in Example 1.

[0149] [Comparative Example 1] Hollow fiber membrane module 5 was obtained by the same procedure as in Example 1, except that the aqueous solution of vinylpyrrolidone / vinyl propionate random copolymer (with a molar fraction of 40% vinyl propionate units and a number average molecular weight of 16,500) was not passed through it.

[0150] [Comparative Example 2] A hollow fiber membrane was obtained by the same procedure as in Example 1, except that a solution containing 63% by weight of N,N-dimethylacetamide and 37% by weight of water was used as the core fluid. The resulting hollow fiber membrane had an inner diameter of 201 μm and a thickness of 41 μm, exhibiting an asymmetric structure with a dense inner surface and a porous outer surface. Hollow fiber membrane module 6 was obtained by the same procedure as in Example 1.

[0151] [Comparative Example 3] A hollow fiber membrane was obtained by the same procedure as in Example 1, except that a solution containing 74 wt% N,N-dimethylacetamide and 26 wt% water was used as the core liquid and the coagulation bath temperature was set to 60°C. The resulting hollow fiber membrane had an inner diameter of 283 μm and a thickness of 48 μm, exhibiting an asymmetric structure with a dense inner surface and a porous outer surface. Hollow fiber membrane module 7 was obtained by the same procedure as in Example 1.

[0152] [Example 5] 20 parts by weight of polysulfone (SOLVAY Udel (registered trademark) P-3500), 6 parts by weight of polyvinylpyrrolidone (ASHLAND LCC Povidone (PLASDONE) K29 / K32), and 3 parts by weight of polyvinylpyrrolidone (ASHLAND LCC Povidone (PLASDONE) K90) were added to a solvent containing 72 parts by weight of N,N-dimethylacetamide and 1 part by weight of water. The solution was heated at 90°C for 14 hours to dissolve the polysulfone, yielding the membrane-forming solution. This membrane-forming solution was discharged from a double-cylinder spinneret with orifices adjusted to 40°C. Simultaneously, a solution containing 72% by weight of N,N-dimethylacetamide and 28% by weight of water, serving as the core liquid, was discharged from the inner tube. After passing the discharged membrane-forming solution through a dry space of 350 mm in length, it was introduced into a coagulation bath containing water at 40°C to obtain a hollow fiber membrane. The resulting hollow fiber membrane has an inner diameter of 276 μm and a thickness of 52 μm, exhibiting an asymmetric structure with a dense inner surface and a porous outer surface. Hollow fiber membrane modules were fabricated using the method described in (1) above, and the molecular weight cutoff of dextran was determined using the method described in (11) above. Based on the results, a vinylpyrrolidone / vinyl propionate random copolymer (with a molar fraction of 40% vinyl propionate units and a number-average molecular weight of 16,500) with a size smaller than the pore size of the inner surface of the hollow fiber membrane was selected. An aqueous solution containing 200 ppm of this copolymer and 1000 ppm of ethanol was passed through the hollow fiber membrane from the inside to the outside to coat the entire membrane. Subsequently, the membrane was irradiated with 25 kGy of γ-rays to obtain hollow fiber membrane module 8.

[0153] The composition of the hollow fiber membrane modules obtained in each embodiment and comparative example, as well as various evaluation results, are shown in Tables 1 and 2.

[0154] [Table 1] [Table 2] Explanation of reference numerals in the attached figures A outer surface side B Inner surface side 1. Cylindrical shell 2 Hollow fiber membrane 3A water collection pipe 3B water collection pipe 4A Inlet 4B Inlet 5A Nozzle 5B nozzle 6. Potting materials 7. Cylindrical shell 8. Hollow fiber membrane opening.

Claims

1. A porous hollow fiber membrane module, which houses a porous hollow fiber membrane within a housing. The porous hollow fiber membrane is mainly composed of polysulfone-based polymers. It has an asymmetric structure with a dense inner surface and a porous outer surface. The average short diameter of the pores on the inner surface is 20 nm or more and 40 nm or less, and the porosity of the inner surface is 5% or more and 30% or less. The porous hollow fiber membrane contains hydrophilic polymers with a weight-average molecular weight of 200,000 to 1,200,000. Furthermore, polymers containing monocarboxylic acid vinyl ester units and with a number-average molecular weight of 1,000 or more and 100,000 or less are supported on both the outer and inner surfaces and within the porous layer of the hollow fiber membrane. When the outer and inner surfaces of the porous hollow fiber membrane were measured using micro-infrared spectroscopy, the peak area (A) of the infrared absorption spectrum originating from the ester groups was determined. COO The peak area of ​​the infrared absorption spectrum of the benzene ring derived from polysulfone polymers (A) CC The ratio of (A) COO ) / (A CC The average value is above 0.01 and below 1.

2. The porous hollow fiber membrane module according to claim 1, wherein, The thickness of the dense layer on the inner surface side of the porous hollow fiber membrane, which does not contain pores with a diameter greater than 130 nm, is less than 1 μm.

3. The porous hollow fiber membrane module according to claim 1 or 2, wherein, The ratio of the major axis to the minor axis of the hole on the inner surface is greater than 2 and less than 6.

4. The porous hollow fiber membrane module according to any one of claims 1 to 3, wherein, The thickness of the porous hollow fiber membrane is greater than 20 μm and less than 100 μm.

5. The porous hollow fiber membrane module according to any one of claims 1 to 4, wherein, The monocarboxylic acid vinyl ester unit is a unit represented by "-CH(OCO-R)-CH2-" (R is an aliphatic hydrocarbon group or an aromatic hydrocarbon group).

6. The porous hollow fiber membrane module according to claim 5, wherein, The R is an aliphatic hydrocarbon group with 1 to 20 carbon atoms.

7. The porous hollow fiber membrane module according to claim 6, wherein, The monocarboxylic acid vinyl ester unit is selected from the group consisting of vinyl acetate unit, vinyl propionate unit, vinyl butyrate unit, vinyl valerate unit, vinyl neovalerate unit, and vinyl hexanoate unit.

8. The porous hollow fiber membrane module according to any one of claims 1 to 7, wherein, The polymer containing monocarboxylic acid vinyl ester units is a copolymer containing hydrophilic units and hydrophobic units containing monocarboxylic acid vinyl ester units.

9. The porous hollow fiber membrane module according to claim 8, wherein, The hydrophilic unit is a vinylpyrrolidone unit.

10. The porous hollow fiber membrane module according to claim 9, wherein, The polymer containing monocarboxylic acid vinyl ester units is a copolymer containing monocarboxylic acid vinyl ester units and vinylpyrrolidone units.

11. The porous hollow fiber membrane module according to any one of claims 1 to 10, wherein, When X-ray photoelectron spectroscopy is used to measure at least one of the outer or inner surfaces of the porous hollow fiber membrane, and the total peak area originating from carbon is taken as 100 (atomic percentage), the area percentage of carbon peaks originating from ester groups is 0.1 (atomic percentage) or more and 25 (atomic percentage) or less.

12. The porous hollow fiber membrane module according to any one of claims 1 to 11, wherein the hydrophilic polymer is polyvinylpyrrolidone.

13. The porous hollow fiber membrane assembly according to any one of claims 1 to 12, wherein the porous hollow fiber membrane has an antibody recovery rate of more than 80%.

14. The porous hollow fiber membrane module according to any one of claims 1 to 13, used in a virus removal process.

15. The porous hollow fiber membrane assembly according to any one of claims 1 to 13, used in the process of separating antibodies from antibody-producing cells.

16. The porous hollow fiber membrane assembly according to any one of claims 1 to 13, used in the process of separating antibody agglutination from antibody.

17. A purification system for obtaining desired cells or proteins from a solution containing cells and proteins, said purification system comprising a porous hollow fiber membrane and a separation membrane, said separation membrane having pores with a smaller pore size than said hollow fiber membrane, said porous hollow fiber membrane and said separation membrane being configured such that said solution is continuously processed by said porous hollow fiber membrane and said separation membrane. The porous hollow fiber membrane is mainly composed of polysulfone-based polymers. It has an asymmetric structure with a dense inner surface and a porous outer surface. The average short diameter of the pores on the inner surface is 20 nm or more and 40 nm or less, and the porosity of the inner surface is 5% or more and 30% or less. The porous hollow fiber membrane contains hydrophilic polymers with a weight-average molecular weight of 200,000 to 1,200,000. Furthermore, polymers containing monocarboxylic acid vinyl ester units and with a number-average molecular weight of 1,000 or more and 100,000 or less are supported on both the outer and inner surfaces and within the porous layer of the hollow fiber membrane. When the outer and inner surfaces of the porous hollow fiber membrane were measured using micro-infrared spectroscopy, the peak area (A) of the infrared absorption spectrum originating from the ester groups was determined. COO The peak area of ​​the infrared absorption spectrum of the benzene ring derived from polysulfone polymers (A) CC The ratio of (A) COO ) / (A CC The average value is above 0.01 and below 1.

18. The purification system according to claim 17, wherein, The thickness of the dense layer on the inner surface side of the porous hollow fiber membrane, which does not contain pores with a diameter greater than 130 nm, is less than 1 μm.

19. The purification system according to claim 17 or 18, wherein, The ratio of the major axis to the minor axis of the hole on the inner surface is greater than 2 and less than 6.

20. The purification system according to any one of claims 17 to 19, wherein, The thickness of the porous hollow fiber membrane is greater than 20 μm and less than 100 μm.

21. The purification system according to any one of claims 17 to 20, wherein, The monocarboxylic acid vinyl ester unit is a unit represented by "-CH(OCO-R)-CH2-" (R is an aliphatic hydrocarbon group or an aromatic hydrocarbon group).

22. The purification system according to claim 21, wherein, The R is an aliphatic hydrocarbon group with 1 to 20 carbon atoms.

23. The purification system according to claim 22, wherein, The monocarboxylic acid vinyl ester unit is selected from the group consisting of vinyl acetate unit, vinyl propionate unit, vinyl butyrate unit, vinyl valerate unit, vinyl neovalerate unit, and vinyl hexanoate unit.

24. The purification system according to any one of claims 17 to 23, wherein, The polymer containing monocarboxylic acid vinyl ester units is a copolymer containing hydrophilic units and hydrophobic units containing monocarboxylic acid vinyl ester units.

25. The purification system according to claim 24, wherein, The hydrophilic unit is a vinylpyrrolidone unit.

26. The purification system according to claim 25, wherein, The polymer containing monocarboxylic acid vinyl ester units is a copolymer containing monocarboxylic acid vinyl ester units and vinylpyrrolidone units.

27. The purification system according to any one of claims 17 to 26, wherein, When X-ray photoelectron spectroscopy is used to measure at least one of the outer or inner surfaces of the porous hollow fiber membrane, and the total peak area originating from carbon is taken as 100 (atomic percentage), the area percentage of carbon peaks originating from ester groups is 0.1 (atomic percentage) or more and 25 (atomic percentage) or less.

28. The purification system according to any one of claims 17 to 27, wherein the hydrophilic polymer is polyvinylpyrrolidone.

29. The purification system according to any one of claims 17 to 28, wherein the porous hollow fiber membrane has an antibody recovery rate of more than 80%.

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