Hollow fiber membranes made from polymer blends containing aromatic sulfone polymers and polyoxazolines

Abstract

A hollow fiber membrane, the hollow fiber membrane being made from a polymer blend including an aromatic sulfone polymer and a polyoxazoline, the polymer blend including 27% to 30% by weight of the aromatic sulfone polymer based on the total weight of the polymer blend, the hollow fiber membrane having an inner surface facing the lumen, an outer surface facing the outside, and an intermediate wall having a wall thickness, the hollow fiber membrane being an overall asymmetric permeable hollow fiber membrane.

Description

[Technical Field]

[0001] The present disclosure relates to porous membranes. Further, the present disclosure relates to methods for producing such membranes. The present disclosure further relates to the use of such membranes for the filtration and purification of liquid media. [Background technology]

[0002] Hollow fiber membranes are used for microfiltration in a wide variety of industrial, pharmaceutical, and medical applications. In these applications, membrane separation processes are gaining importance because they offer the advantage that the substances to be separated are not thermally stressed or even damaged. Ultrafiltration membranes can be used for the removal or separation of macromolecules. Numerous additional applications of membrane separation processes are known from the beverage industry, biotechnology, water treatment, and sewage technology. Such membranes are generally classified according to their retention capacity, i.e., their capacity to retain particles or molecules of a certain size, or their effective pore size, i.e., the size of the pores that determine the separation behavior. Ultrafiltration membranes thus cover the separation behavior-determining pore size range of approximately 0.01 to about 0.1 μm and can retain particles or molecules with sizes in the range of more than 20,000 Daltons or more than about 200,000 Daltons. There is a need for better polymeric membranes. Summary of the Invention

[0003] Accordingly, in one aspect, the present disclosure provides a hollow fiber membrane made from a polymer blend comprising an aromatic sulfone polymer and a polyoxazoline, the polymer blend comprising 27% to 30% by weight of the aromatic sulfone polymer, based on the total weight of the polymer blend, the hollow fiber membrane having an inner surface facing the lumen, an outer surface facing the outside, and an intermediate wall having a wall thickness, the hollow fiber membrane being an overall asymmetric permeable hollow fiber membrane.

[0004] In another aspect, the present disclosure provides the use of a hollow fiber membrane of the present disclosure for the filtration of antibodies.

[0005] In another aspect, the present disclosure provides a method comprising flowing an antibody-containing solution through a hollow fiber membrane according to any one of the claims and collecting the antibody.

[0006] Various aspects and advantages of exemplary embodiments of the present disclosure have been summarized. The above summary is not intended to describe each illustrated embodiment or every implementation of the present disclosure. Additional features and advantages are disclosed in the following embodiments. The following drawings and detailed description more particularly exemplify specific embodiments that utilize the principles disclosed herein. [Brief explanation of the drawings]

[0007] [Figure 1] FIG. 1 is a schematic perspective view of a partial cross section of an exemplary hollow fiber membrane. [Figure 2] FIG. 1 is a cross-sectional view of an exemplary hollow fiber membrane. [Figure 3A] 1 is an SEM photograph at 4,000x magnification of a cross section of a hollow fiber membrane according to the present disclosure. [Figure 3B] 3B is a SEM photograph of the crossed region of FIG. 3A at a magnification of 20,000 times. DETAILED DESCRIPTION OF THE INVENTION

[0008] Before describing any embodiment of the present disclosure in detail, it is to be understood that the invention is not limited in its application to the details of use, construction, and arrangement of components set forth in the following description. The invention is capable of other embodiments and of being practiced or carried out in various ways that will become apparent to those skilled in the art upon reading this disclosure. It is also to be understood that the phraseology and terminology used herein are for purposes of description and should not be regarded as limiting. The use of "including," "comprising," or "having," and variations thereof, herein is meant to encompass the items listed thereafter and equivalents thereof, as well as additional items. It is to be understood that other embodiments may be utilized and structural or logical changes may be made without departing from the scope of the present disclosure.

[0009] One embodiment of a hollow fiber membrane according to the present disclosure is shown in Figure 1. Figure 1 shows a perspective view, partially in cross section, of a portion of an exemplary hollow fiber membrane 12. The hollow fiber membrane 12 may have a continuous hollow lumen 16 extending from one end of the fiber (yarn) to the other, an outward-facing outer surface 18 forming the outside of the fiber, an inner surface 20 facing the hollow lumen 16 and defining the boundary of the continuous hollow lumen 16, and an intermediate wall 22 having a wall thickness 26. The hollow fiber membrane 12 may be made from a polymer blend including an aromatic sulfone polymer and a polyoxazoline. The hollow fiber membrane may be an overall asymmetric permeable hollow fiber membrane.

[0010] The wall thickness 26 measured between the outer surface 18 and the inner surface 20 of the hollow fiber membrane 12 can range from 20 to 300 μm, 30 to 200 μm, or 40 to 80 μm.

[0011] Similarly, to achieve desirable flow through the lumen of hollow fiber membranes according to the present disclosure, particularly to achieve favorable pressure drops, the inner diameter of the hollow fiber membranes described herein is preferably in the range of 50-800 μm, 50-700 μm, 50-600 μm, 100-500 μm, 100-400 μm, or 100-300 μm. The wall thickness and diameter (i.e., inner or lumen diameter, and outer diameter) of the membranes described herein are also measured by conventional inspection methods, such as by using scanning electron micrographs or transmission electron micrographs (SEM or TEM, respectively) at magnifications of up to 20,000:1. In some embodiments, hollow fiber membranes can have a serpentine structure extending from the inner surface to the outer surface. In some embodiments, hollow fiber membranes can have a serpentine structure or a serpentine path extending through the entire membrane wall. These serpentine structures can, for example, help the membrane retain larger viral contaminants and allow smaller biopharmaceuticals (such as monoclonal antibodies (mAbs)) to pass through the membrane. These serpentine structures can increase the likelihood of capturing viral contaminants while maintaining high mAb throughput. When hollow fiber membranes have a serpentine structure, they may have a small number of structural defects, i.e., closed cells or macrovoids. The inner, upstream side of the membrane is characterized by a porous surface, which is constructed by an isotropic nodular structure. When the pore compartments are connected within the membrane and therefore have a serpentine morphology in place, hollow fiber membranes can have a high transmembrane flow (TMF).

[0012] In some embodiments, the hollow fiber membrane may have two zones: a zone having the smallest pore size and a zone having the largest pore size. In some embodiments, the zone having the smallest pore size is adjacent to the inner surface. In some of these embodiments, the zone having the largest pore size is adjacent to the outer surface. In other embodiments, the zone having the smallest pore size is adjacent to the outer surface. In some of these embodiments, the zone having the largest pore size is adjacent to the inner surface. By "adjacent," it is meant that the largest or smallest pore size zone is located at a distance ranging from 0 to 8 μm from the surface. In some embodiments, the size of the pores in the zone having the smallest pore size can be in the range of 10 nm to 100 nm, 10 nm to 90 nm, 10 nm to 80 nm, 10 nm to 70 nm, 10 nm to 60 nm, 10 nm to 50 nm, 10 nm to 40 nm, 10 nm to 30 nm, 10 nm to 20 nm, 20 nm to 80 nm, 20 nm to 70 nm, 20 nm to 60 nm, 20 nm to 50 nm, 30 nm to 70 nm, 30 nm to 60 nm, 30 nm to 50 nm, 30 nm to 40 nm, 40 nm to 90 nm, 40 nm to 80 nm, 40 nm to 70 nm, 40 nm to 60 nm, or 40 nm to 50 nm. In some embodiments, the size of the pores in the zone having the smallest pore size can be less than 100 nm, 90 nm, 80 nm, 70 nm, 60 nm, 50 nm, 40 nm, 30 nm, or 20 nm. In some embodiments, the size of the pores in the zone having the smallest pore size can be greater than 10 nm, 15 nm, 20 nm, or 25 nm. In some embodiments, the size of the pores in the zone having the largest pore size can range from 0.05 μm to 10 μm. The average pore size of the zone having the largest pore size is larger than the average pore size of the zone having the smallest pore size. The zone having the smallest pore size can form a retaining layer. When the zone having the smallest pore size is adjacent to the outer surface, the retaining layer can be adjacent to the outer surface of the membrane, forming a more conductive membrane structure for filtering liquids, e.g., biopharmaceuticals.In some embodiments, at least some of the pores in the zone with the smallest pore size or the zone with the largest pore size may be connected, for example, through channels between the pores. These connected pores may form void spaces in the hollow fiber membrane, which may help retain larger viral contaminants and allow smaller biopharmaceuticals (e.g., mAbs) to pass through the membrane, facilitating collection of samples such as mAbs after filtration. In some embodiments, the hollow fiber membrane may have a serpentine structure extending from the inner surface to the outer surface of the hollow fiber membrane. In some embodiments, the hollow fiber membrane may have a first zone of pores and a second zone of pores, the first zone of pores adjacent to the inner surface and the second zone of pores adjacent to the outer surface, and the density of pores in the first zone may be greater than the density of pores in the second zone. In some embodiments, the hollow fiber membrane has a first zone of pores and a second zone of pores, the first zone of pores adjacent to the inner surface and the second zone of pores adjacent to the outer surface, and the density of pores in the second zone is greater than the density of pores in the first zone. In some embodiments, the zone with the smallest pore size has a lower flow rate than the zone with the largest pore size.

[0013] The average pore diameter or pore size of the pores can be measured, for example, by the method described in U.S. Patent Application Publication No. 2017 / 0304780 (Asahi et al.). The average pore diameter or pore size of the pores can be determined by photographing the cross section of the hollow fiber using a scanning electron microscope (SEM). For example, the magnification is set to 50,000x, and a field of view is set horizontally relative to a cross section perpendicular to the length of the hollow fiber or a cross section parallel to the length and passing through the center of the hollow portion. After photographing the set field of view, the field of view is moved horizontally in the film thickness direction, and the next field of view is photographed.

[0014] This photographing process is repeated until a complete cross-section of the membrane is captured from the outer surface to the inner surface without any gaps. The resulting photographs are then combined to obtain a single cross-sectional photograph of the membrane. In this cross-sectional photograph, the average pore size of the pores in each region (2 μm circumferentially of the membrane) × (1 μm from the outer surface to the inner surface) is calculated from the outer surface to the inner surface, and the gradient structure of the membrane cross section is quantified every 1 μm from the outer surface to the inner surface. This quantification allows us to determine whether the membrane has a gradient porous structure.

[0015] The average pore diameter or pore size can be calculated using a method that uses image analysis. Pore and solid areas are distinguished based on brightness, and indistinguishable areas and noise are corrected using a freehand tool. After binarization, the pores are assumed to be perfect circles, and the pore diameter is calculated from the pore area value. This calculation is performed for all pores, and the average pore diameter is calculated for each 1 μm x 2 μm area. Pores located at the edge of the field of view and partially within the field of view are also counted (i.e., the diameter is calculated assuming that the area of the pores partially within the field of view is the area of a perfect circle).

[0016] Another embodiment of a hollow fiber membrane according to the present disclosure is shown in Figure 2. Figure 2 shows a cross-sectional view of an exemplary hollow fiber membrane 112. The hollow fiber membrane 112 may have a continuous hollow lumen 116 extending from one end of the fiber to the other, an outward-facing outer surface 118 forming the outside of the fiber, an inner surface 120 facing the hollow lumen 116, and an intermediate wall 122 having a wall thickness 126 that defines the boundary of the continuous hollow lumen 116. The hollow fiber membrane 112 may have a first cross-sectional zone 128 that begins at the inner surface 120 and extends (in some embodiments, laterally) into the intermediate wall 122, terminating at an interior distance within the intermediate wall 122. In the first cross-sectional zone 128, the pore size gradually decreases in the direction of the arrow (i.e., according to a pore size measurement made along a vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface of the membrane, the pore size gradually decreases across the first cross-sectional zone in the direction from the inner surface 120 to the outer surface 118 for an intermediate distance between the inner surface and the outer surface).

[0017] The hollow fiber membrane 112 may have a second cross-sectional zone 130 beginning where the first cross-sectional zone terminates and extending (in some embodiments, laterally) to the membrane's outer surface 118. In the second cross-sectional zone 130, the pore size gradually increases in the direction of the arrow (i.e., the pore size gradually increases across the second cross-sectional zone 130 in the direction from the beginning of the second cross-sectional zone within the wall to the outer surface 118, according to a pore size measurement taken along a vector defining the shortest cross-sectional distance from the beginning of the second cross-sectional zone to the membrane's outer surface 118). In some embodiments, the pore size at the outer surface 118 may be smaller than the pore size at the inner surface 120.

[0018] The location within the wall 122 where the first cross-sectional zone 128 ends and the second cross-sectional zone begins is defined as the transition location.

[0019] In some embodiments of the hollow fiber membrane shown in FIG. 2, the pore size within the first cross-sectional zone 128 gradually decreases in the direction of the arrow (i.e., the pore size gradually decreases across the first cross-sectional zone 128 in the direction from the inner surface 120 to the outer surface 118 over a distance of about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% of the membrane wall, according to a pore size measurement taken along a vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface of the membrane). In the second cross-sectional zone 130, the pore size gradually increases in the direction of the arrow (i.e., the pore size gradually increases across the second cross-sectional zone in the direction from the beginning of the second cross-sectional zone within the wall to the outer surface 118, according to a pore size measurement made along the vector defining the shortest cross-sectional distance from the beginning of the second cross-sectional zone 130 to the outer surface 118 of the membrane). The pore size at the outer surface 118 may be smaller than the pore size at the inner surface 112.

[0020] In some embodiments of the hollow fiber membrane shown in FIG. 2, the pore size within the first cross-sectional zone 128 gradually decreases in the direction of the arrow (i.e., the pore size gradually decreases across the first cross-sectional zone in the direction from the inner surface 120 to the outer surface 118 over a distance of about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the membrane wall, according to a pore size measurement taken along a vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface of the membrane). In the second cross-sectional zone 130, the pore size gradually increases in the direction of the arrow (i.e., the pore size gradually increases across the second cross-sectional zone in a direction from the beginning of the second cross-sectional zone within the wall to the outer surface 118, according to a pore size measurement taken along a vector defining the shortest cross-sectional distance from the beginning of the second cross-sectional zone to the outer surface 118 of the membrane). The pore size at the outer surface 118 may be about 0.05 to 0.5 micrometers, and the pore size at the inner surface 112 may be about 0.05 to 5 micrometers.

[0021] In some embodiments of the hollow fiber membrane shown in FIG. 2, the pore size within the first cross-sectional zone 128 gradually decreases in the direction of the arrow (i.e., the pore size gradually decreases across the first cross-sectional zone in the direction from the inner surface 120 to the outer surface 118 over a distance of about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% of the membrane wall, according to a pore size measurement taken along a vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface of the membrane). In the second cross-sectional zone 130, the pore size gradually increases in the direction of the arrow (i.e., the pore size gradually increases across the second cross-sectional zone in a direction from the beginning of the second cross-sectional zone within the wall to the outer membrane surface, according to a pore size measurement taken along a vector defining the shortest cross-sectional distance from the beginning of the second cross-sectional zone to the membrane's outer surface 118). The pore size at the outer surface 118 may be about 0.05-0.5 micrometers, the pore size at the inner surface 112 may be about 0.05-5 micrometers, and the pore size at the transition location may be about 0.015-0.035 micrometers.

[0022] In some embodiments of the hollow fiber membrane shown in FIG. 2, the pore size within the first cross-sectional zone 128 gradually decreases in the direction of the arrow (i.e., the pore size gradually decreases across the first cross-sectional zone in the direction from the inner surface 120 to the outer surface 118 over a distance of about 10%-20%, 20%-30%, 30%-40%, 40%-50%, 50%-60%, 60%-70%, 70%-80%, 80%-90%, or 90%-95% of the membrane wall, according to pore size measurements made along a vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface of the membrane).

[0023] The pore size at the transition location (i.e., where the first cross-sectional zone ends and the second cross-sectional zone begins) can form at least a portion of a retentive layer or zone within the hollow fiber membrane. The retentive layer or zone is the section of the hollow fiber membrane that has the greatest (i.e., maximum) ability or capacity to capture small contaminant components of a liquid sample as the liquid sample is filtered through the membrane. Typically, a liquid sample filtered through a hollow fiber membrane contains a desired component, which preferably is collected in the filtrate after filtration, and a contaminant component, which preferably is captured by the membrane. The retentive layer or zone filters contaminants from the liquid sample primarily based on the size difference between the contaminants and the desired component. The desired component(s) in the liquid sample are of a size that allows them to pass through the retentive layer or zone and be collected in the filtrate, resulting in a purified liquid sample. For example, in a liquid sample containing both antibodies and viruses, the larger viruses (typically 15-30 nm in diameter) can be separated from the smaller antibodies (typically 5-10 nm in diameter) as the liquid sample passes through a retaining layer or zone. The viral component of the liquid sample can be preferentially retained in the retaining layer or zone, while the antibody component of the liquid sample passes through the retaining layer or zone and is collected in the filtrate. In some embodiments, the zone with the smallest pore size (the retaining layer) has a thickness of 5-100 μm, 10-90 μm, 20-80 μm, 30-70 μm, or 40-60 μm.

[0024] In some embodiments, the pore size at the transition location is less than 0.04 micrometers, less than 0.035 micrometers, or less than 0.03 micrometers.

[0025] In some embodiments, the pore size at the transition location is about 0.01-0.04 micrometers, 0.01-0.035 micrometers, 0.01-0.03 micrometers, 0.015-0.04 micrometers, 0.015-0.035 micrometers, or 0.015-0.03 micrometers.

[0026] In some embodiments of the hollow fiber membrane shown in FIG. 2 , the pore size in the first cross-sectional zone 128 gradually decreases in the direction of the arrow (i.e., the pore size gradually decreases across the first cross-sectional zone in a direction from the inner surface 120 to the outer surface 118 to a distance of 3 to 50 micrometers from the outer surface, according to a pore size measurement taken along a vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface of the membrane). In the second cross-sectional zone 130, the pore size gradually increases in the direction of the arrow (i.e., the pore size gradually increases across the second cross-sectional zone in a direction from the beginning of the second cross-sectional zone within the wall to the outer surface 118, according to a pore size measurement taken along a vector defining the shortest cross-sectional distance from the beginning of the second cross-sectional zone to the outer membrane surface 118). The pore size at the outer surface 118 may be smaller than the pore size at the inner surface 120.

[0027] In some embodiments of the hollow fiber membrane shown in FIG. 2 , pore size measurements taken along a vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface of the membrane indicate that the pore size in first cross-sectional zone 128 gradually decreases across the first cross-sectional zone in the direction from inner surface 120 to outer surface 118 to a distance of 3 to 15 micrometers from the outer surface.

[0028] In some embodiments of the hollow fiber membrane shown in FIG. 2 , pore size measurements taken along a vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface of the membrane indicate that the pore size in first cross-sectional zone 128 gradually decreases across the first cross-sectional zone in the direction from inner surface 120 to outer surface 118 to a distance of 3 to 8 micrometers from the outer surface.

[0029] In some embodiments of the hollow fiber membrane shown in FIG. 2 , the wall thickness of the hollow fiber membrane is 30-100 micrometers, 40-90 micrometers, or 50-65 micrometers, and the pore size of the membrane at the inner surface facing the lumen gradually decreases across the first cross-sectional zone 128 in a direction from the inner surface 120 to the outer surface 118 to a distance of 3-50 micrometers from the outer surface, as measured by a pore size measurement taken along a vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface of the membrane. In the second cross-sectional zone 130, the pore size gradually increases in the direction of the arrow (i.e., the pore size gradually increases across the second cross-sectional zone in a direction from the beginning of the second cross-sectional zone within the wall to the outer surface 118, as measured by a pore size measurement taken along a vector defining the shortest cross-sectional distance from the beginning of the second cross-sectional zone to the outer surface 118 of the membrane). The pore size at the outer surface 118 may be smaller than the pore size at the inner surface 120.

[0030] In some embodiments of the hollow fiber membrane shown in FIG. 2 , the wall thickness of the hollow fiber membrane is 30 to 100 micrometers, 40 to 90 micrometers, or 50 to 65 micrometers, and the pore size of the membrane at its inner surface facing the lumen gradually decreases in the direction from the inner surface 120 to the outer surface 118 to a distance of 3 to 50 micrometers from the outer surface across a first cross-sectional zone 128, according to pore size measurements made along a vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface 118 of the membrane.

[0031] In some embodiments of the hollow fiber membrane shown in FIG. 2 , the wall thickness of the hollow fiber membrane is 30 to 100 micrometers, 40 to 90 micrometers, or 50 to 65 micrometers, and the pore size of the membrane at the inner surface facing the lumen gradually decreases in the direction from the inner surface 120 to the outer surface 118 to a distance of 3 to 15 micrometers from the outer surface across the first cross-sectional zone 128, according to pore size measurements made along a vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface 118 of the membrane.

[0032] In some embodiments of the hollow fiber membrane shown in FIG. 2 , the wall thickness of the hollow fiber membrane is 30 to 100 micrometers, 40 to 90 micrometers, or 50 to 65 micrometers, and the pore size of the membrane at its inner surface facing the lumen gradually decreases in the direction from the inner surface 120 to the outer surface 118 to a distance of 3 to 8 micrometers from the outer surface across the first cross-sectional zone 128, according to pore size measurements made along a vector defining the shortest cross-sectional distance from the inner surface of the membrane to the outer surface 118 of the membrane.

[0033] In some embodiments, the pore size at the exterior surface is about 0.05 to 2 micrometers, 0.05 to 1 micrometer, or 0.05 to 0.5 micrometers.

[0034] In some embodiments, the pore size on the interior surface is between about 0.05 and 5 micrometers.

[0035] In some embodiments, the pore size at the outer surface is between 0.05 and 0.5 micrometers, the pore size at the inner surface is between about 0.05 and 5 micrometers, and the pore size at the transition location is between about 0.015 and 0.04 micrometers.

[0036] In some embodiments, the pore size on the exterior surface is between 0.05 and 0.5 micrometers and the pore size on the interior surface is between about 0.05 and 5 micrometers; The pore size at the transition location is approximately 0.015 to 0.035 micrometers.

[0037] In some embodiments, the pore size on the outer surface is about 0.05-0.5 micrometers and the pore size on the inner surface is about 0.05-5 micrometers; The pore size at the transition location is approximately 0.015 to 0.03 micrometers.

[0038] In some embodiments, the wall thickness of the hollow fiber membrane is 30-100 micrometers, the pore size on the outer surface is about 0.05-2 micrometers, the pore size on the inner surface is about 0.05-5 micrometers, and the minimum or smallest pore size or smallest pore size within the membrane is about 0.015-0.035 micrometers.

[0039] In some embodiments, the hollow fiber membrane has a wall thickness of 30-100 micrometers, the pore size on the outer surface is about 0.05-1 micrometer, the pore size on the inner surface is about 0.05-5 micrometer, and the smallest or narrowest pore size within the membrane is about 0.015-0.035 micrometer.

[0040] In some embodiments, the hollow fiber membrane has a wall thickness of 30-100 micrometers, a pore size on the outer surface of about 0.05-0.5 micrometers, a pore size on the inner surface of about 0.05-5 micrometers, and the smallest or narrowest pore size within the membrane is about 0.015-0.035 micrometers.

[0041] The aromatic sulfone polymers of the present disclosure can be, for example, polysulfone, polyethersulfone, polyphenylenesulfone, polyarylethersulfone, or copolymers or modifications of these polymers, or mixtures of these polymers. In a preferred embodiment, the aromatic sulfone polymer can be a polysulfone or polyethersulfone having repeating molecular units as shown in the following formulas (I) and (II):

[0042] [ka]

[0043] More preferably, polyethersulfone according to formula (II) is used as the aromatic sulfone polymer, since it has a lower hydrophobicity than, for example, polysulfone, which may have a molecular weight of about 72 kg / mol.

[0044] In some embodiments, the aromatic sulfone polymer can be present at a concentration of 27% to 30%, 27% to 29%, 27% to 28%, 28% to 30%, or 28% to 29% by weight, based on the total weight of the polymer blend. 27% to 30% by weight of aromatic sulfone polymer is important for membranes with pore sizes less than 30 nm intended to remove viruses / phages (20-30 nm) from monoclonal antibody (5-10 nm) solutions.

[0045] In some embodiments of the polymer blend, the polyoxazoline can be present at a concentration of 1 wt % to 35 wt %, 5 wt % to 35 wt %, 5 wt % to 30 wt %, 5 wt % to 25 wt %, 5 wt % to 20 wt %, 5 wt % to 15 wt %, 7 wt % to 15 wt %, 7 wt % to 12 wt %, or 8 wt % to 11 wt %, based on the total weight of the polymer blend.

[0046] In some embodiments of the polymer blend, the polyoxazoline may be present at a concentration of 8% to 11% by weight, based on the total weight of the polymer blend.

[0047] In some embodiments, the polyoxazoline of the present disclosure can be a poly(2-oxazoline). Poly(2-oxazoline) can be prepared by cationic ring-opening polymerization of various 2-oxazoline monomers. Polymerization of 2-alkyl-substituted 2-oxazoline monomers provides poly(2-alkyl-2-oxazoline).

[0048] In some embodiments, the poly(2-oxazoline) of the present disclosure can be poly(2-ethyl-2-oxazoline) (PEtOx). Poly(2-oxazoline) has a high potential for protein repulsion. The residues of the poly(2-oxazoline) can be varied to change the properties of the polymer, for example, from hydrophilic to hydrophobic. The poly(2-oxazoline) can have a molecular weight of about 25 kg / mol to about 500 kg / mol. The poly(2-oxazoline) can have a molecular weight of about 50 kg / mol.

[0049] Poly(2-ethyl-2-oxazoline) can have a molecular weight of about 25 kg / mol to about 500 kg / mol. Poly(2-ethyl-2-oxazoline) can have a molecular weight of about 25 kg / mol to about 100 kg / mol. Poly(2-ethyl-2-oxazoline) can have a molecular weight of about 50 kg / mol.

[0050] The poly(2-oxazoline) can be present in a concentration of 0.5 to 30 wt%, 1 to 30 wt%, 5 to 30 wt%, or 10 to 30 wt%, based on the weight of the membrane. The poly(2-oxazoline) can be present in a concentration of greater than 0.5 wt%, greater than 1 wt%, greater than 2 wt%, greater than 3 wt%, greater than 4 wt%, greater than 5 wt%, greater than 6 wt%, greater than 7 wt%, greater than 8 wt%, greater than 9 wt%, greater than 10 wt%, greater than 15 wt%, or greater than 20 wt%, based on the weight of the membrane. The poly(2-oxazoline) can be present in a concentration of less than 30 wt%, less than 28 wt%, less than 25 wt%, less than 23 wt%, less than 20 wt%, less than 15 wt%, or less than 10 wt%, based on the weight of the membrane. In some embodiments, the weight percent ratio of aromatic sulfone polymer to poly(2-oxazoline) in the membrane can be 4:1 to 25:1, 4:1 to 10:1, 5:1 to 10:1, 10:1 to 15:1, 15:1 to 20:1, or 20:1 to 25:1.

[0051] The aromatic sulfone polymer and poly(2-oxazoline) may be distributed throughout the membrane. The aromatic sulfone polymer and poly(2-oxazoline) may be uniformly distributed throughout the membrane. The aromatic sulfone polymer and poly(2-oxazoline) may be uniformly distributed throughout the membrane.

[0052] In some embodiments, the poly(2-oxazoline) may be distributed throughout the membrane. The poly(2-oxazoline) may be distributed throughout the membrane. The poly(2-oxazoline) may be uniformly distributed throughout the membrane. In some embodiments, the poly(2-oxazoline) may be uniformly distributed throughout the membrane. The poly(2-ethyl-2-oxazoline) may be distributed throughout the membrane. In some embodiments, the poly(2-ethyl-2-oxazoline) may be uniformly distributed throughout the membrane. In some embodiments, the poly(2-ethyl-2-oxazoline) may be uniformly distributed throughout the membrane. In some embodiments, the poly(2-oxazoline) may not be uniformly distributed throughout the membrane. In some embodiments, the poly(2-ethyl-2-oxazoline) may not be uniformly distributed throughout the membrane. For example, the concentration of poly(2-ethyl-2-oxazoline) at or adjacent to the outer surface may be higher than the concentration of poly(2-ethyl-2-oxazoline) at or adjacent to the inner surface.

[0053] In some embodiments, the polymer blend may further comprise an additional hydrophilic polymer. Exemplary hydrophilic polymers may include polyvinylpyrrolidone, polyethylene glycol, glycerol, polyvinyl alcohol, polyglycol monoesters, polysorbates, carboxymethylcellulose, polyacrylic acid, polyacrylates, or modifications or copolymers of these polymers. In some embodiments, the hydrophilic polymer may be polyethylene glycol. In some embodiments, the polymer blend does not include polyvinylpyrrolidone.

[0054] In some embodiments, the hydrophilic polymer can be present in a concentration of 1 to 75 wt.% based on the weight of the membrane. In some embodiments, the polymer blend can include more than 7 wt.%, more than 10 wt.%, more than 20 wt.%, more than 30 wt.%, more than 40 wt.%, more than 50 wt.%, or more than 60 wt.% polyvinylpyrrolidone. In some embodiments, the polymer blend can include less than 3 wt.%, less than 2 wt.%, or less than 1 wt.% polyvinylpyrrolidone.

[0055] In some embodiments, the polymer blend can include a solvent and a non-solvent. Exemplary blends can include glycol, glycerol, butyrolactone, ε-caprolactam, N-methylpyrrolidone, water, or combinations thereof.

[0056] In some embodiments, the polymer blend can have 5 to 18 wt% poly(2-ethyl-2-oxazoline), based on the total weight of the polymer blend. In some embodiments, the polymer blend can have 5 to 15 wt% poly(2-ethyl-2-oxazoline), based on the total weight of the polymer blend. In some embodiments, the polymer blend can have 7 to 12 wt% poly(2-ethyl-2-oxazoline), based on the total weight of the polymer blend. In some embodiments, the polymer blend can have 8 to 11 wt% poly(2-ethyl-2-oxazoline), based on the total weight of the polymer blend.

[0057] In some embodiments, the polymer blend can have 25 to 60 wt% N-methylpyrrolidone based on the total weight of the polymer blend. In some embodiments, the polymer blend can have 25 to 50 wt% N-methylpyrrolidone based on the total weight of the polymer blend. In some embodiments, the polymer blend can have 25 to 40 wt% N-methylpyrrolidone based on the total weight of the polymer blend.

[0058] In some embodiments, the polymer blend can have 27-30 wt% polyethersulfone and 5-15 wt% poly(2-ethyl-2-oxazoline), based on the total weight of the polymer blend. In some embodiments, the polymer blend can have 27-30 wt% polyethersulfone and 7-12 wt% poly(2-ethyl-2-oxazoline), based on the total weight of the polymer blend.

[0059] In some embodiments, the polymer blend can have 20-40 wt% polyethylene glycol based on the total weight of the polymer blend, hi some embodiments, the polymer blend can have 25-35 wt% polyethylene glycol based on the total weight of the polymer blend.

[0060] In some embodiments, the polymer blend can have 27-30 wt % polyethersulfone, 5-15 wt % poly(2-ethyl-2-oxazoline), 30-40 wt % N-methylpyrrolidone, and 5-40 wt % polyethylene glycol, based on the total weight of the polymer blend.

[0061] In some embodiments, the polymer blend can have 27-30 wt % polyethersulfone, 7-12 wt % poly(2-ethyl-2-oxazoline), 30-35 wt % N-methylpyrrolidone, and 25-35 wt % polyethylene glycol, based on the total weight of the polymer blend.

[0062] The wall thickness of the hollow fiber membranes disclosed herein is also preferably within the range of 10 to 400 μm, 20 to 300 μm, 30 to 200 μm, or 40 to 80 μm. Wall thicknesses less than 20 μm may result in lower than certain desirable mechanical properties of the hollow fiber membrane, and wall thicknesses greater than 400 μm result in reduced transmembrane flow rates. Similarly, to achieve desirable flow through the lumen of a hollow fiber membrane according to the present disclosure, particularly to achieve a desirable pressure drop, the inner diameter of the hollow fiber membranes described herein is preferably within the range of 50 to 800 μm, 50 to 700 μm, 50 to 600 μm, 100 to 500 μm, 100 to 400 μm, or 100 to 300 μm.

[0063] The hollow fiber membranes according to the present invention preferably have a permeability of at least 0.01 mL / (cm 2 ·min·bar), preferably at least 0.1 mL / (cm 2 ·min·bar), more preferably at least 0.15mL / (cm 2 ·min·bar), even more preferably at least 0.2 mL / (cm 2 The hollow fiber membranes disclosed herein exhibit a transmembrane flow rate for water of 0.01 to 10 mL / (cm). This ensures an adequate and stable filtration capacity for the application. 2 ·min·bar), preferably 0.15 to 5 mL / (cm 2 ·min·bar), more preferably 0.1 to 3mL / (cm 2 It is further preferred that the membrane exhibits a transmembrane flux for water in the range of 1 / 2 min bar (bar). Transmembrane fluxes in these ranges allow for adequate and stable filtration capacity in the preferred application without degrading retention capacity or compromising mechanical stability. Transmembrane flux is preferably measured as described in the experimental section.

[0064] Hollow fiber membranes according to the present disclosure can be made by the method disclosed in International Publication No. WO 2019 / 229667(A1) (Malek et al.), which is incorporated herein by reference in its entirety. A polymer blend comprising an aromatic sulfone polymer and a polyoxazoline can be selected as a spinning solution in the method for preparing hollow fiber membranes. The polymer blend selected as the spinning solution can also include one or more hydrophilic polymers, a solvent, and / or a non-solvent. In some embodiments, hollow fiber membranes can be made from a homogeneous spinning solution of an aromatic sulfone polymer and a poly(2-oxazoline) and a bore liquid. The bore liquid can include water, a solvent, and a non-solvent. Accordingly, the present invention further provides a method for producing a hollow fiber membrane, comprising the steps of: providing a spinning solution comprising an aromatic sulfone polymer and a polyoxazoline, and a bore solution comprising water, a solvent, and a non-solvent; and spinning an aromatic sulfone polymer and poly(2-oxazoline) hollow fiber with a spinneret outer diameter in the range of 300 to 1000 μm, a spinneret needle outer diameter in the range of 200 to 1000 μm, and a spinneret needle inner diameter in the range of 100 to 1000 μm.

[0065] In some embodiments, the spinning solution can further comprise a hydrophilic polymer. A long-chain polymer is advantageously used as at least one hydrophilic polymer compatible with the hydrophobic aromatic sulfone polymer. The aromatic sulfone polymer has repeating polymer units that are themselves hydrophilic. The hydrophilic polymer is preferably polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polyglycol monoester, polysorbate (e.g., polyoxyethylene sorbitan monooleate), carboxymethyl-cellulose, or a modified or copolymerized version of these polymers. Polyvinylpyrrolidone and polyethylene glycol are particularly preferred.

[0066] In some embodiments, the spinning solution includes polyethylene glycol (PEG). In some embodiments, the polyethylene glycol in the spinning solution can have a molecular weight (MW) of about 100 to about 1,800 g / mol. In some embodiments, the polyethylene glycol in the spinning solution can have a molecular weight (MW) of about 200, 400, 500, 600, 1000, 1200, or 1,500 g / mol.

[0067] Within the context of the present disclosure, the at least one hydrophilic polymer can also comprise a mixture of different hydrophilic polymers, for example, a mixture of chemically different hydrophilic polymers or a mixture of hydrophilic polymers having different molecular weights, for example, a mixture of polymers whose molecular weights differ by a factor of five or more.

[0068] After preferably being degassed and filtered to remove gases and undissolved particles, the homogenous spinning solution, along with a bore fluid, is extruded through the annular gap of a conventional hollow fiber die to produce hollow fibers. The bore fluid, i.e., the coagulation medium for the aromatic sulfone polymer and the internal filler that simultaneously stabilizes the lumen of the hollow fiber, is extruded through a central nozzle opening aligned coaxially with the annular gap of the hollow fiber die. Within this disclosure, the terms "hollow fiber die" and "spinneret" may be used interchangeably. The bore fluid may contain water and glycerol, but may also contain additional formulation ingredients and / or solvents, such as polyethylene glycol (PEG). Preferably, the bore fluid further contains a non-solvent for the membrane-forming polymer, such as water, a low-molecular-weight polyethylene glycol having an average molecular weight less than 1000 daltons, or a low-molecular-weight alcohol, such as ethanol or isopropanol, and / or a protic solvent, such as ε-caprolactam. Preferably, the bore fluid contains water, N-methylpyrrolidone, and polyethylene glycol. The solvent may be present at 5 to 70% by weight based on the weight of the solution.

[0069] The solvent system used must be compatible with the aromatic sulfone polymer and poly(2-oxazoline) used so as to produce a homogeneous spinning solution. The solvent system preferably contains a polar aprotic solvent, such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, or a mixture thereof, or a protic solvent, such as ε-caprolactam. Furthermore, the solvent system can contain up to 70% by weight of a latent solvent, whereby, in the context of the present invention, a latent solvent is understood as a solvent that barely dissolves the sulfone polymer or dissolves it only at high temperatures. When ε-caprolactam is used as the solvent, for example, butyrolactone, propylene carbonate, or polyalkylene glycol can be used. Furthermore, the solvent system can contain a non-solvent for the membrane-forming polymer, such as water, glycerin, low-molecular-weight polyethylene glycol with an average molecular weight of less than 1000 daltons, or low-molecular-weight alcohol, such as ethanol or isopropanol. Preferably, the solvent system contains N-methylpyrrolidone.

[0070] In one embodiment, the spinning solution comprises an aromatic sulfone polymer, poly(2-oxazoline), polyethylene glycol, N-methylpyrrolidone, and water. In another embodiment, the spinning solution comprises polyethersulfone, poly(2-ethyl-2-oxazoline), polyethylene glycol, N-methylpyrrolidone, and water. In yet another embodiment, the spinning solution comprises polyethersulfone, poly(2-ethyl-2-oxazoline), PEG200 or PEG1500, N-methylpyrrolidone, and water.

[0071] The width of the annular gap and the inner diameter of the central nozzle opening were selected according to the desired properties of the hollow fiber membrane according to the present disclosure, i.e., the spinneret exhibits a dope spinneret outer diameter in the range of 300-1000 μm, a spinneret needle outer diameter in the range of 200-1000 μm, and a spinneret needle inner diameter in the range of 100-1000 μm.

[0072] After leaving the hollow fiber die (i.e., spinneret) and before entering the coagulation medium, the hollow fibers can pass through an environmental control zone with defined environmental conditions. The environmental control zone can thereby take the form of, for example, an enclosed chamber. For technical reasons, it may be necessary for an air gap to exist between the hollow fiber die and the environmental control zone. However, this gap should advantageously be as small as possible, and the environmental control zone preferably follows immediately after the hollow fiber die.

[0073] In this regard, it is preferred that the hollow fibers have a residence time (retention time) of 0.5 to 10 seconds within the environmentally controlled zone, whereby the environmentally controlled zone contains air having a relative humidity of 20 to 95% and a temperature of 25 to 75°C. The residence time of the hollow fibers within the environmentally controlled zone is preferably 0.5 to 5 seconds. To establish stable conditions within the environmentally controlled zone, air flows through the environmentally controlled zone preferably at a velocity of less than 0.5 m / s, particularly preferably at a velocity in the range of 0.15 to 0.35 m / s.

[0074] In one embodiment, the environmentally controlled zone contains air having a relative humidity of 20-95% and a temperature of 25-75°C. In one embodiment, the environmentally controlled zone contains air having a relative humidity of 60-75% and a temperature of 30-50°C. In one embodiment, the environmentally controlled zone contains air having a relative humidity of 75-90% and a temperature of 30-50°C. In one embodiment, the environmentally controlled zone contains air having a relative humidity of 60-75% and a temperature of 50-70°C. In one embodiment, the environmentally controlled zone contains air having a relative humidity of 75-90% and a temperature of 50-70°C.

[0075] When the hollow fibers are guided through the environmental control zone, water vapor, which acts as a non-solvent, is absorbed on the outside of the hollow fibers prior to coagulation, thereby pre-coagulating the hollow fibers. At the same time, the retention time should be set within the preferred range for the method according to the present disclosure. These measures influence the formation of the outer layer of the hollow fiber membrane according to the present invention, so that, in some embodiments, the outer layer can have an essentially isotropic structure.

[0076] After passing through the environmental control zone, the pre-coagulated hollow fibers are passed through an aqueous coagulation medium, preferably adjusted to 20-90° C., to complete the formation of the membrane structure. The coagulation medium is preferably adjusted to a temperature in the range of 20-90° C. Preferably, the coagulation medium, such as a precipitation bath, is water or a water bath.

[0077] In the coagulation medium, the membrane structure is first precipitated to the extent that it is already sufficiently stable and can be transferred in the coagulation medium, for example, via a deflection roller or similar means. During further processing, coagulation is completed and the membrane structure is stabilized. The solvent system and extraction of soluble substances are carried out simultaneously here. Generally, most of the hydrophilic polymer is extracted from the membrane structure, so the coagulation bath simultaneously serves as a washing or extraction bath. Water is preferably used as the coagulation or washing medium in the coagulation or washing bath. In some embodiments, the solvent system and extraction of soluble substances can be carried out in different steps. The hollow fiber bundle can be placed in a box and washed with hot water. Most of the hydrophilic polymer can be extracted from the membrane structure in this step.

[0078] The hollow fiber membranes according to the present disclosure can be textured (if necessary) to improve the exchange properties of the hollow fiber membranes within the bundle. The membranes can then be recovered. The hollow fiber membranes can be dried. The dried membranes can then be wound into coils. Finally, the hollow fiber membranes can be processed using conventional methods, e.g., wound into coils or directly formed into bundles with a suitable fiber (yarn) count and length. Prior to producing the bundle, auxiliary threads, e.g., in the form of multifilament yarns, can be added to the hollow fiber membranes to ensure spacing of the hollow fiber membranes relative to one another and to improve flow around the individual hollow fiber membranes within the bundle.

[0079] According to the present disclosure, the concentration of the sulfone polymer in the spinning solution is preferably in the range of 27 to 30 wt%. Concentrations below 27 wt% may result in disadvantages regarding virus retention. The sulfone polymer may also contain additives such as antioxidants, nucleating agents, and UV absorbers to selectively modify the membrane properties. The concentration of poly(2-oxazoline) in the spinning solution may be in the range of 5 to 30 wt%.

[0080] In some embodiments, the spinning solution can have 27-30 wt % aromatic sulfone polymer by weight of the solution, 7-15 wt % poly(2-oxazoline) by weight of the solution, 30-40 wt % solvent by weight of the solution, and 25-50 wt % hydrophilic polymer by weight of the solution.

[0081] In some embodiments, the spinning solution can have 27-30 wt % polyethersulfone based on the weight of the solution, 10-30 wt % poly(2-ethyl-2-oxazoline) based on the weight of the solution, and 50-63 wt % N-methylpyrrolidone based on the weight of the solution.

[0082] In some embodiments, the spinning solution can have 27-30 wt % polyethersulfone by weight of the solution, 5-20 wt % poly(2-ethyl-2-oxazoline) by weight of the solution, 20-68 wt % N-methylpyrrolidone by weight of the solution, and 5-40 wt % polyethylene glycol by weight of the solution.

[0083] In some embodiments, the spinning solution can have 27-30 wt % polyethersulfone, 5-15 wt % poly(2-ethyl-2-oxazoline), 30-40 wt % N-methylpyrrolidone, and 5-40 wt % polyethylene glycol, based on the total weight of the solution.

[0084] In some embodiments, the spinning solution can have 27-30 wt % polyethersulfone, 7-12 wt % poly(2-ethyl-2-oxazoline), 30-35 wt % N-methylpyrrolidone, and 25-35 wt % polyethylene glycol, based on the total weight of the solution.

[0085] In some embodiments, the spinning solution can have 5 to 18 wt% poly(2-ethyl-2-oxazoline) based on the total weight of the solution. In some embodiments, the spinning solution can have 5 to 15 wt% poly(2-ethyl-2-oxazoline) based on the total weight of the solution. In some embodiments, the spinning solution can have 7 to 12 wt% poly(2-ethyl-2-oxazoline) based on the total weight of the solution. In some embodiments, the spinning solution can have 8 to 11 wt% poly(2-ethyl-2-oxazoline) based on the total weight of the solution.

[0086] In some embodiments, the spinning solution can have 25 to 60 wt% N-methylpyrrolidone based on the total weight of the solution, hi some embodiments, the spinning solution can have 25 to 50 wt% N-methylpyrrolidone based on the total weight of the solution.

[0087] In some embodiments, the spinning solution can have 25-40 wt% N-methylpyrrolidone based on the total weight of the solution, 27-30 wt% polyethersulfone and 5-15 wt% poly(2-ethyl-2-oxazoline) based on the total weight of the solution.

[0088] In some embodiments, the spinning solution can have 27-30 wt % polyethersulfone and 7-12 wt % poly(2-ethyl-2-oxazoline), based on the total weight of the solution.

[0089] In some embodiments, the spinning solution can have 27-30 wt % polyethersulfone and 8-11 wt % poly(2-ethyl-2-oxazoline), based on the total weight of the solution.

[0090] In some embodiments, the spinning solution can have 20-40 wt% polyethylene glycol based on the total weight of the solution, hi some embodiments, the spinning solution can have 25-35 wt% polyethylene glycol based on the total weight of the solution.

[0091] In some embodiments, the polyethylene glycol component of the polymer blend or spinning solution can have a molecular weight of 200 g / mol (PEG200), 400 g / mol (PEG400), 600 g / mol (PEG600), 1000 g / mol (PEG1000), 1200 g / mol (PEG1200), or 1500 g / mol (PEG1500).

[0092] In some embodiments, the polyethylene glycol component of the polymer blend or spinning solution can have a molecular weight of 200 to 600 g / mol. In some embodiments, the polyethylene glycol component of the polymer blend or spinning solution can have a molecular weight of 500 to 1000 g / mol. In some embodiments, the polyethylene glycol component of the polymer blend or spinning solution can have a molecular weight of 1000 to 1500 g / mol.

[0093] The present invention provides polymer membranes with excellent protein-repelling properties. These membranes therefore block more slowly, exhibit higher throughput behavior, and thus exhibit longer life spans. These membranes also exhibit asymmetric structures that are promising for the preparation of highly selective membranes. The membrane's protein-repelling properties can provide better filtration properties due to reduced fouling, resulting in higher throughput.

[0094] In some embodiments, the hollow fiber membranes of the present disclosure can be suitable for use in applications in the field of filtration, for example, for filtering antibodies such as monoclonal antibodies (mAbs). Due to the unique combination of properties of the hollow fiber membranes described herein, preferably obtained from the methods described herein, the present disclosure further provides for the use of the membranes described herein for the filtration of liquids, for example, microfiltration or ultrafiltration. "Microfiltration" and "ultrafiltration" have their common meanings in the art. Preferably, the uses described herein involve the clarification and / or purification of liquid media, particularly aqueous liquids. In some embodiments, liquids that can be filtered by the hollow fiber membranes of the present disclosure can contain biological products selected from capsids, viruses, virus-like particles, or antibody-containing solutions. The hollow fiber membranes can remove more than 3, 4, 5, 6, or 7 log (log reduction values, LRVs) of contaminating bacteriophages or viruses that are 15 nm or larger. The hollow fiber membranes can be operated using either a constant flow rate or a constant pressure. These membrane attributes allow for faster processing times, greater flexibility in the processing equipment used to perform the filtration, and operation under a variety of conditions.

[0095] In some embodiments, the present disclosure provides a method. The method can include flowing an antibody-containing solution through a hollow fiber membrane of the present disclosure and collecting the antibody. Viruses or bacteriophages 15 nm or larger can be at least partially removed from the antibody-containing solution. In some embodiments, the antibody-containing solution can be a concentrated antibody solution with a concentration of greater than 50 mg / mL.

[0096] Illustrative Embodiments Embodiment 1 is a hollow fiber membrane made from a polymer blend including an aromatic sulfone polymer and a polyoxazoline, the polymer blend including 27% to 30% by weight of the aromatic sulfone polymer, based on the total weight of the polymer blend; the hollow fiber membrane has an inner surface facing the lumen, an outer surface facing the outside, and an intermediate wall having a wall thickness; and the hollow fiber membrane is an overall asymmetric permeable hollow fiber membrane.

[0097] Embodiment 2 is the hollow fiber membrane of embodiment 1, wherein the aromatic sulfone polymer comprises polysulfone or polyethersulfone.

[0098] Embodiment 3 is the hollow fiber membrane of embodiment 1 or 2, wherein the polyoxazoline is poly(2-ethyl-2-oxazoline) (PEtOx).

[0099] Embodiment 4 is the hollow fiber membrane of any one of Embodiments 1 to 3, wherein a zone having the smallest pore size is adjacent to the inner surface.

[0100] Embodiment 5 is the hollow fiber membrane of embodiment 4, wherein a zone having the largest pore size is adjacent to the exterior surface.

[0101] Embodiment 6 is the hollow fiber membrane of any one of Embodiments 1 to 3, wherein a zone having the smallest pore size is adjacent to the outer surface.

[0102] Embodiment 7 is the hollow fiber membrane of embodiment 6, wherein a zone having the largest pore size is adjacent to the interior surface.

[0103] Embodiment 8 is the hollow fiber membrane according to any one of embodiments 4 to 7, wherein the size of the pores in the zone having the smallest pore size is in the range of 10 nm to 20 nm.

[0104] Embodiment 9 is the hollow fiber membrane according to any one of Embodiments 4 to 8, wherein at least some of the pores in the zone having the smallest pore size or the zone having the largest pore size are connected.

[0105] Embodiment 10 is the hollow fiber membrane of embodiment 9, wherein at least some of the pores in the zone having the smallest pore size or the zone having the largest pore size are connected via channels between the pores.

[0106] An eleventh embodiment is the hollow fiber membrane according to any one of the first to tenth embodiments, wherein the hollow fiber membrane has a serpentine structure extending within the hollow fiber membrane.

[0107] Embodiment 12 is the hollow fiber membrane of embodiment 11, wherein at least some of the serpentine structures extend from the inner surface toward the outer surface.

[0108] Embodiment 13 is the hollow fiber membrane of any one of embodiments 1 to 12, wherein the polymer blend comprises more than 7 wt. % or less than 3 wt. % polyvinylpyrrolidone.

[0109] Embodiment 14 is the hollow fiber membrane according to any one of embodiments 1 to 13, wherein the polymer blend does not contain polyvinylpyrrolidone.

[0110] Embodiment 15 is the hollow fiber membrane of any one of embodiments 4 to 10, wherein the zone having the smallest pore size has a lower flow rate than the zone having the largest pore size.

[0111] Embodiment 16 is the hollow fiber membrane according to any one of embodiments 4 to 10, wherein the zone having the smallest pore size (retentive layer) has a thickness of 5 to 100 μm.

[0112] Embodiment 17 is the hollow fiber membrane according to any one of embodiments 1 to 16, wherein the hollow fiber membrane has a log reduction value (LRV) of greater than 3 for viruses or bacteriophages that are 15 nm or larger.

[0113] An eighteenth embodiment is the hollow fiber membrane according to any one of the first to seventeenth embodiments, which is capable of removing viruses or bacteriophages having a size of 15 nm or more.

[0114] Embodiment 19 is the use of the hollow fiber membrane according to any one of embodiments 1 to 18 for filtration of antibodies.

[0115] Embodiment 20 is a method comprising flowing an antibody-containing solution through the hollow fiber membrane of any one of embodiments 1 to 18, and collecting the antibody.

[0116] Embodiment 21 is the method of embodiment 20, wherein viruses or bacteriophages that are 15 nm or larger are removed from the antibody-containing solution.

[0117] Embodiment 22 is the method of embodiment 20 or 21, wherein the antibody-containing solution is a concentrated antibody solution.

[0118] Embodiment 23 is a porous hollow fiber membrane comprising an aromatic sulfone polymer and a polyoxazoline, the hollow fiber membrane having an inner surface facing the lumen of the hollow fiber membrane, an outer surface facing the outside, and an intermediate wall having a wall thickness, a first cross-sectional zone beginning at the inner surface and extending laterally into the intermediate wall terminating at an interior distance within the intermediate wall, the pore size gradually decreasing across the first cross-sectional zone in a direction from the inner surface to the outer surface, the hollow fiber membrane having a second cross-sectional zone beginning where the first cross-sectional zone terminates and extending laterally to the outer surface of the membrane; The porous hollow fiber membrane has pores whose size gradually increases across the second cross-sectional zone in a direction from the beginning of the second cross-sectional zone to the outer surface.

[0119] Embodiment 24 is the porous hollow fiber membrane of embodiment 23, wherein the pore size on the outer surface is smaller than the pore size on the inner surface.

[0120] Embodiment 25 is the porous hollow fiber membrane of embodiment 23 or 24, wherein the pore located where the first cross-sectional zone ends and the second cross-sectional zone begins forms at least a portion of a retention zone.

[0121] Embodiment 26 is the porous hollow fiber membrane of any one of embodiments 23 to 25, wherein the pores located where the first cross-sectional zone ends and the second cross-sectional zone begins have a pore size of less than 0.035 micrometers.

[0122] Embodiment 27 is the porous hollow fiber membrane of any one of embodiments 23 to 26, wherein the pores located where the first cross-sectional zone ends and the second cross-sectional zone begins have a pore size of less than 0.03 micrometers.

[0123] Embodiment 28 is the porous hollow fiber membrane of any one of embodiments 23 to 27, wherein the pores located where the first cross-sectional zone ends and the second cross-sectional zone begins have a pore size of about 0.01 to 0.035 micrometers.

[0124] Embodiment 29 is the porous hollow fiber membrane of any one of embodiments 23 to 28, wherein the pores located where the first cross-sectional zone ends and the second cross-sectional zone begins have a pore size of about 0.01 to 0.03 micrometers.

[0125] Embodiment 30 is a method comprising flowing a liquid containing antibodies and viruses through a porous hollow fiber membrane, the hollow fiber membrane comprising an aromatic sulfone polymer and a polyoxazoline, the hollow fiber membrane having an inner surface facing the hollow fiber membrane lumen, an outer surface facing the outside, and an intermediate wall having a wall thickness, the first cross-sectional zone beginning at the inner surface and extending laterally within the intermediate wall and terminating at an interior distance within the intermediate wall, wherein pore size gradually decreases across the first cross-sectional zone in a direction from the inner surface to the outer surface, and the hollow fiber membrane has a second cross-sectional zone beginning where the first cross-sectional zone terminates and extending laterally to the outer surface of the membrane, wherein pore size gradually increases across the second cross-sectional zone in a direction from the beginning of the second cross-sectional zone to the outer surface; and collecting the liquid.

[0126] Embodiment 31 is a method comprising flowing a liquid containing antibodies and viruses through a porous hollow fiber membrane comprising an aromatic sulfone polymer and a polyoxazoline, the hollow fiber membrane having an inner surface facing the hollow fiber membrane lumen, an outer surface facing outward, and an intermediate wall having a wall thickness, the first cross-sectional zone beginning at the inner surface and extending laterally within the intermediate wall and terminating at an interior distance within the intermediate wall, wherein pore size gradually decreases across the first cross-sectional zone in a direction from the inner surface to the outer surface, and the hollow fiber membrane has a second cross-sectional zone beginning where the first cross-sectional zone terminates and extending laterally to the outer surface of the membrane, wherein pore size gradually increases across the second cross-sectional zone in a direction from the beginning of the second cross-sectional zone to the outer surface; retaining at least a portion of the viruses on the membrane; and collecting the liquid from the membrane.

[0127] Embodiment 32 is the method of embodiment 30 or 31, wherein the pore size in the outer surface is smaller than the pore size in the inner surface.

[0128] Embodiment 33 is the method of any one of embodiments 30 to 32, wherein the virus is removed from the liquid.

[0129] Embodiment 34 is the method of any one of embodiments 30 to 33, wherein at least 3 log reduction values (LRV) of viruses are removed from the fluid.

[0130] Embodiment 35 is the method of any one of embodiments 30 to 34, wherein at least 4 log reduction values (LRV) of viruses are removed from the fluid.

[0131] Embodiment 36 is the method of any one of embodiments 30-35, wherein the liquid is water.

[0132] Embodiment 37 is the method of any one of embodiments 30 to 36, wherein the virus is 15 nm or greater in diameter.

[0133] Embodiment 38 is the method of any one of embodiments 30 to 37, wherein the virus has a diameter of 15 to 30 nm.

[0134] Embodiment 39 is the method of any one of embodiments 30 to 38, wherein the antibody has a diameter of 5 to 10 nm.

[0135] Embodiment 40 is the method of any one of embodiments 30 to 39, wherein a pore located where the first cross-sectional zone ends and the second cross-sectional zone begins forms at least a portion of a retention zone.

[0136] Embodiment 41 is a method according to any of the eighth to eighteenth embodiments, wherein the virus is retained within the retention zone.

[0137] Embodiment 41 is an article comprising the porous hollow fiber membrane according to any one of embodiments 1 to 18 and 23 to 29.

[0138] The following examples are intended to illustrate, but not limit, the present disclosure. [Example]

[0139] The objects and advantages of this invention are further illustrated by the following examples, but the particular materials and amounts thereof recited in these examples, as well as other conditions and details, should not be construed to unduly limit this invention.

[0140] The following abbreviations are used herein: mL = milliliter, L = liter, kg = kilogram, g = gram, mg = milligram, m = meter, cm = centimeter, mm = millimeter, nm = nanometer, s = second, min = minute, hr = hour, psi = pounds per square inch, and wt.% = weight percent.

[0141] Scanning electron microscope (SEM) images were obtained using an FEI 250 scanning electron microscope (Thermo Fisher Scientific, Waltham, MA) equipped with xT Microscope Control operating software or a Coxem EM-30AX scanning electron microscope (Coxem Company, Daejeon, Korea) equipped with NanoStation operating software.

[0142] [Table 1]

[0143] Method A. How to measure transmembrane flux (TMF) A hollow fiber membrane test module was prepared by placing 10 hollow fiber membranes (10 cm long) in a straight, cylindrical polycarbonate tube (8 mm inner diameter, 60 mm long). The tube had a side-located outlet located approximately midway between the two ends of the cylinder. The hollow fiber membranes were secured within the tube using hot-melt adhesive at both ends. After solidification, the protruding ends of the hollow fiber membranes and excess adhesive were removed using a razor blade. The membrane openings were visually inspected, and only modules in which all of the hollow fiber membranes had an open, unobstructed lumen were used. Caps with ports for attachment to flexible tubing were attached to both ends of the polycarbonate tube. The completed test module was mounted on a stand, positioned vertically, filled with 18 megohm water, and connected to the measurement system.

[0144] The measurement system included a pressure pot filled with 18 megohm water connected to one end of the test module by flexible tubing, two pressure gauges (the first was positioned between the pressure pot and the test module, and the second was positioned downstream from the opposite side of the module), and a flush valve located downstream from the module and the second pressure gauge. The measurement system also included a heater, through which water passed, located between the pressure pot and the first pressure gauge. The heater heated the water to 25°C.

[0145] A pressure of 5.8 psi was applied to the pressure pot. At the start of the test, the air in the system was replaced by closing the side outlet and opening the flush valve. The flush valve was then closed, the side outlet was opened, and the module was operated in a dead-end filtration configuration. Water flowed from the pressure pot through the membrane lumen for 4 minutes, filtered through the membrane wall, and exited the module through the side outlet into the first collection container. The first collection container was then replaced with a tared second collection container. Filtered water was collected in the second collection container for 60 seconds. The amount of water collected in the second container was measured using a digital balance. The differential pressure was measured by reading the difference between the two pressure gauges.

[0146] Based on the membrane dimensions, differential pressure, and weight of water, the transmembrane flux (TMF) was calculated according to Equation 1.

[0147]

number

[0148] Method B. Method for measuring viscosity of spinning solutions (polymer blends) The viscosity of the casting solution was measured at 60 °C and a shear rate of 10 s using a HAAKE RheoStress 1 rheometer (Thermo Fisher Scientific, Waltham, MA) equipped with a Z20DIN sensor device (Thermo Fisher Scientific). -1 was measured.

[0149] Method C. Phi-X174 phage culture preparation Phi-X174 bacteriophage (ATCC 13706-B1) was obtained from ATCC (Manassas, VA). Phage cultures were generated by adding 5% sodium chloride to a 1 L culture of E. coli (ATCC 13706) in CRITERION Nutrient Broth (Hardy Diagnostics, Santa Maria, CA) and growing it to an OD of 0.45 at 37°C with mixing at 210 revolutions per minute (rpm). The culture was inoculated with approximately 1,000 plaque-forming units (pfu) of Phi-X174 phage. The inoculated culture was grown for an additional 4 hours at 37°C with mixing at 210 rpm. The inoculated Phi-X174 culture was then purified using anion exchange chromatography. The purified Phi-X174 was sterile filtered through a 0.2 micron syringe filter. Phage concentrations were determined according to Method D and stored at 4°C.

[0150] Method D. Measurement of Phi-X174 phage concentration Phage concentrations in filtrate samples, feed solutions, and Phi-X174 culture preparations were measured using the following procedure. The solutions of interest were serially diluted (10-fold). Top agar (2.5 mL of CRITERION Nutrient Broth (Hardy Diagnostics) containing 0.9% agar) was mixed with 50 microliters of E. coli (ATCC 13706) culture (grown in CRITERION Nutrient Broth with 5% sodium chloride at 37°C overnight with shaking at 210 rpm) and 100 microliters of diluted Phi-X174 phage. The mixture was poured onto a standard nutrient agar plate (CRITERION Nutrient Broth containing 1.5% agar) and incubated at 37°C for 3–4 hours. After incubation, plaque-forming units (pfu) were counted. The number of pfu correlated with the number of phage particles. Phage particle concentration (particles / mL) was calculated from the pfu count adjusted for dilution. The log reduction value (LRV) was determined by the difference between the number of plaques present in the feed solution and the number of plaques present in the filtrate (see Equation 2). A ">" designation for the reported LRV indicates that no pfu were observed for any of the serially diluted samples of filtrate.

[0151]

number

[0152] Methods E. Preparation of Porcine Circovirus (PCV2d) Porcine circovirus (PCV2d USA / NC24897 / 2016 P14 mutant, 5.62 × 10 6The virus pellet was resuspended in 5.7 mL of phosphate buffer (25 mM, 4 mS / cm). After resuspension, the solution was centrifuged at 1000 g for 10 minutes to remove any undissolved particles. A total of 5.5 mL of suspended virus was collected. For virus TCID50 titration in PK-15 cells, a 20-microliter aliquot of the suspension was diluted in 180 microliters of phosphate-buffered saline (PBS, 1X). The concentration of the suspended virus was 4.64 × 10 7 The PCV2d virus was diluted in a total of 20 mL of PBS (1X) and filtered through a BC1 EMPHAZE AEX Hybrid Purifier (3M Company, Maplewood, MN). The PCV2d concentration after filtration was 3.16 x 10 6 The concentration was TCID50 / mL. The stock solution was stored frozen.

[0153] Example 1 A spinning solution was prepared by vigorously mixing 27 wt% polyethersulfone, 9 wt% poly(2-ethyl-2-oxazoline), 32.4 wt% N-methylpyrrolidone, 29.6 wt% poly(ethylene glycol) 200 (PEG 200), and 2 wt% ultrapure deionized water at a temperature of approximately 55°C. The resulting spinning solution was cooled to approximately 50°C, filtered, and degassed. A temperature-controlled spinneret (35°C) with a dope outer diameter of 0.41 mm, a needle outer diameter of 0.3 mm, and a spinneret needle inner diameter of 0.15 mm was used. The spinneret was fixed at a distance of 25 cm above the precipitation bath.

[0154] The spinning solution and a mixture of NMP, polyethylene glycol (PEG200), and water (50:45:5) were used as the bore fluid in the spinneret needle of the spinneret to produce hollow fibers. The hollow fibers were transferred to a water-filled precipitation bath heated to approximately 35°C. Immediately after this coagulation and fixation step, the wet hollow fiber membranes were wound onto a wheel and then assembled into a hollow fiber membrane bundle having a length of approximately 30 cm and containing approximately 1,200 individual hollow fiber membranes. The hollow fiber membranes were extracted with hot water (approximately 90°C) for approximately 1 hour and then dried in air at approximately 90°C for approximately 1 hour. The resulting hollow fiber membranes had a physical inner diameter of approximately 200 micrometers and a wall thickness of approximately 60 micrometers.

[0155] The membrane wall cross-sections were examined using SEM (8,000-20,000x magnification). Scanning electron microscope (SEM) images of the cross-sections of hollow fiber membranes are shown in Figures 3A and 3B. For the prepared membranes, the pore size at the inner surface facing the lumen was approximately 0.06-3 micrometers. The pore size gradually decreased in the direction from the inner membrane surface to the outer membrane surface over a distance of approximately 57 micrometers (95%) across the membrane wall (pore size measurements were taken along the vector defining the shortest cross-sectional distance from the inner membrane surface to the outer surface of the membrane). The pore size then transitioned to gradually increase in size toward the outer surface (along the same vector direction), with the pore size at the outer membrane surface being approximately 0.05-0.2 micrometers. At the location on the membrane wall where the pore size transition occurred, the pore size was less than 0.03 micrometers.

[0156] Transmembrane flux (TMF) values were measured according to Method A and the results are reported in Table 1.

[0157] Example 2. Filtration of mAb solution A 5 mg / mL mAb solution in Tris-HCl buffer (pH 7 and conductivity 5 mS / cm) was prepared from Chinese hamster ovary (CHO) suspension cell cultures expressing a biosimilar IgG1 mAb (pI ∼7.9). The mAb solution was filtered using a 0.2 micron PES membrane filter followed by a 3M Polisher ST BC4 capsule (3M Company). The mAb solution was stored at 4°C until use. The mAb concentration was determined by measuring the absorbance of the solution at 280 nm and comparing the results with a previously prepared standard concentration curve.

[0158] Hollow fiber membrane test modules were prepared and tested according to the following procedure. Polycarbonate tubing with a length of 30 mm and an inner diameter of 4 mm was used. One hole was drilled in the side of each tube. An open-bore connector was attached to the hole using UV / visible light-curing adhesive to form a side port. A cap was attached to the side port. Approximately 25-30 hollow fibers prepared according to Example 1 were placed in each tube. The inserted hollow fibers were cut with a razor blade to provide approximately 15 mm of hollow fiber overhang at each end of the tube. The overhanging hollow fibers were sealed with wax and then encased in the tube using polyurethane resin. After 24 hours of curing, the overhanging ends were removed using a razor blade. The membrane openings were inspected using a microscope, and only tubes in which all of the hollow fiber membranes had an open, unobstructed lumen were used. Caps with open ports for attachment to flexible tubing were secured to each end of the polycarbonate tubing with adhesive. The total surface area of the internal hollow fibers (i.e., the total lumen surface area) is approximately 5 cm 2 The test modules were sterilized using gamma irradiation (25-45 kGy) before use.

[0159] The completed test module was mounted on a stand and placed in a vertical orientation. The open port on the cap at the bottom of the module was connected using flexible tubing to a three-way valve located at the bottom of a vertically mounted pressure pot. The pressure pot was first filled with ultrapure water (obtained from a MILLI-Q water purification system (EMD Millipore, Billerica, MA)). The three-way valve between the pressure pot and the test module was opened, allowing water to flow into the hollow fiber lumens and out the opposite end of the module. Once the hollow fiber lumens were filled with water, the open port at the top of the test module was capped. The pressure was gradually increased to 30 psi. The cap on the side port of the test module was removed, allowing the filtrate to exit the module and into the first collection container. Water was filtered through the hollow fiber module at 30 psi for a minimum of 10 minutes. The three-way valve at the bottom of the pressure pot was then closed, and any remaining water in the pressure pot was removed.

[0160] The pressure pot was depressurized and filled with 5 mg / mL mAb solution. The pressure pot was then sealed, pressurized to 30 psi, and the three-way valve was opened. The filtrate was collected in a tared second collection vessel placed on a digital balance, and the filtrate weight was recorded every 10 seconds. Filtration was carried out for 150 minutes. The flux of the mAb solution (380 LMH) remained constant throughout the filtration period. The ratio of the flux at 150 minutes to the flux at 60 minutes was 1.0. The ratio of the flux at 60 minutes to the flux at 20 minutes was 1.0. The total mAb filtered over 150 minutes was 5.0 kg / m 2 It was calculated that:

[0161] Example 3. Filtration of mAb solution spiked with Phi-X174 phage 10 mg / mL solution of mAb 7 The same method as described in Example 2 was followed, except that pfu / mL of Phi-X174 phage was spiked.

[0162] The filtrate was collected in a tared second collection vessel placed on a digital balance, and the filtrate weight was recorded every 10 seconds. Filtration was carried out for 60 minutes. The flux of the spiked mAb solution (380 LMH) remained essentially constant throughout the filtration period. The ratio of the flux at 60 minutes to the flux at 20 minutes after the start of filtration was 0.97. The total mAb filtered in 60 minutes was 1.9 kg / m 2 The LRV of the membrane-filtered Phi-X174 phage is reported in Table 1.

[0163] Example 4. Filtration of PCV2d PCV2d (above, 3.16 × 10 6 A 6 mL sample of TCID50 / mL was diluted with 143 g of PBS (1X). The total surface area of the internal hollow fibers (i.e., the total lumen surface area) was approximately 1 cm. 2 The same method as described in Example 2 was followed, except that either 4.5 mL or 10 mL of PCV2d solution was filtered through the test module.

[0164] The concentration of PCV2d in the feed solution was compared with that in the filtrate (TCID50 / mL measured using PK-15 cells) to calculate the LRV of the virus. The results are reported in Table 1.

[0165] [Table 2]

[0166] All references and publications cited herein are expressly incorporated by reference in their entirety into this disclosure. Exemplary embodiments of the invention have been discussed, and reference has been made to possible variations within the scope of the invention. For example, features illustrated in connection with one exemplary embodiment may be used in connection with other embodiments of the invention. These and other variations and modifications of the invention will be apparent to those skilled in the art without departing from the scope of the invention, and it should be understood that the invention is not limited to the exemplary embodiments described herein. Therefore, the present invention is to be limited only by the claims provided below and their equivalents.

Claims

1. A hollow fiber membrane made from a polymer blend comprising an aromatic sulfone polymer and a polyoxazoline, wherein the polymer blend comprises 27% to 30% by weight of the aromatic sulfone polymer based on the total weight of the polymer blend. The hollow fiber membrane comprises an inner surface facing its lumen, an outer surface facing the outside, and an intermediate wall having a wall thickness. A hollow fiber membrane wherein the hollow fiber membrane is a permeable hollow fiber membrane that is asymmetrical overall.

2. The hollow fiber membrane according to claim 1, wherein the aromatic sulfone polymer comprises a polysulfone or a polyethersulfone.

3. The hollow fiber membrane according to claim 1 or 2, wherein the polyoxazoline is poly(2-ethyl-2-oxazoline) (PETOx).

4. The hollow fiber membrane according to claim 1 or 2, wherein a zone having the smallest pore size is adjacent to the inner surface.

5. The hollow fiber membrane according to claim 4, wherein the zone having the largest pore size is adjacent to the outer surface.

6. The hollow fiber membrane according to claim 1 or 2, wherein a zone having the smallest pore size is adjacent to the outer surface.

7. The hollow fiber membrane according to claim 6, wherein the zone having the largest pore size is adjacent to the inner surface.

8. The hollow fiber membrane according to claim 4, wherein the size of the pores in the zone having the minimum pore size is in the range of 10 nm to 20 nm.

9. The hollow fiber membrane according to claim 4, wherein at least some of the pores in the zone having the minimum pore size or the zone having the maximum pore size are connected.

10. The hollow fiber membrane according to claim 9, wherein at least some pores in the zone having the minimum pore size or the zone having the maximum pore size are connected via channels between the pores.

11. The hollow fiber membrane according to claim 1 or 2, wherein the hollow fiber membrane has a meandering structure extending within the hollow fiber membrane.

12. The hollow fiber membrane according to claim 11, wherein at least some of the meandering structures extend from the inner surface toward the outer surface.

13. The hollow fiber membrane according to claim 1 or 2, wherein the polymer blend contains more than 7% by weight or less than 3% by weight of polyvinylpyrrolidone.

14. The hollow fiber membrane according to claim 1 or 2, wherein the polymer blend does not contain polyvinylpyrrolidone.

15. The hollow fiber membrane according to claim 4, wherein the zone having the minimum pore size has a lower flow rate than the zone having the maximum pore size.

16. The hollow fiber membrane according to claim 4, wherein the zone (retaining layer) having the minimum pore size has a thickness of 5 to 100 μm.

17. The hollow fiber membrane according to claim 1 or 2, wherein the hollow fiber membrane has a logarithmic reduction value (LRV) greater than 3 with respect to viruses or bacteriophages of 15 nm or more.

18. The hollow fiber membrane according to claim 1 or 2, wherein the hollow fiber membrane can remove viruses or bacteriophages having a wavelength of 15 nm or more.

19. Use of the hollow fiber membrane according to claim 1 or 2 for antibody filtration.

20. The antibody-containing solution is passed through the hollow fiber membrane described in claim 1 or 2, Collecting the aforementioned antibodies, Methods that include...

21. The method according to claim 20, wherein viruses or bacteriophages that are 15 nm or larger are removed from the antibody-containing solution.

22. The method according to claim 20, wherein the antibody-containing solution is a concentrated antibody solution.

Images