High-flux virus removal cellulose filtration membrane and its manufacturing process

Abstract

This application relates to a high-flux virus-removing cellulose filtration membrane, which includes a porous body with a first outer surface and a second outer surface on both sides. The porous body mainly includes a pre-filtration layer and a separation layer with an average pore size smaller than that of the pre-filtration layer. The first outer surface includes a plurality of first fibers, and adjacent first fibers form a first hole. The average pore size of the first hole is 300 - 4500 nm, the average diameter of the first fibers is 60 - 600 nm, the porosity of the filtration membrane is 15 - 50%, the PMI average pore size of the filtration membrane is 15 - 25 nm, and the flux of the filtration membrane is 35 L·h -1 ·m -2 @30 psi or more. This application further discloses the manufacturing process of the above filtration membrane. By adjusting the surface morphology of the first outer surface, the filtration membrane ensures that the deformation of the cellulose-based filtration membrane under a use pressure of 30 psi is small, has a high flux and loading capacity, and the good hydrophilicity further endows the filtration membrane with a high protein yield.

Description

Technical Field

[0001] This application relates to the field of membrane separation technology, and particularly to a high-flux virus-removing cellulose filtration membrane and its manufacturing process.

Background Art

[0002] Various biopharmaceuticals are developing vigorously because they can prevent, treat, and diagnose various infectious diseases, immune diseases, and other diseases that are difficult to prevent and treat in the usual ways. Biopharmaceuticals are generally obtained by processing effective antigen components of microorganisms (such as bacteria, rickettsia, viruses, etc.) and their metabolites, animal toxins, human or animal blood or tissues, etc. In addition to general production requirements, the production of vaccines, broad-spectrum biopharmaceuticals, etc. further has a series of characteristics. For example, generally, cultures of microorganisms, viruses, living cells, etc. are carried out, and then subsequent processing is performed on the obtained biological substances, and operations such as purification, cleaning, inactivation, extraction, freezing, freeze-drying, etc. are required.

[0003] In the production process of biopharmaceuticals, it is difficult to avoid the introduction of various viruses, which challenges the virus safety of biopharmaceuticals. Considering the important impact of viruses on the safety of biopharmaceuticals, for example, relevant documents such as the 2020 edition of the "Chinese Pharmacopoeia" and ICH Q5A "Virus Safety Evaluation of Biologics" have all put forward clear requirements for the virus safety of biopharmaceuticals. When applying for drug approval, the reported content of the virus safety evaluation test results of biopharmaceuticals also directly affects the review results. In fact, currently, for various biological and pharmaceutical companies, in the production of biopharmaceuticals, a virus removal and / or virus inactivation process is almost inevitably included to ensure the virus safety of the produced biopharmaceuticals.

[0004] Membrane separation technology has the advantages of high separation efficiency, low energy consumption, no need to add chemical reagents, being able to separate systems that cannot be separated by ordinary methods (such as azeotropic systems), being less likely to cause denaturation of active substances, and being directly applicable to large-scale production after simple expansion. Therefore, it is applied in the virus removal process of the production process of biological agents by various biological and pharmaceutical companies. Since the key point of membrane separation technology is the membrane filter (or filtration membrane), the virus filtration and removal ability of the filtration membrane directly affects the virus removal ability of the virus removal process in the production process of biological agents and also directly affects the virus safety of biological agents.

[0005] The raw materials of virus removal filtration membranes are generally polyvinylidene fluoride (PVDF), polyethersulfone (PES), and cellulose-based materials, etc. Here, the flux of PES filtration membranes is generally high, and the virus filtration and removal effect is good. However, due to the poor hydrophilicity of PES materials, the protein adsorption rate is high, and the protein yield is relatively low. The hydrophilic modified PVDF filtration membranes often have high hydrophilicity and low protein adsorption. Compared with the hydrophilic modified PVDF filtration membranes, cellulose-based filtration membranes have good hydrophilicity themselves, so the protein adsorption rate is relatively lower and often has a higher protein yield. The disadvantage of cellulose-based filtration membranes compared with PES filtration membranes is that the flux is relatively lower and the filtration efficiency is often not high.

[0006] For example, the Japanese Patent No. JP1984204911A discloses that the regenerated cellulose membrane (RC membrane) has good removal ability for human immunodeficiency virus (about 100 nm). However, it has low removal ability for viruses with sizes of 20 - 100 nm, such as hepatitis B virus (about 42 nm), nAnB hepatitis virus (30 - 60 nm), and murine minute virus (about 20 nm), so it cannot meet the current strict virus removal requirements.

[0007] For example, in a Chinese patent with the authorization announcement number CN1759924B, a multi-layer composite ultrafiltration membrane is disclosed. The composite ultrafiltration membrane includes at least one layer of a first porous membrane layer having a first surface equivalent to a second surface, and at least one layer of a second porous membrane layer having an equivalent first surface and a second surface. The first layer and the second layer are connected and stacked, and have a porosity connection transition region from the equivalent first surface of the second layer to the equivalent second surface of the first layer. Here, at least one of the layers is an asymmetric ultrafiltration membrane. Such a composite membrane has a good filtration and removal effect on micro-viruses. However, as a polyethersulfone-based filtration membrane, the composite membrane has poor hydrophilicity, high protein adsorption, and a sharp change in pore size at the interface of the filtration membrane in the thickness direction (i.e., in the vertical direction of the membrane layer, the region where the pore size of the membrane material changes rapidly) and high protein adsorption due to non-hydrophilic materials, both of which cause a reduction in protein yield.

[0008] For example, in a Chinese invention patent application document with the application number CN105980038A, a membrane for removing viruses is disclosed. It contains cellulose and has a first-side surface for receiving a protein-containing solution and a second-side surface for discharging the permeate that permeates through the virus-removing membrane. The logarithmic removal rate (Log Removal Value, LRV) for porcine parvovirus (about 18 - 26 nm) can reach 4 or more (LRV > 4). The filtration membrane belongs to the cellulose-based filtration membrane. Since cellulose has good hydrophilicity, the filtration membrane has a high protein yield. However, it is manufactured by the copper-ammonia method, which causes significant pollution, has high environmental protection costs, and requires the use of highly irritating and foul-smelling ammonia (aqueous ammonia) in the production process, which is likely to cause health problems for workers.

[0009] Currently, all the commonly seen usage methods of virus removal filtration membranes are dead-end filtration. During use, it is necessary to pressurize the raw material liquid to be filtered (the pressure reaches 30 psi and even 50 psi during integrity testing). Since the material of cellulose itself is soft, the mechanical strength of cellulose-based filtration membranes is generally poor. When the filtration membrane is deformed by the pressure applied during use, it may cause changes in the internal pore structure of the filtration membrane, and further affect the flux and loading capacity of the filtration membrane. Excessive deformation may ultimately cause the filtration membrane to rupture and break, leading to the risk of virus leakage. Therefore, the cellulose-based filtration membrane in the patent application document with the application number CN105980038A can only pressurize the raw material liquid to be filtered to about 15 psi during filtration, and this pressure is significantly lower than the operating pressure of general filtration membranes.

[0010] Reducing the pressure of the raw material liquid can reduce the deformation of the cellulose-based filtration membrane during use. However, reducing the pressure of the raw material liquid also means a decrease in the pressure difference across the filtration membrane. Since the pressure difference across the raw material liquid is the main driving force for the raw material liquid to pass through the filtration membrane, reducing the pressure of the raw material liquid often means a reduction in flux, which has a very significant impact on filtration efficiency. Currently, with the continuous expansion of the production scale of biological and pharmaceutical companies, the virus filtration and removal process of intermediate culture raw material liquids is an important process node that limits the production efficiency of biological products. Therefore, it is not advisable to solve the problem of deformation caused by the pressure of cellulose-based filtration membranes by means of reducing the pressure of the raw material liquid.

[0011] According to the above problems, in order to ensure that the cellulose-based filtration membrane has a good virus filtration and removal effect and a high protein yield, it is currently difficult to solve and urgently needs to be solved how to ensure that the cellulose-based filtration membrane can still be used normally under a high operating pressure (for example, 30 psi), maintain a high flux and loading capacity, and have no risk of virus leakage. Summary of the Invention Problems to be Solved by the Invention

[0012] In view of the drawbacks existing in the prior art, the object of the present application is to provide a high-flux virus removal cellulose filtration membrane and its manufacturing process. By adjusting the pore size and fiber diameter of the feed liquid surface with a large average pore size, the deformation of the virus removal filtration membrane under a use pressure of 30 psi is small, and it is ensured that a high virus filtration and removal ability, flux, and loading amount can still be maintained. Moreover, since the filtration membrane uses a cellulose-based raw material as the film-forming material and has good hydrophilicity, the filtration membrane has a high protein yield.

Means for Solving the Problems

[0013] According to a first aspect, the present application provides a high-flux virus removal cellulose filtration membrane and adopts the following technical solutions.

[0014] A high-flux virus removal cellulose filtration membrane, comprising a porous body having non-directional meandering passages therein. One surface of the porous body is a first outer surface, and the other surface of the porous body is a second outer surface. The porous body includes a pre-filtration layer and a separation layer for blocking viruses. The SEM (Scanning Electron Microscope) measured average pore size of the pre-filtration layer is larger than that of the separation layer. One side of the pre-filtration layer is the first outer surface. The first outer surface includes a plurality of first fibers. Adjacent first fibers are connected to each other to surround a first hole. The SEM measured average pore size of the first hole is 300 - 4500 nm, the SEM measured average diameter of the first fibers is 60 - 600 nm, the porosity of the filtration membrane is 15 - 50%, the PMI (Pore Mouth Index) average pore size of the filtration membrane is 15 - 25 nm, and the flux of the filtration membrane is 35L·h -1 ·m -2 @30 psi or more.

[0015] Optionally, the porosity of the filtration membrane is 20 - 50%.

[0016] Optionally, the PMI average pore size is 18 to 22 nm.

[0017] Optionally, the flux of the filtration membrane is 40 L·h -1 ·m -2 @ 30 psi or more, preferably, the flux of the filtration membrane is 50 L·h -1 ·m -2 @ 30 psi or more, more preferably, the flux of the filtration membrane is 60 L·h -1 ·m -2 @ 30 psi or more, still more preferably, the flux of the filtration membrane is 70 L·h -1 ·m -2 @ 30 psi or more.

[0018] By using the above technical solution, when observing the scanning electron microscope image (SEM image) of the cross-section of the filtration membrane in the present application, it can be found that the filtration membrane has an asymmetric pore structure in the thickness direction. Here, the porous body close to the first outer surface has a larger average pore size, that is, a pre-filtration layer. The pre-filtration layer filters and removes particles with large particle sizes in the raw material liquid, reduces the possibility of large-particle-size particles blocking the separation layer, and enables the filtration membrane to have a high flux and a fouling tolerance. The porous body close to the second outer surface has a relatively small average pore size, that is, a separation layer. Generally, it is considered that a separation layer has an average pore size of less than 40 nm. The separation layer can effectively block viruses of about 20 nm and reduce the virus risk of biological agents.

[0019] For cellulose-based filtration membranes, their good hydrophilicity can reduce the amount of protein blocked by the filtration membrane, thereby improving the protein yield. Currently, for the biological and pharmaceutical companies with continuously increasing production scales, a high protein yield in the virus filtration and removal process is the direction pursued by each biological and pharmaceutical company. However, due to the characteristic that the material of cellulose itself is soft, general cellulose-based filtration membranes often have poor mechanical performance (compared with hollow fiber membranes, the pressure resistance performance of flat membranes is even worse). The cellulose-based filtration membranes with poor mechanical performance will undergo large deformations when receiving a large pressure from the raw material liquid during use, which is a difficult problem to solve for current cellulose-based filtration membranes and an essential and urgent problem to be solved.

[0020] In order to reduce the virus risk of biopharmaceuticals, the virus removal filtration membrane must first have a good virus filtration and removal effect. When the porosity of the filtration membrane is 15 - 50% and the average PMI pore size is 15 - 25 nm, the relatively low porosity and small average PMI pore size can ensure that the filtration membrane has a good filtration and removal effect on small-sized viruses (for example, the typical small-sized virus PP7 phage), and its log removal rate can reach 5 and even 7 or more (that is, LRV > 5 and LRV > 7).

[0021] According to this, when the inventors of the present application control the average pore size measured by SEM of the first holes on the first outer surface to be 300 - 4500 nm and the average diameter measured by SEM of the first fibers to be 60 - 600 nm, in addition to the filtration membrane having a good virus filtration and removal effect, the flux of the filtration membrane is 35 L·h -1 ·m -2 @ 30 psi or more (that is, under a large pressure of 30 psi, the flux of the filtration membrane is 35 L·h -1 ·m -2Surprisingly, it has been found that it is possible to ensure the above, and furthermore, unexpectedly, by controlling the surface morphology of the first outer surface, the mechanical strength of the filtration membrane can be significantly improved, and not only can the filtration membrane have a high flux during use, but also a high loading capacity. This result greatly improves the inherent defect that the current cellulose-based filtration membrane has poor mechanical performance and is prone to deformation, and enables the cellulose-based filtration membrane to be used for a long time at a high operating pressure (e.g., 30 psi).

[0022] This is considered to be because when the filtration membrane is used, the one that directly contacts the raw material liquid is the first outer surface having a large-size hole structure. Therefore, the first outer surface serving as the feed liquid surface is the region where the filtration membrane is subjected to the greatest pressure. If the first outer surface of the filtration membrane undergoes too large a deformation under the action of the raw material liquid, it may cause a large deformation of the entire filtration membrane, thereby compressing the pore structure of the filtration membrane. The resistance of the raw material liquid to the compressed small-size pore structure is significantly improved, and the fouling tolerance of the small-size pore structure is also significantly reduced. Therefore, it is necessary to improve the pressure resistance capacity of the first outer surface.

[0023] Regarding the size of the first holes, the separation layer of the filtration membrane with both low porosity and small PMI average pore diameter is likely to be blocked. When large particulate matter affects the pore structure of the separation layer with low porosity, it significantly reduces the flux and loading capacity of the filtration membrane. Therefore, the pre-filter layer and the first outer surface of the filtration membrane must have a better filtration effect on large particulate matter. The first holes with an SEM-measured average pore diameter of 300 - 4500 nm on the first outer surface can ensure that the pre-filter layer extending to the first outer surface and the inside of the membrane has a good blocking effect on large particulate matter and a large fouling tolerance, reducing the possibility of large particulate matter passing through the pre-filter layer and significantly reducing the possibility of the separation layer being interfered with by large particulate matter. Since the influence of the separation layer with a small pore diameter on the flux of the filtration membrane is greater, by increasing the size of the first holes, the fouling tolerance of the pre-filter layer to large particulate matter can be improved, thereby improving the flux and loading capacity of the filtration membrane.

[0024] However, the first outer surface with a large hole structure often has poor mechanical properties. When subjected to a large external pressure, excessive deformation is likely to occur. If the pore structure of the filtration membrane collapses due to excessive deformation, both the flux and the loading capacity of the filtration membrane will significantly decrease. The inventors of the present application have discovered that when the SEM-measured average pore diameter of the first holes is large and the SEM-measured average diameter of the first fibers is 60 to 600 nm, the thick first fibers can form a strong three-dimensional network structure with a large size of the first holes but a thick and robust skeletal structure. The thick first fibers have a good supporting effect on the first holes, significantly reducing the possibility of excessive deformation when the first outer surface is subjected to pressure. When the deformation of the first outer surface shape, which is the main pressure-bearing area, is small, the overall deformation of the filtration membrane is small, the pore structure is less likely to collapse, thereby endowing the filtration membrane with good flux and loading capacity.

[0025] The above conclusion is different from the general view. Generally, when the raw material liquid passes through the filtration membrane, one of the main resistances is considered to be the resistance of the solid fiber part to the raw material liquid. Therefore, the smaller the size of the first fiber, the smaller the resistance to the raw material liquid, and the raw material liquid can pass through the first outer surface and the pre-filtration layer more quickly. However, for cellulose-based filtration membranes, within a certain range, the larger the diameter of the first fiber, the larger the flux and loading capacity of the filtration membrane, which is a very unexpected result. In addition, if the diameter of the first fiber is too small, it will further cause an increase in the specific surface area of the first outer surface or the filtration membrane (generally, the smaller the fiber diameter, the higher the specific surface area is considered). A filtration membrane with a high specific surface area often has a high protein adsorption rate in the raw material liquid, causing a decrease in protein yield. The diameter of the first fiber should not be too large either. If the diameter of the first fiber is too large, the mechanical performance of the first outer surface can be further improved, but the improvement rate of the mechanical performance becomes slower with the gradual increase of the diameter of the first fiber, showing a limiting diminishing effect. The resistance of the larger-sized first fiber to the raw material liquid gradually increases, causing a decrease in the flux of the filtration membrane. Therefore, on the premise that the average pore diameter of the first hole measured by SEM is 300 - 4500 nm, if the average diameter of the first fiber measured by SEM is too large or too small, it may lead to a decrease in the flux and loading capacity of the filtration membrane.

[0026] It should be noted that the void structure of the filtration membrane is different before and after pressure application. For example, if the average pore diameter of the filtration membrane when not in use (unpressurized) is 50 μm, it does not mean that the average pore diameter of the filtration membrane during use (after pressure application) is still 50 μm. This is because virus removal filtration membranes generally adopt the dead-end filtration method, and the raw material liquid is subjected to a large external pressure (for example, 30 psi, which may reach 50 psi or more during the integrity test). The raw material liquid directly transmits the large external pressure to the virus removal filtration membrane, causing the filtration membrane to deform towards the lower end in the flowing direction of the raw material liquid, thereby changing the porosity, average pore diameter, pore size distribution, etc. of the filtration membrane.

[0027] As can be understood, the "non-directed meandering passage" in this application refers to a groove structure with a random orientation and / or a hole structure with a discrete distribution within the porous body, and these non-directed meandering passages penetrate each other, so that the raw material liquid can permeate through the filtration membrane through the passages that penetrate each other. Viruses and large particulate matters in the raw material liquid are blocked on the feed liquid side of the filtration membrane or within the non-directed meandering passages inside the porous body, thereby achieving the effect of virus filtration and removal.

[0028] The "continuous fiber migration" in this application means that all the fibers in the membrane thickness direction of the porous body are integrally formed, all the fibers are integrally interconnected, and there is no need to adhere each fiber with a substance such as an additional adhesive. It means that the three-dimensional network-like fibers will not separate from each other unless they are torn and peeled off by an external force. At the same time, the continuously migrating three-dimensional network-like fibers are also connected to the first outer surface and the second outer surface.

[0029] Parameters such as the SEM measurement average pore size, the thickness of the layer structure, and the SEM measurement average fiber diameter in this application refer to the average values calculated after morphological characterization of the membrane structure using a scanning electron microscope and then further measurement using computer software (such as Matlab, NIS-Elements, etc.) or manually. When measuring, parts that are clearly small or clearly large in size are not considered. It should be noted as supplementary explanation that the measurement method of the porosity may be obtained by calculation using computer software (such as Matlab, NIS-Elements, etc.), or the porosity of the membrane may be measured by the gravimetric method. In terms of the test of the average pore size, in addition to the measurement and analysis of the SEM image, the average pore size of each layer may also be directly analyzed by an average pore size distribution meter, or the average pore size and the like may be tested by the bubble pressure method. The above parameter measurement methods are just examples. As can be understood, those skilled in the art can also obtain the above parameters by other measurement means.

[0030] In addition, it should be noted that since cellulose exhibits an obvious shrinkage phenomenon when dry, all the morphological parameters of the cellulose-based filtration membrane can be obtained by taking SEM images under wet conditions or freeze-drying conditions.

[0031] Optionally, the connection site of adjacent first fibers is a node, the number of first fibers connected to each node is 3 to 8, and the ratio of the SEM-measured average pore diameter of the first holes to the SEM-measured average diameter of the first fibers is 4 to 20.

[0032] Optionally, the ratio of the SEM-measured average pore diameter of the first holes to the SEM-measured average diameter of the first fibers is 4 to 10.

[0033] According to the above technical solution, the factors affecting the mechanical performance of the first outer surface or the filtration membrane include, in addition to the ratio of the pore diameter of the holes on the first outer surface to the diameter of the first fibers, the nodes connecting the first fibers. Compared with the long and thin first fibers, the short and thick node structure can play an important supporting role for the holes and the first fibers on the first outer surface.

[0034] In the process of constructing a three-dimensional network structure with the first fibers, the node serves as a structure for connecting the first fibers, playing an important supporting and reinforcing role, reducing the deformation of the filtration membrane under pressure, and improving the defect of poor mechanical strength inherent in the cellulose-based filtration membrane. However, as a substantial part of the filtration membrane, the node, like the first fiber, provides resistance to the raw material liquid. Therefore, the ratio of the node to the first fiber also needs to be strictly controlled. If the number of first fibers connected to each node is too small, it indicates that the reinforcing effect of the node in the three-dimensional network structure constructed by the first fibers is weak. Although the resistance provided by a small number of nodes to the raw material liquid is low, in the filtration membrane, the collapse of the void structure is likely to occur under the action of external pressure, causing a decrease in flux and a decrease in the loading capacity. If the number of first fibers connected to each node is too large, it indicates that the occupancy rate of the nodes in the three-dimensional network structure constructed by the first fibers is too high, and a better reinforcing effect can be achieved. However, there is a limiting diminishing effect on the reinforcing effect of the nodes (that is, as the number of nodes increases, the improvement rate of the mechanical performance of the filtration membrane slows down). At this time, the influence of the knots on the resistance of the raw material liquid is large, which instead leads to a decrease in flux. Therefore, the number of first fibers connected to each node should neither be too large nor too small, as either too large or too small may lead to a decrease in the flux and loading capacity of the filtration membrane.

[0035] It should be noted that the three-dimensional network structure of the filtration membrane is obtained by jointly constructing with the first fibers and nodes. The first fibers play a major role in constructing the skeleton, while the nodes play an important connecting and reinforcing role. When the number of first fibers connected to each node is 3 - 8, the diameter of the first fibers should not be too small. Otherwise, even if the reinforcing effect of the nodes exists, the filtration membrane is still likely to deform under pressure. The diameter of the first fibers should not be too large. After the diameter of the first fibers increases, the resistance received by the raw material liquid is large, and the filtration membrane is not easily deformed under pressure. However, for a filtration membrane with a diameter of the first fibers that is too large, even if it does not deform at all, the flux of the non-deformed filtration membrane itself is low, so a high flux cannot be obtained.

[0036] If the ratio of the SEM-measured average pore diameter of the first holes to the SEM-measured average diameter of the first fibers is too large, it indicates that the diameter of the first fibers is too small. First fibers with too small a diameter cannot form good support for the holes, and the holes are likely to collapse when pressured, not only causing deformation of the filtration membrane under pressure but also further leading to a decrease in protein yield. If the ratio of the SEM-measured average pore diameter of the first holes to the SEM-measured average diameter of the first fibers is too small, although the mechanical properties of the first outer surface can be further improved, the rate of improvement in mechanical properties slows down with the gradual increase in the diameter of the first fibers. The resistance of the larger-sized first fibers to the raw material liquid also increases, causing a decrease in the flux of the filtration membrane. Therefore, the ratio of the SEM-measured average pore diameter of the first holes to the SEM-measured average diameter of the first fibers needs to be strictly controlled.

[0037] As can be understood, in the structure constituting the first outer surface, the differences between the nodes and the first fibers are mainly that their sizes and shapes are different. First, the size of the nodes is larger than that of the first fibers. Second, the shape of the first fibers is mainly elongated, while the nodes may be irregular lump-like structures or strip-like structures with a large aspect ratio, or may be shapes similar to polygons.

[0038] That is, when the SEM-measured average pore diameter of the first holes is 300 - 4500 nm, the SEM-measured average diameter of the first fibers is 60 - 600 nm, the number of the first fibers connected to each node is 3 - 8, and the ratio of the SEM-measured average pore diameter of the first holes to the SEM-measured average diameter of the first fibers is 4 - 20, it can be ensured that the three-dimensional network structure of the first outer surface of the filtration membrane has strong mechanical stability, and because the resistance to the raw material liquid is small, a filtration membrane with good comprehensive flux and loading capacity can be obtained.

[0039] Optionally, the density of the nodes is 2 - 15 pieces / μm 2 and the average area of the nodes is (0.2 - 1.5)×10 5 nm 2 and the area occupancy rate of the nodes is 20 - 50%, and the hole area ratio of the first outer surface is 5 - 40%.

[0040] According to the above technical solution, since the diffusion movement of the raw material liquid in the film thickness direction must avoid the solid fibers and nodes, generally, if there are too many fibers and nodes and their size is too large, it is considered that the resistance force received by the raw material liquid will increase. Therefore, generally, the lower the area occupancy rate of the nodes, the better. However, the inventors of the present application have discovered that within a certain range, the higher the node density, the average area of the nodes, and the area occupancy rate of the nodes, the better. This is presumably because the node density within a unit area characterizes the compactness of the three-dimensional network structure to a certain extent. The higher the density of the nodes, the more the nodes and the first fibers can cooperate to form a more stable three-dimensional network structure, with higher strength but lower porosity. The lower the density of the nodes, the more the nodes and the first fibers can cooperate to form a more sparse three-dimensional network structure, with lower strength but higher porosity. Both the strength and porosity of the three-dimensional network structure have a certain influence on the flux and protein yield of the filtration membrane, but the degree of influence of the two is not the same. The inventors of the present application have found that when the density of the nodes on the first outer surface is 2 to 15 pieces / μm 2 and the hole area ratio is 5 to 40%, it is discovered that the filtration membrane can obtain high flux and protein yield.

[0041] In addition to this, the important reinforcing effect that the nodes play in the three-dimensional network structure is affected by their size. If the average area of the nodes is too small (i.e., the size of the nodes is too small), even if the area occupancy rate of the nodes is large, the reinforcing effect on the three-dimensional network structure is not obvious (the difference from the size of the first fibers is small, and the reinforcing effect is small). If the average area of the nodes is too large (i.e., the size of the nodes is large), although the reinforcing effect on the three-dimensional network structure is good, if the resistance force on the raw material liquid is too large, it will conversely cause a decrease in flux (even if the filtration membrane does not deform, the resistance force received by the raw material liquid is too large, and the flux is small).

[0042] The inventors of the present application found that when 3 to 8 first fibers are connected to each node, the average diameter of the first fibers measured by SEM is 60 to 600 nm, and the density of the nodes is 2 to 15 nodes / μm 2 and the average area of the nodes is (0.2 to 1.5)×10 6 mm 2 and the area occupancy of the nodes is 20 to 50%, the filtration membrane has a good virus filtration and removal effect and clearly has a much higher flux and loading capacity. This is presumably because when the size of the first fiber is small, denser nodes are required to support the first fiber, thereby ensuring that the holes do not collapse due to pressure. When the size of the first fiber is large, since the self-supporting effect of the first fiber is good, the distribution density of the nodes may decrease, thereby reducing the resistance of the solid nodes to the raw material liquid. That is, by the cooperation of the node density, the size of the first fiber, the number of the first fibers connected to the nodes, etc., it can be ensured that the filtration membrane can obtain a higher flux and loading capacity.

[0043] Optionally, the average length of the first fibers between two adjacent nodes is 100 to 1000 nm, and the aspect ratio of the first fibers between two adjacent nodes is 1 to 10.

[0044] Optionally, the aspect ratio of the first fibers between two adjacent nodes is 1.5 to 5.

[0045] According to the above technical solution, the mechanical properties of the three-dimensional network structure formed by the nodes and the first fibers are mainly affected by the nodes and the first fibers. The inventors of the present application found that for the first fibers, even if their average diameter measured by SEM is the same, the average length and different aspect ratios of the first fibers between two nodes also cause a significant change in the flux of the filtration membrane.

[0046] This indicates that when the length of the first fiber between two nodes is too large and the aspect ratio is too large, the average pore diameter of the first holes on the first outer surface is often large, and the diameter of the first fiber is often small. Larger-sized holes often require higher support force, and as the size of the holes improves, the requirement of the holes for the support force does not improve linearly but accelerates. Therefore, the holes formed by the first fibers with too large a length and too large an aspect ratio are likely to collapse under pressure, resulting in a decrease in the flux and loading capacity of the filtration membrane during actual use.

[0047] When the length of the first fiber between two nodes is small and the aspect ratio is too small, it often indicates that the average pore diameter of the first holes on the first outer surface is small. The first fiber and the nodes can form a good support effect on the holes, but the small-sized holes on the first outer surface are easily blocked by large particulate matter, and the resistance to the raw material liquid by the overly dense nodes and the first fiber is too large. Both of these two factors will lead to a decrease in the loading capacity and flux of the filtration membrane.

[0048] Optionally, each first hole is formed surrounded by an average of 4 to 15 nodes and the first fibers between the nodes, and the size change rate of the first fibers between two adjacent nodes is 5 to 30%.

[0049] According to the above technical solution, the inventors of the present application unexpectedly discovered that on the premise that parameters such as the size of the first fiber and the nodes are almost the same, the number of nodes forming the holes and the size change rate of the first fiber have a very obvious influence on the flux of the filtration membrane.

[0050] In a three-dimensional network structure formed by nodes and first fibers, the nodes and the first fibers cooperate to support the first holes. If the number of nodes constituting each first hole is too small, it will not only cause a decrease in the supporting force received by the first holes (fewer nodes are more likely to cause stress concentration, leading to a decrease in the pressure-bearing capacity of the first holes and making collapse more likely to occur), but also cause a decrease in the roundness of the first holes. For hole structures with the same area, the circular hole structure has a smaller resistance to the material liquid compared to the non-circular hole structure, and the pressure-bearing capacity of the circular hole structure is also higher, which is considered to have a higher flux and loading capacity. If the number of nodes constituting each first hole is too large, the roundness of the first holes will improve, and the supporting force received will also be greater, but it will reduce the resistance of the first holes themselves to the raw material liquid. However, the excessive resistance formed by the excessive nodes and first fibers to the raw material liquid is greater than the reduction value of the resistance of the first holes to the raw material liquid, resulting in a decrease in the flux of the filtration membrane.

[0051] In addition, the greater the size change rate of the first fibers, the more irregular the virtual geometric structure surrounded by the edges of the formed holes. Although a first hole with high roundness can be formed by multiple first fibers, if the size of the first fibers changes significantly in the length direction, that is, if the first fibers have a protruding or concave structure in the length direction, these protruding or concave structures will improve the irregularity of the first holes and reduce the roundness of the first holes, thereby increasing the resistance of the first holes to the filtrate. Note that a large size change rate of the first fibers often means a low uniformity of the mechanical strength of the first fibers. When the filtration membrane receives external pressure, the weak parts of the first fibers may collapse, leading to the collapse of the hole structure and a decrease in the flux of the filtration membrane.

[0052] As can be understood, roundness refers to the degree of approximation between the virtual geometric structure surrounded by the edge of the hole and a circle. Since a circle is considered to approximate a polygon surrounded by countless sides, the more first fibers that make up the hole, the closer the hole is to a circle and the higher the roundness.

[0053] Optionally, the bubble point of the filtration membrane is 0.8 to 1.6 MPa.

[0054] According to the above technical solution, when the bubble point of the filtration membrane is 0.8 to 1.6 MPa, the filtration membrane not only has a good virus filtration and removal effect, but also has a high flux. This is because both the porosity and the PMI average pore diameter of the filtration membrane are low, and the feed liquid receives a large resistance in the thickness direction of the filtration membrane. If there is a part of the region with a large pore diameter in the filtration membrane, the resistance received by the feed liquid in this region is small and the flux is large. Therefore, the feed liquid may gather in the low-resistance region and cause breakthrough, thereby increasing the risk of virus leakage of the filtration membrane. The inventors of the present application have discovered that when the bubble point of the filtration membrane is 0.8 to 1.6 MPa, such a phenomenon hardly occurs. This is considered to be because when the bubble point of the filtration membrane is high, even if there are defects in the filtration membrane, it is difficult for these defects to break through in a 30 psi filtration system. Therefore, in a 30 psi filtration system, when the bubble point of the filtration membrane is 0.8 to 1.6 MPa, it can be ensured that the filtration membrane has good performance stability.

[0055] Optionally, the second outer surface has second holes, the SEM measurement average pore diameter of the second holes is 25 to 35 nm, the ratio of the SEM measurement average pore diameter of the first outer surface to that of the second outer surface is 10 to 150, and the hole area ratio of the second outer surface is 2 to 15%.

[0056] According to the above technical solution, the ratio of the SEM-measured average pore diameter of the first outer surface to that of the second outer surface approximately indicates the change gradient of the pore diameter in the membrane thickness direction of the entire filtration membrane, and approximately indicates the relative relationship of the void structure between the pre-filter layer and the separation layer. If the ratio of the SEM-measured average pore diameter of the first outer surface to that of the second outer surface is too large, it often means that the SEM-measured average pore diameter of the pre-filter layer is too large or the SEM-measured average pore diameter of the separation layer is too small. In either case, it will lead to a reduction in the flux and service life of the filtration membrane. If the ratio of the average pore diameter of the first outer surface to that of the second outer surface is too small, it means that the average pore diameter of the pre-filter layer is too small or the average pore diameter of the separation layer is too large. The former is likely to cause a decrease in the service life of the filtration membrane, and the latter is likely to cause a decrease in the virus filtration and removal effect of the filtration membrane.

[0057] Optionally, the porosity of the pre-filter layer is 30-70%, the SEM-measured average pore diameter of the pre-filter layer is 150-500 nm, the SEM-measured average pore diameter of the pre-filter layer gradually decreases from near the first outer surface to near the second outer surface, and the reduction rate of the pore diameter near the first outer surface of the pre-filter layer is greater than that near the second outer surface of the pre-filter layer.

[0058] According to the above technical solution, in order to ensure that the influence of large particulate matter on the separation layer is small due to the first holes with large pore diameters on the first outer surface, the pre-filter layer must have a good blocking effect and dirt tolerance for large particulate matter. Since the change rate of the pore diameter of the pre-filter layer first increases rapidly and then decreases slowly, the pore diameter at the upper end of the pre-filter layer (the side close to the first outer surface) decreases rapidly, forming a region of rapid pore diameter change. The influence of this rapid change region on the flow of proteins and small-sized viruses is small, but the influence on large particulate matter is extremely large. By cooperating with the pore size of the pre-filter layer that is significantly lower than that of the first holes (the SEM-measured average pore diameter of the pre-filter layer is 150 - 500 nm, and the SEM-measured average pore diameter of the first holes is 300 - 4500 nm), it can be ensured that the upper end of the pre-filter layer has a good blocking effect on large particulate matter, and the possibility of large particulate matter leaking from the pre-filter layer and affecting the separation layer can be reduced. The change in the pore diameter at the lower end of the pre-filter layer (because it is close to the second outer surface) is small. By cooperating with the porosity of the pre-filter layer up to 30 - 70%, the dirt tolerance of the pre-filter layer can be improved, ensuring that the pre-filter layer can accommodate a sufficient amount of large particulate matter and improving the loading capacity of the filter membrane. Therefore, for the pre-filter layer, due to the porosity, the SEM-measured average pore diameter of 150 - 500 nm, and the pore diameter change trend, it is ensured that the filter membrane has a high flux and loading capacity while the size of the first holes is large.

[0059] Optionally, the pre-filter layer includes long support fibers, the support fibers are connected to each other to form the void structure of the pre-filter layer, the SEM-measured average diameter of the support fibers is 60 - 350 nm, and the ratio of the SEM-measured average pore diameter of the pre-filter layer to the SEM-measured average diameter of the support fibers is 0.5 - 3.5.

[0060] Optionally, the ratio of the SEM-measured average pore diameter of the pre-filter layer to the SEM-measured average diameter of the support fibers is 1.0 - 2.5.

[0061] According to the above technical solution, after the first outer surface, the preliminary filtration layer is the area with a large pressure in the filtration membrane and the main area determining the blocking effect on large particle substances and the fouling tolerance of the filtration membrane. Therefore, for a specific cellulose-based filtration membrane, the importance of the preliminary filtration layer is extremely high. If the hole structure collapses when the preliminary filtration layer is under pressure, it may lead to a decrease in the fouling tolerance of the preliminary filtration layer. The separation layer is easily affected by large particle substances, thereby causing a decrease in the flux and loading capacity of the filtration membrane.

[0062] Compared with the first hole with a large pore diameter, generally, it is considered that the support force required for the void structure with a small SEM-measured average pore diameter of the preliminary filtration layer is significantly reduced. However, the preliminary filtration layer has a certain thickness, and the density of the formed three-dimensional network structure is relatively low. Moreover, the preliminary filtration layer is actually the main pressure-bearing area in the thickness direction of the filtration membrane. The void structure of the preliminary filtration layer with a poor original pressure resistance requires stronger support to ensure that the preliminary filtration layer does not deform excessively under a large external pressure (30 psi).

[0063] The inventors of the present application have discovered that when the ratio of the SEM-measured average pore diameter of the preliminary filtration layer to the SEM-measured average diameter of the support fibers is 0.5 to 3.5 and the average diameter of the support fibers is 60 to 350 nm, the mechanical performance of the preliminary filtration layer itself is strong. In cooperation with the stable three-dimensional network structure of the first outer surface, the preliminary filtration layer with a poor original pressure resistance is less likely to collapse due to external pressure. At this time, the preliminary filtration layer and the first outer surface cooperate with each other and can also exert a strong reinforcing effect on the separation layer. Thereby, when the filtration membrane is used, the whole filtration membrane is not likely to be deformed too much due to a large external pressure, ensuring that the filtration membrane simultaneously has a good virus filtration and removal effect, high flux, and high loading capacity.

[0064] When the ratio of the SEM-measured average pore diameter of the preliminary filtration layer to the SEM-measured average diameter of the support fibers is too large, the average pore diameter of the preliminary filtration layer is large, or the support fibers are thin. The preliminary filtration layer with a structure of large pores and thin fibers theoretically has a larger dirt tolerance, but since the collapse of the void structure is likely to occur under pressure, it instead leads to a decrease in the dirt tolerance. And the blocking effect of the preliminary filtration layer with a structure of large pores and thin fibers on large particulate matter is often poor, greatly improving the probability that the separation layer is affected by large particulate matter. When the separation layer is blocked by large particulate matter, the flux of the filtration membrane is significantly reduced. When the ratio of the SEM-measured average pore diameter of the preliminary filtration layer to the SEM-measured average diameter of the support fibers is too small, the average pore diameter of the preliminary filtration layer is small, or the support fibers are thick. Such a structure with small pores and thick fibers often has little deformation under pressure, but has too great an impact on the flux and loading capacity of the filtration membrane. Even if the filtration membrane does not deform under pressure, a high flux and loading capacity cannot be obtained.

[0065] Optionally, one side of the separation layer is the second outer surface, the thickness of the separation layer is 10 - 60 μm, and the ratio of the thickness of the separation layer to the thickness of the porous body is 40 - 95%.

[0066] According to the above technical solution, when the thickness of the porous body is small, the flow path of the raw material liquid in the membrane thickness direction is short and the resistance is small. When the resistance is small, the filtration membrane often has a high flux. However, the filtration and removal effect of the short-distance meandering passage on viruses is often poor. When the thickness of the porous body is large, the flow path of the raw material liquid in the membrane thickness direction is long and the resistance is large. A longer meandering passage can often obtain a better virus filtration and removal effect, but it often means a decrease in flux.

[0067] Therefore, generally, regardless of whether the thickness of the porous body is large or small, it is often considered necessary to make a choice between flux and virus filtration and removal effect. By adjusting the membrane structure, it is possible to reduce the influence on the flux of the filtration membrane to a certain extent while obtaining a high virus filtration and removal effect. However, a high virus filtration and removal effect and high flux often cannot be achieved simultaneously.

[0068] However, the inventors of the present application unexpectedly discovered that for a filtration membrane with a separation layer occupancy rate reaching 40-95%, when the filtration membrane deforms under pressure, the changes in the pore structures of each part of the separation layer are different. For example, when the filtration membrane is under pressure, it bulges and deforms towards the drainage side (the second outer surface). At this time, the pore structures of the first outer surface, the pre-filter layer, and the part of the separation layer close to the first outer surface are all subject to a pressing force, so the pore structure may be compressed. The pore structures of the part of the separation layer close to the second outer surface are all subject to a tensile force, so the pore structure may be stretched. That is, some of the pore structures of the separation layer close to the first outer surface are compressed, and some of the pore structures of the separation layer close to the second outer surface are stretched. Such a phenomenon may not exist in a filtration membrane with a low separation layer occupancy rate (since the separation layer is close to the second outer surface, the separation layer may only be subject to a tensile force, and the pore structure is stretched).

[0069] Therefore, for a filtration membrane with a high occupancy rate of the separation layer thickness, since the distance between the separation layer and the first outer surface is not large, the deformation mode of the separation layer near the first outer surface is mainly compression, and the deformation mode of the separation layer near the second outer surface is mainly tension. Such a deformation mode causes the average pore size of the first outer surface, the pre-filter layer, and the part of the separation layer near the first outer surface to become smaller due to compression, resulting in the formation of a region with a small pore size in the filtration membrane, and the void structure of the second outer surface and the part of the separation layer near the second outer surface to become larger due to tension. Since the main influencing factor of the flux of the filtration membrane is the small pore size void structure in the separation layer, and its influence is greater than the void structures of the pre-filter layer and the first outer surface, when the average pore size of the separation layer is small and further becomes smaller under pressure, it will cause a significant decrease in the flux of the filtration membrane.

[0070] That is, generally speaking, when the filtration membrane is made of a cellulose-based material, it is considered that the occupancy rate of the separation layer should not be high. This is because the cellulose material is soft, the cellulose-based filtration membrane is easy to deform, and compared with a filtration membrane with a small occupancy rate of the separation layer, the deformation occurring in a filtration membrane with a large occupancy rate of the separation layer has a greater impact on the filtration membrane flux. Therefore, it is not preferable to make both the cellulose-based material and a high separation layer occupancy rate compatible.

[0071] However, the inventors of the present application found that because the pore size of the separation layer is relatively small and the formed three-dimensional network structure is denser, it originally has a high self-supporting effect and is relatively at the lower position, so the pressure it receives is smaller than that of the first outer surface and the pre-filter layer. Moreover, the first outer surface and the pre-filter layer form a stable and high-pressure-resistant three-dimensional network structure, thereby forming a certain degree of structural reinforcement for the separation layer, and thereby reducing the deformation of the entire filtration membrane under a pressure of 30 psi. Therefore, even if the separation layer has a large occupancy rate and a cellulose-based material is adopted, the filtration membrane can still obtain a large flux and loading capacity, and this result is very unexpected.

[0072] That is, for a filtration membrane with a high occupancy rate of the thickness of the separation layer, the appropriate holes on the first outer surface, the ratio of the sizes of the first fibers, and the strong three-dimensional network structure with high pressure resistance formed by the pre-filter layer can all reduce the deformation of the filtration membrane after pressure application. Thereby, in the separation layer, the possibility that the void structure collapses due to pressure and a small pore diameter region is generated is reduced, ensuring that the filtration membrane has high flux and high loading capacity during use.

[0073] Optionally, the porosity of the separation layer is 6 - 30%, the average pore diameter measured by SEM of the separation layer is 35 - 85 nm, and the average pore diameter change gradient measured by SEM of the separation layer from near the first outer surface to near the second outer surface is 2 nm / μm or less.

[0074] According to the above technical solution, for a filtration membrane capable of filtering and removing 20 nm viruses, although the average pore diameter measured by SEM of the separation layer is significantly large at 35 - 85 nm, the large average pore diameter measured by SEM cooperates with the high occupancy rate and large thickness of the separation layer to effectively block viruses with a size of 20 nm, thereby giving the filtration membrane a good virus filtration and removal effect and high flux.

[0075] This is presumably because compared with a filtration membrane with a low occupancy rate of the separation layer, a filtration membrane with a high occupancy rate of the separation layer has a thicker small pore meandering passage structure in terms of membrane thickness, so a lower PMI average pore diameter can be obtained with a large average pore diameter measured by SEM. In such a filtration membrane, even if the average pore diameter measured by SEM of the separation layer is large, due to the large thickness of the separation layer, a good virus filtration and removal effect can still be obtained.

[0076] According to this, although the thickness of the separation layer is large and the average pore size of the PMI is small, the actual pore size is larger than that of a filtration membrane with a low occupancy rate of the separation layer (if the actual pore size of the separation layer of a filtration membrane with a low occupancy rate of the separation layer is large, combined with the short small pore meandering passage structure in the membrane thickness direction, often the required virus rejection rate cannot be obtained. Therefore, a filtration membrane with a low occupancy rate of the separation layer often has a small actual pore size to block 20-nm viruses). Due to the large actual pore size, even if the thickness of the separation layer is large, the resistance to the raw material liquid is not large. Combined with the first holes on the first outer surface supported by the thick first fibers with a large pore size, the deformation of the filtration membrane during actual use is reduced, so that the filtration membrane not only has a good virus filtration and removal effect during actual use, but also can further have high flux and high loading capacity.

[0077] Optionally, the change gradient of the average pore size of the separation layer from near the first outer surface to near the second outer surface is 1 nm / μm or less, and preferably, the change gradient of the average pore size of the separation layer from near the first outer surface to near the second outer surface is 0.5 nm / μm or less.

[0078] According to the above technical solution, the factor that has the greatest impact on the flux and virus filtration and removal effect of the filtration membrane is the separation layer. When the occupancy rate of the thickness of the separation layer is 40-95%, in order to obtain a good virus filtration and removal effect, the average pore size of the separation layer may be appropriately increased to 35-85 nm, and its porosity may be appropriately increased to 6-30%. At this time, the separation layer can ensure having a good virus filtration and removal effect and reduce the impact on the flux.

[0079] Note that the inventors of the present application have discovered that even if the porosity and the SEM-measured average pore diameter of the separation layer are substantially the same, the flux of the filtration membrane still fluctuates greatly. The higher the asymmetry of the separation layer (the greater the change in the SEM-measured average pore diameter in the filtration membrane thickness direction of the separation layer, the greater the change gradient of the SEM-measured average pore diameter is considered to be), the lower the flux of the filtration membrane. This indicates that, on the premise that the SEM-measured average pore diameter of the separation layer is substantially the same, if the asymmetry of the separation layer is high, the separation layer has regions with large pore diameters and regions with small pore diameters. Here, it is considered that the influence of the region with small pore diameters on the flux of the filtration membrane is extremely large. For a substantially symmetric filtration membrane, since the pore diameters of each region are substantially the same, the small pore region does not affect the flux of the filtration membrane, and the flux of the filtration membrane is often high.

[0080] Optionally, the separation layer includes long separation fibers, the separation fibers are connected to each other to form the void structure of the separation layer, the SEM-measured average diameter of the separation fibers is 20 to 50 nm, and the ratio of the SEM-measured average pore diameter of the separation layer to the SEM-measured average diameter of the separation fibers is 1 to 3.

[0081] Optionally, the ratio of the average pore diameter of the separation layer to the average diameter of the separation fibers is 1.5 to 2.5.

[0082] According to the above technical solution, when the ratio of the SEM-measured average pore diameter of the first holes to the SEM-measured average diameter of the first fibers is controlled within a reasonable range, the mechanical performance of the entire filter membrane can be improved. However, when the size of the first holes is large, a greater supporting force is required. It should be noted that as the fiber diameter increases, the supporting force that the fibers can provide increases almost exponentially. Therefore, the pore size of the void structure of the separation layer is clearly much smaller, the structure is denser, and the self-supporting effect of the formed three-dimensional network structure is good. However, the diameter of the separation fibers is also clearly smaller, and the supporting force that they can provide decreases exponentially compared to the first fibers with a large diameter. Therefore, regarding the ratio of the size of the first holes to the size of the first fibers and the ratio of the pore size of the separation layer to the size of the separation fibers, there is no direct comparison meaning between the two. Their systems are different, the formed three-dimensional network structures are different, the supporting forces required for the pore structures are different, and the supporting forces that the fibers can provide are different. Since the influence of the void structure of the separation layer on the filter membrane flux and the virus filtration and removal effect is the greatest, the influence of the void structure and fiber structure of the separation layer itself on the performance of the filter membrane is significant. When the flux of the separation layer decreases significantly, it will inevitably lead to a significant decrease in the flux of the filter membrane.

[0083] The inventors of the present application have discovered that when the ratio of the SEM-measured average pore diameter of the separation layer to the SEM-measured average diameter of the separation fibers is 1 to 3 and the average pore diameter of the separation layer is 20 to 50 nm, the separation fibers can well support the void structure of the separation layer, and it is difficult for compression deformation to occur due to external pressure. Through the cooperation of the reasonable void and fiber structure of the separation layer and the reasonable void and fiber structure of the first outer surface, a filter membrane with a high occupancy rate of the separation layer can be given high mechanical performance. When the filter membrane is subjected to external pressure, it is ensured that in the part of the separation layer close to the first outer surface, the compression phenomenon of the obvious void structure hardly occurs, thereby ensuring that the filter membrane simultaneously has a good virus filtration and removal effect and high flux.

[0084] When the ratio of the SEM-measured average pore diameter of the separation layer to the SEM-measured average diameter of the separation fibers is too large, the SEM-measured average pore diameter of the separation layer is large, or the separation fibers are thick and the pores are large, and the separation layer structure with thin fibers is prone to deformation when subjected to external pressure, leading to a decrease in flux. Even if the separation layer with large pores and thin fibers has a large thickness, it cannot maintain a good blocking effect against viruses, and there is a possibility that the virus filtration and removal effect of the filtration membrane cannot meet the requirements. When the ratio of the SEM-measured average pore diameter of the separation layer to the SEM-measured average diameter of the separation fibers is too small, the SEM-measured average pore diameter of the separation layer is small, or the separation fibers are thick. For a filtration membrane with a high original occupancy rate of the separation layer, the resistance of the dense separation layer to the raw material liquid is large. The separation layer with small pores and thick fibers will inevitably have too large a resistance to the raw material liquid. Such a structure often has a good virus filtration and removal effect, but the flux and loading amount will inevitably decrease significantly.

[0085] Optionally, the SEM-measured average pore diameter of the first holes is 1000 - 4500 nm, the porosity of the filtration membrane is 25 - 50%, the thickness of the separation layer is 10 - 30 μm, the ratio of the thickness of the separation layer to the thickness of the porous body is 40 - 70%, and the flux of the filtration membrane is 60 - 180 L·h -1 ·m -2 @ 30 psi.

[0086] According to the above technical solution, when the ratio of the thickness of the separation layer to the thickness of the porous body is 40 - 70%, the occupancy rate of the thickness of the separation layer is relatively low, and the occupancy rate of the thickness of the pre-filter layer is relatively high. The filtration membrane often has a large porosity, flux, and loading amount. The high flux and loading amount impose higher requirements on the dirt tolerance of the pre-filter layer. Therefore, the SEM-measured average pore diameter of the first holes is relatively large, thereby providing a larger dirt tolerance. Even if the SEM-measured average pore diameter of the first holes is large, the thick pre-filter layer can achieve a good blocking effect against large particle substances, and the separation layer is still less affected by large particle substances.

[0087] Optionally, the SEM-measured average pore diameter of the first holes is 300 to 2,500 nm, the porosity of the filtration membrane is 15 to 45%, the thickness of the separation layer is 20 to 50 μm, the ratio of the thickness of the separation layer to that of the porous body is 60 to 95%, and the flux of the filtration membrane is 35 to 130 L·h -1 ·m -2 @ 30 psi.

[0088] According to the above technical solution, when the ratio of the thickness of the separation layer to that of the porous body is 60 to 95%, the occupancy of the thickness of the separation layer is relatively high. At this time, the preliminary filtration layer must achieve a good large-particle substance blocking effect. Therefore, the SEM-measured average pore diameter of the first holes is relatively low, thereby ensuring that the preliminary filtration layer with a small thickness can effectively block large-particle substances, and thereby reducing the possibility that large-particle substances leak from the preliminary filtration layer and affect the separation layer.

[0089] According to a second aspect, the present application provides a manufacturing process for a high-flux virus-removing cellulose filtration membrane, and adopts the following technical solutions.

[0090] A manufacturing process for a high-flux virus-removing cellulose filtration membrane, comprising: Step S1 of manufacturing a membrane casting solution and casting it on a carrier to form a liquid film, wherein the membrane casting solution contains 10 to 30 parts of cellulose acetate, 30 to 60 parts of a first good solvent, 20 to 40 parts of a pore-forming agent, and 1 to 5 parts of an inorganic salt; Step S1 in which the pore-forming agent is a poor solvent with a surface tension of 25 dyne / cm or less; Step S2 of performing preliminary phase separation, immersing the liquid film in a preliminary phase separation liquid, performing preliminary phase separation with a preliminary phase separation time of 2 to 10 s to obtain a semi-finished product membrane, wherein the preliminary phase separation liquid contains a second good solvent and a non-solvent, and the volume occupancy of the non-solvent is 30 to 60%; Step S3 of performing phase separation coagulation, immersing the semi-finished product membrane in a coagulation bath, performing phase separation hardening, with the temperature of the coagulation bath being 20 to 45°C, the temperature of the coagulation bath being 5 to 15°C higher than the temperature of the carrier, and the duration of phase separation coagulation being 20 to 60 s to obtain a formed membrane, wherein the coagulation bath is water.

[0091] Optionally, the pore-forming agent is at least one of ethanol, 1-propanol, hexafluoroisopropanol or trifluoroethanol.

[0092] According to the above technical solution, the membrane casting solution can phase-transition in the preliminary sub-phase solution, and the non-solvent can promote the sub-phase separation of the originally homogeneous membrane casting solution into a solvent-rich phase and a polymer-rich phase. The solvent-rich phase finally removes the void structure forming the filtration membrane, and the polymer-rich phase forms the solid part of the filtration membrane (e.g., the first fibers on the first outer surface) after curing.

[0093] The phase-transition process is the main stage that affects the void structure of the filtration membrane. This process determines the final distribution of each component in the membrane casting solution. For the first outer surface, the preliminary sub-phase stage can basically determine the void structure of the first outer surface of the finally manufactured filtration membrane. In this application, the preliminary sub-phase solution is formulated using a non-solvent and an organic solvent. Here, the non-solvent plays a main role in promoting phase transition. However, the addition of the organic solvent can control the phase-transition process of the first outer surface by controlling the content of the non-solvent in the preliminary sub-phase solution, thereby not only controlling the void structure of the first outer surface, but also improving the stability of the preliminary sub-phase of the first outer surface, improving the uniformity of each void structure of the first outer surface, and reducing the possibility of defects caused by a non-uniform phase-transition process on the first outer surface.

[0094] The blending ratio of the second good solvent and the non-solvent in the preliminary phase-separated liquid needs to be strictly limited. If the occupancy rate of the non-solvent in the preliminary phase-separated liquid is too high, not only is there a possibility that a dense skin layer structure will occur on the first outer surface, but it is also likely to cause the generation of defects due to non-uniform phase separation. If the occupancy rate of the non-solvent in the preliminary phase-separated liquid is too low, the phase separation rate on the first outer surface is too slow, the dilution of the second good solvent for the membrane casting solution on the first outer surface is excessive, and over time, the second good solvent penetrates into the membrane casting solution, thereby forming a hole structure that is too large in the thick membrane casting solution. Since the too-large hole structure cannot obtain effective support from the fibers, there may be collapse due to pressure during use, which instead leads to a decrease in the flux and loading capacity of the filtration membrane, and a decrease in the filtration and removal effect of the preliminary filtration layer of the filtration membrane on large particulate matter.

[0095] It should be noted that since a pore-forming agent and inorganic salts are added to the membrane casting solution, in the process where the preliminary phase-separated liquid acts on the first outer surface to cause phase transition, the pore-forming agent and the second good solvent in the preliminary phase-separated liquid cooperate (the surface tension of the pore-forming agent is extremely low), which can promote the penetration of the preliminary phase-separated liquid into the membrane, thereby obtaining a better preliminary phase separation effect and ensuring the stable implementation of the preliminary phase separation. The inorganic salts cooperate with the non-solvent in the preliminary phase-separated liquid to promote the implementation of the phase transition, enabling the preliminary phase-separated liquid to have a lower non-solvent content, be more stable, and obtain a better phase separation effect.

[0096] After performing the preliminary phase separation treatment on the first outer surface, the semi-finished membrane is placed in a coagulation bath. The coagulation bath quickly penetrates into the membrane through the hole structure on the first outer surface and the passage formed by the pore-forming agent. During this process, the pore-forming agent added to the membrane casting solution plays an important role in the penetration of the coagulation bath. By quickly penetrating into the membrane, the coagulation bath can promote the rapid phase transition inside the membrane and harden it into a separation layer structure with a small pore diameter. If the coagulation bath cannot quickly penetrate into the membrane, the phase transition rate inside the membrane will slow down, leading to a large size of the generated void structure, and generating an obviously asymmetric separation layer structure, which may also affect the virus filtration and removal effect and the flux of the filtration membrane.

[0097] As the pore former in this application, a substance with low surface energy is selected. Compared with the currently commonly used pore formers with high surface energy (for example, polyvinylpyrrolidone with a surface energy of about 60 - 65 dyne / cm), the pore former with low surface energy is more likely to induce infiltration into the interior of the membrane in the coagulation bath, thereby forming a void structure with appropriate size. Moreover, during phase separation and curing, the pore former with low surface tension is more likely to be further concentrated on the side of the membrane casting solution closer to the air. Combined with the non-solvent in the preliminary phase separation liquid, it can promote the phase transition of the first outer surface. In addition, the pore former with low surface energy and the coagulation bath can quickly dissolve in each other, promote uniform dispersion in the membrane casting solution of the coagulation bath, and improve the uniformity of the void structure of the separation layer. This is very important for the system with a high occupancy rate of the separation layer and a large pore size in the separation layer in this application. If the phase separation uniformity of the separation layer is poor, the distribution of the void structure in the separation layer will be non-uniform. Here, the combination of the region with a small pore size and the thick separation layer may lead to a significant decrease in the flux and loading capacity of the filtration membrane. Therefore, by adding an appropriate amount of pore former to the membrane casting solution, inducing the penetration and entry of the coagulation bath into the interior of the membrane casting solution, quickly reaching the coagulation bath to the side closer to the carrier of the membrane casting solution, and through rapid phase separation in the thickness direction of the membrane casting solution, in the filtration membrane, a separation layer structure with a small pore size and a small change gradient of the average pore size can be formed. Combined with the separation layer with a high occupancy rate, it can not only endow the filtration membrane with a good virus filtration and removal effect, but also endow it with a higher flux and loading capacity.

[0098] In addition, in the process of the coagulation bath penetrating into the membrane, there must be resistance (the same applies to the pore-forming agent), so the distribution of the coagulation bath in the membrane thickness direction is necessarily non-uniform (the closer to the carrier, the less the amount of the coagulation bath). Generally, the non-uniform distribution of the coagulation bath will inevitably lead to a non-uniform phase separation process, that is, it will inevitably lead to a non-uniform void structure in the membrane thickness direction (the membrane casting solution closer to the carrier has less amount of the coagulation bath, so the phase separation is slow and there is a possibility of generating a void structure with a large size). However, the inventors of the present application creatively control the temperature difference between the carrier and the coagulation bath, causing the temperature to be lower the closer the membrane casting solution is to the carrier. Although the amount of the coagulation bath is less the closer to the carrier, the combination of a small amount of the coagulation bath and low temperature can also obtain a similar fast phase separation rate. Cooperating with the pore-forming agent with a large occupancy ratio added to the membrane casting solution, the coagulation bath can penetrate into the membrane better, reducing the non-uniformity of the distribution of the coagulation bath in the membrane casting solution, and greatly improving the uniformity of the void structure distribution in the membrane thickness direction of the finally obtained separation layer, thereby endowing the filtration membrane with a higher flux and loading capacity.

[0099] As can be understood, the pore-forming agent being a poor solvent with a surface tension of 25 dyne / cm or less refers to the surface tension of the pore-forming agent being 25 dyne / cm or less at a temperature of 20°C.

[0100] Optionally, the first good solvent is at least one of acetone, dioxane, dimethylacetamide, N-methylpyrrolidone, acetic acid, propionic acid, butyric acid, and valeric acid, The second good solvent is miscible with the first good solvent. The second good solvent is at least one of acetone, dioxane, dimethylacetamide, N-methylpyrrolidone, acetic acid, propionic acid, butyric acid, and valeric acid, and the non-solvent is water. The cation of the inorganic salt is one or more of sodium, potassium, calcium, and magnesium, and the anion of the inorganic salt is one or more of sulfate, sulfite, or carbonate.

[0101] According to the above technical solution, since the first good solvent in the membrane casting solution is miscible with the second good solvent in the preliminary phase separation liquid, the second good solvent can perform a certain extraction function and promote the phase separation of the homogeneous membrane casting solution in the first good solvent to form a solvent-rich phase. The non-solvent can promote the phase separation of the polymer phase from the homogeneous membrane casting solution to form a polymer-rich phase. The two cooperate to promote the membrane casting solution to undergo a stable and rapid phase transition process under the action of the preliminary phase separation liquid, and obtain the required pore structure.

[0102] Cellulose-based raw materials are oxidized and decomposed by oxygen gas at high temperatures, ultimately reducing the mechanical performance of the obtained filtration membrane. By adding inorganic salts to the membrane casting solution, not only can the execution of the phase transition process be promoted, but when the anions of the inorganic salts are reducing anions such as sulfite ions, the possibility of oxidation of the cellulose-based raw materials in the membrane casting solution can also be further reduced.

[0103] Optionally, the film is placed in a sodium hydroxide solution for hydrolysis, washed after hydrolysis to form a solid film, and 0.1 - 5 wt% of glycerin is added to the sodium hydroxide solution.

[0104] According to the above technical solution, after cellulose acetate is hydrolyzed by an alkali and then hydrolyzed to regenerated cellulose, compared with cellulose acetate, regenerated cellulose has better hydrophilicity, so the protein adsorption of the filtration membrane is lower and the protein yield is higher. However, since the ester group is cleaved and the acetyl group is desorbed during the hydrolysis process of cellulose acetate, the fiber structure of the filtration membrane is likely to be refined and the pore structure is likely to collapse, changing the virus filtration and removal performance and flux of the filtration membrane.

[0105] In the process of alkaline hydrolysis of the cellulose acetate filtration membrane, the inventors of the present application unexpectedly discovered that adding a small amount of glycerin can achieve an obvious anti-shrinkage effect, with a small size change of the filtration membrane before and after hydrolysis, and the flux of the filtration membrane and the virus filtration and removal effect also do not change significantly. This result is very unexpected.

[0106] This is considered to be because in the process of alkaline hydrolysis of cellulose acetate, defects are formed in the fibers due to the cleavage of ester groups and the detachment of acetyl groups, and the fibers cannot exert a good supporting effect on the hole structure. The three hydroxyl groups of glycerin (propanetriol) have very strong polarity and can bind to the exposed polar groups in the regenerated cellulose after contacting the regenerated cellulose after hydrolysis. However, the non-polar part of glycerin penetrates into and fills the defects in the regenerated cellulose, thereby filling and supporting the defects generated in the hydrolysis process, and greatly reducing changes in the mechanical performance and filtration performance of the filtration membrane before and after hydrolysis.

[0107] However, during alkaline hydrolysis, the addition amount of glycerin also needs to be strictly controlled. If the addition amount of glycerin is too small, glycerin is not sufficient to fill the defects in the regenerated cellulose fibers, leading to significant changes in the mechanical performance and filtration performance of the filtration membrane after hydrolysis. If the addition amount of glycerin is too large, glycerin may not only fill the defective parts of the regenerated cellulose fibers but also adsorb excessively on the regenerated cellulose fibers, which can cause the occlusion of the void structure.

[0108] Optionally, the solid membrane after hydrolysis is left in an alkaline environment and cross-linked with a water-soluble cross-linking agent. After the cross-linking is completed, it is washed to obtain the finished product membrane. Here, the cross-linking agent is at least one of epihalohydrin, dihaloalkane, and dihaloalcohol. The cross-linking time is 2 - 40 min, and the temperature is 30°C - 80°C.

[0109] According to the above technical solution, for a cellulose-based raw material that is originally soft in texture, when hydrolyzing cellulose acetate into regenerated cellulose, the hydrophilicity of the filtration membrane can be improved. However, this often means a stable decrease in the size of the fiber structure in the filtration membrane and a decrease in the mechanical performance of the filtration membrane, which is fatal for a cellulose-based filtration membrane with originally poor mechanical performance. Through crosslinking treatment, multiple fiber polymer chains can be connected, thereby forming a microscopic three-dimensional network self-supporting structure, which can greatly improve the mechanical performance and size stability of the fiber structure in the filtration membrane and improve the mechanical performance of the filtration membrane.

Advantages of the Invention

[0110] In short, this application includes at least one of the following beneficial technical effects.

[0111] 1. By controlling the porosity and PMI average pore size of the filtration membrane, it is ensured that the filtration membrane has a good filtration and removal effect on viruses with small sizes. According to this, by characterizing the first outer surface three-dimensional network structure by the first hole and the structure of the first fiber, when the first outer surface as the direct pressure-bearing area receives external pressure, the three-dimensional network structure can exert good support and anti-deformation capabilities, thereby reducing the change in the void structure of the filtration membrane before and after pressure application, improving the flux and loading capacity during the actual use of the filtration membrane, and since the filtration membrane uses a hydrophilic cellulose-based raw material as the film-forming material, the protein adsorption rate of the filtration membrane is low. Summing up the above, the filtration membrane can simultaneously have a good virus filtration and removal effect, high flux, high loading capacity, and high protein yield.

[0112] 2. By limiting the interrelationships between the first holes, the first fibers, and the nodes on the first outer surface, such as the number of first fibers connected to the nodes, the density of the nodes, the average area, and the number of nodes forming the first holes, etc., not only can it be ensured that the void structure of the filtration membrane is strongly supported and difficult to collapse, but also it can be ensured that the influence of the resistance received by the raw material liquid from the solid part on the flux is smaller than the influence of the deformation of the filtration membrane under pressure on the flux. Moreover, by ensuring that the hole structure of the filtration membrane has a high roundness, it can be ensured that the filtration membrane has a smaller stress concentration and a smaller resistance to the raw material liquid, and it can be ensured that the filtration membrane has a high flux and a high loading capacity.

[0113] 3. The support fibers of the pre-filter layer form good support for the void structure, cooperate with the small deformation of the first outer surface under pressure, and can ensure that the pre-filter layer deforms slightly when it is pressured as the main pressure-receiving area. Thereby, a large dirt tolerance and a good interception effect for large particulate matter can be obtained, the possibility of clogging of the separation layer by large particulate matter can be reduced, and thereby the service life and flux of the filtration membrane during actual use can be improved.

[0114] 4. For a filtration membrane with a high occupancy rate of the separation layer, the deformation modes of each region of the separation layer after being pressured are different. Here, in the region of the separation layer close to the first outer surface, compression of the void structure occurs due to pressure, thereby introducing regions in the separation layer that are too small in size. Since a soft cellulose-based raw material is adopted, such a phenomenon becomes more prominent. By forming a three-dimensional network structure with strong pressure resistance using the first outer surface and the pre-filter layer with a stable support effect, the cellulose-based filtration membrane with a high occupancy rate of the separation layer also becomes difficult to deform under pressure, and thereby a high flux and loading capacity can be obtained during use.

[0115] By limiting the porosity of the separation layer, the average pore diameter measured by SEM, and the change gradient of the average pore diameter measured by SEM, it is possible to ensure that the filtration membrane has both a good virus filtration and removal effect and a high flux. This is because, compared with an asymmetrically structured separation layer having a small pore diameter region that significantly affects the flux of the filtration membrane, a highly symmetric separation layer has no small pore diameter region, so that the filtration membrane has a high flux, and a highly symmetric separation layer has a large thickness. Even if the average pore diameter measured by SEM of the separation layer is large, a good virus filtration and removal effect can be guaranteed. It is considered that this is because a large average pore diameter measured by SEM can ensure that the filtration membrane has a large flux and a large loading capacity.

Brief Description of the Drawings

[0116]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Embodiments for Carrying Out the Invention

[0117] Hereinafter, the present application will be described in more detail in connection with FIGS. 1 to 6.

[0118] To more clearly explain the overall concept of this application, it will be described in detail below in the form of examples. Unless otherwise specified, in the following examples and comparative examples, all raw materials and equipment used are available for purchase through common commercial channels. Here, the structural morphology of the filtration membrane was characterized using a scanning electron microscope of model S-5500 provided by Hitachi.

[0119] Example 1 A high-flux virus-removing cellulose filtration membrane, comprising the following process steps.

[0120] S1. Prepare a membrane casting solution. In the membrane casting solution, specifically, according to parts by weight, it contains 20 parts of cellulose acetate, 45 parts of the first good solvent, 30 parts of a pore-forming agent, and 3 parts of an inorganic salt. Here, as the cellulose acetate, diacetate fiber was used; as the first good solvent, acetone was used; as the pore-forming agent, ethanol was used; and as the inorganic salt, sodium sulfate was used. After the preparation of the membrane casting solution is completed, the membrane casting solution is cast on a carrier and fully plated to form a liquid film.

[0121] S2. Perform preliminary phase separation. Put the liquid film into the preliminary phase separation liquid and perform preliminary phase separation with a preliminary phase separation time of 6 s to obtain a semi-finished product membrane. The preliminary phase separation liquid contains a second good solvent and a non-solvent, and the volume percentage of the non-solvent in the preliminary phase separation liquid is 45%. The second good solvent is acetone, and the non-solvent is deionized water.

[0122] S3. Perform phase separation and solidification. Put the semi-finished product membrane into a coagulation bath and perform phase separation and hardening. The coagulation bath is deionized water, the temperature of the coagulation bath is 30 °C, the temperature of the carrier is 25 °C, that is, the temperature difference between the coagulation bath and the carrier is 5 °C, the duration of phase separation and solidification is 40 s, and after the phase separation is completed, washing is performed to obtain a formed film, and the formed film is a cellulose virus-removing filtration membrane.

[0123] Example 2 The main difference between Example 2 and Example 1 is that after step S3, hydrolysis and crosslinking are further performed on the formed film to obtain a regenerated cellulose filtration membrane. The specific steps are as follows.

[0124] The formed film was placed in an aqueous sodium hydroxide solution with a concentration of 0.05 mol / L and a temperature of 50 °C for hydrolysis. The hydrolysis time was 60 min, and glycerin with a mass percentage of 2.5% was added to the aqueous sodium hydroxide solution. Then, after the hydrolysis was completed, the film was taken out and washed with water until the pH became neutral to obtain a solid film.

[0125] Furthermore, the solid film obtained after hydrolysis was placed in an aqueous crosslinking agent solution with a pH of 9.5 for crosslinking. The crosslinking agent was epichlorohydrin. The concentration of the crosslinking agent in the aqueous crosslinking agent solution was 10 wt%, the crosslinking time was 20 min, and the crosslinking temperature was 50 °C.

[0126] Examples 3 - 12 The differences between Examples 3 - 12 and Example 2 mainly lie in that the composition components of the membrane casting solution and the process parameters of the steps are different during the manufacture of the cellulose virus removal filtration membrane. Specifically, they are filled in the following table.

Table 1

[0127] Comparative Example Comparative Example 1 In Comparative Example 1, mainly by reducing the content of cellulose acetate in the membrane casting solution and controlling the conditions of preliminary phase separation, etc., the whole filtration membrane was made to have a higher porosity and a larger void structure size. Specifically, it is as follows.

[0128] A high-flux virus removal cellulose filtration membrane, comprising the following process steps.

[0129] S1. Prepare a membrane casting solution. In the membrane casting solution, specifically, it contains 8 parts by weight of cellulose acetate, 52 parts of a first good solvent, 50 parts of a pore-forming agent, and 4 parts of an inorganic salt according to the parts by weight. Here, as the cellulose acetate, diacetate fiber was used; as the first good solvent, acetone was used; as the pore-forming agent, ethanol was used; and as the inorganic salt, sodium sulfate was used. After the preparation of the membrane casting solution is completed, cast the membrane casting solution onto a carrier and plate it sufficiently to form a liquid film.

[0130] S2. Perform preliminary phase separation. Put the liquid film into a preliminary phase separation solution and perform preliminary phase separation with a preliminary phase separation time of 15 s to obtain a semi-finished product membrane. The preliminary phase separation solution contains a second good solvent and a non-solvent, and the volume percentage of the non-solvent in the preliminary phase separation solution is 15%. The second good solvent is acetone, and the non-solvent is deionized water.

[0131] S3. Perform phase separation and solidification. Put the semi-finished product membrane into a coagulation bath and perform phase separation and hardening. The coagulation bath is deionized water, the temperature of the coagulation bath is 35 °C, the temperature of the carrier is 28 °C, that is, the temperature difference between the coagulation bath and the carrier is 7 °C. The duration of phase separation and solidification is 46 s. After the phase separation is completed, perform washing to obtain a formed membrane, and the formed membrane is a cellulose virus removal filter membrane.

[0132] S4. Hydrolyze. Put the formed membrane into an aqueous sodium hydroxide solution with a concentration of 0.05 mol / L and a temperature of 50 °C for hydrolysis, and glycerin with a mass percentage of 3.8% is added to the aqueous sodium hydroxide solution. Hydrolyze until the cellulose acetate is completely hydrolyzed into regenerated cellulose. Then, take out the membrane after the hydrolysis is completed and wash it with water until the pH becomes neutral to obtain a solid membrane, and the solid membrane is a cellulose virus removal filter membrane.

[0133] S5. Crosslink. Further put the solid membrane obtained after hydrolysis into an aqueous crosslinking agent solution with a pH of 9.5 for crosslinking. The crosslinking agent is epichlorohydrin, the concentration of the crosslinking agent in the aqueous crosslinking agent solution is 10 wt%, the crosslinking time is 25 min, and the crosslinking temperature is 55 °C.

[0134] Comparative Example 2 A high-flux virus-removing cellulose filtration membrane, comprising the following process steps.

[0135] S1. Prepare a membrane casting solution. In the membrane casting solution, specifically, according to parts by weight, it contains 10 parts of cellulose acetate, 40 parts of a first good solvent, and 1 part of an inorganic salt. Here, as the cellulose acetate, diacetate fiber is used, as the first good solvent, acetone is used, as the pore-forming agent, ethanol is used, and as the inorganic salt, sodium sulfate is used. After the preparation of the membrane casting solution is completed, the membrane casting solution is cast onto a carrier and plated sufficiently to form a liquid film.

[0136] S2. Perform preliminary phase separation. Put the liquid film into the preliminary phase separation liquid and perform preliminary phase separation with a preliminary phase separation time of 10 s to obtain a semi-finished product membrane. The preliminary phase separation liquid contains a second good solvent and a non-solvent, and the volume percentage of the non-solvent in the preliminary phase separation liquid is 70%. The second good solvent is acetone, and the non-solvent is deionized water.

[0137] S3. Perform phase separation and solidification. Put the semi-finished product membrane into a coagulation bath and perform phase separation and hardening. The coagulation bath is deionized water, the temperature of the coagulation bath is 25°C, the temperature of the carrier is 25°C, the duration of phase separation and solidification is 30 s. After the phase separation is completed, perform washing to obtain a formed film, and the formed film is a cellulose virus-removing filtration membrane.

[0138] S4. Hydrolyze. Put the formed film into an aqueous sodium hydroxide solution with a concentration of 0.05 mol / L and a temperature of 50°C for hydrolysis, and glycerin with a mass percentage of 1% is added to the aqueous sodium hydroxide solution. Hydrolyze until the cellulose acetate is completely hydrolyzed into regenerated cellulose. Then, take out the membrane after the hydrolysis is completed and wash it with water until the pH becomes neutral to obtain a solid membrane, and the solid membrane is a cellulose virus-removing filtration membrane.

[0139] S5. Perform crosslinking, and further place the solid film obtained after hydrolysis in an aqueous crosslinking agent solution with a pH of 9.5 for crosslinking. The crosslinking agent is epichlorohydrin. The concentration of the crosslinking agent in the aqueous crosslinking agent solution is 10 wt%, the crosslinking time is 30 min, and the crosslinking temperature is 50 °C.

[0140] It should be noted that during the preliminary phase separation in Comparative Example 2, the water content of the preliminary phase separation liquid was high, and phase separation occurred rapidly near the first outer surface of the filtration membrane, forming a void structure with a small size. That is, the separation layer of Comparative Example 2 is located in the region close to the first outer surface. Since no pore-forming agent was added to the membrane casting solution, the resistance to the penetration of the coagulation bath into the membrane is large, and the temperatures of the membrane casting solution and the carrier are also the same. Therefore, the phase separation rates in the thickness direction of the membrane casting solution are different. The closer to the carrier (i.e., the second outer surface), the slower the phase separation rate of the membrane casting solution, and the larger the size of the formed void structure, forming a prefiltration layer structure with a large pore diameter. Therefore, the prefiltration layer of Comparative Example 2 is located in the region close to the second outer surface. This is different from the situation in Examples 1 to 12 and Comparative Example 1, where the separation layer is located on the side closer to the second outer surface and the prefiltration layer is located on the side closer to the first outer surface.

[0141] Performance detection and data recording I. Structural characterization By performing morphological characterization on the membrane structure of the filtration membrane obtained in the example using a scanning electron microscope, the necessary data can be obtained.

[0142] II. Virus filtration and removal effect (log removal rate of PP7 phage) The filtration membranes produced in each example or comparative example were used as samples for a virus challenge test. Here, the detection method referred to the guidance document TR41 distributed by the reference PDA. During the test, PP7 phage was used as the blocking virus, the material flow was immunoglobulin IVIG, the buffer system was PBS, and the pressure applied to the raw material liquid during the virus challenge test was 30 psi. The LRV was calculated by detecting the titer of PP7 phage in the challenge liquid and the filtrate, the protein yield was calculated by detecting the protein concentration in the challenge liquid and the filtrate, and the flux was calculated by recording the flow rate and time. After one virus challenge, it was shown that the greater the flux of the filtration membrane, the smaller the degree of membrane blockage, that is, the filtration membrane had a greater flux.

[0143] III. Mechanical Performance and Bubble Point 3.1 Mechanical Performance The filtration membranes produced in each example and comparative example were used as samples, and a tensile performance test was conducted using a universal tensile testing machine to detect the tensile strength and elongation at break of the filtration membrane.

[0144] 3.2 Bubble Point The filtration membranes produced in each example or comparative example were used as samples. After wetting the samples with the test liquid, pressure was applied to the wet samples with the test gas, and the air pressure was gradually increased. When continuous bubbles began to appear in the middle of the filtration membrane, the air pressure value at this time was read and taken as the bubble point of the filtration membrane. In the above test, the test liquid was 3M's FX3250 perfluorocarbon, the surface tension of the test liquid was 0.012 N / m, and the test gas was nitrogen gas.

[0145] Here, the morphological parameters of each layer membrane structure of the filtration membranes produced in Examples 1 to 12 and Comparative Examples 1 to 2 were entered in the following table.

Table 2

[0146] In the above table, the unit of the thickness of each layer is μm, the unit of the average pore diameter measured by SEM for each layer is nm, the unit of the porosity of each layer is %, the unit of the change gradient of the average pore diameter measured by SEM is nm / μm, and the unit of the fiber diameter of each layer was nm.

[0147] The morphological parameters of the first outer surface and the second outer surface of the filtration membranes produced in Examples 1 to 12 and Comparative Examples 1 to 2 were entered in the following table.

Table 3

[0148] In the above table, the unit of the pore diameter is nm in all cases, the units of the length and diameter of the fibers are both nm, the unit of the fiber size change rate is %, and the unit of the node density is number / μm 2 and the unit of the node area is 10 4 mm 2 and the unit of the node area ratio is %, and the unit of the hole area ratio was %.

[0149] It should be noted that the first outer surface of Comparative Example 2 rapidly phase-separated under the action of the pre-phase separation liquid with a high water content, and a void structure with a small average pore diameter was formed on the first outer surface and in the part close to the first outer surface of the filtration membrane. Therefore, no obvious structures such as fibers and nodes were formed on the first outer surface of Comparative Example 2, and thus there was no relevant data. When performing each of the above-described tests, the filtration membrane produced in Comparative Example 2 still had a large-pore pre-filtration layer on the liquid supply side and a small-pore separation layer still on the liquid drainage side.

[0150] The overall virus filtration removal effect and mechanical performance of the filtration membranes produced in Examples 1 to 12 and Comparative Examples 1 to 2 were entered in the following table.

Table 4

[0151] In the above table, the unit of the filtration membrane thickness is μm, the unit of the PMI average pore size is nm, the unit of the flux is L·h -1 ·m -2 and the unit of the bubble point is MPa, and the unit of the porosity is %.

[0152] In Examples 2 to 12 and Comparative Examples 1 to 2, since all the filtration membranes are regenerated cellulose membranes, the regenerated cellulose has good hydrophilicity, the protein adsorption rate is low, and all of them can achieve a protein yield of 98% or more. Regarding the cellulose acetate membrane of the filtration membrane in Example 1, its hydrophilicity is slightly lower than that of the regenerated cellulose membrane, and its protein yield is 96.4%.

[0153] Conclusion By comparing the technical solutions and various performance parameters of Example 1 and Example 2, it was found that for filtration membranes with similar membrane structures, the protein yield of the filtration membrane manufactured using cellulose acetate as the film-forming material was low, while the protein yield of the filtration membrane obtained using the regenerated cellulose obtained by hydrolysis of cellulose acetate as the film-forming material was high. Regarding the filtration membrane in Example 1, since it has not been subjected to hydrolysis and cross-linking treatment and the soft cellulose of the material has not been cross-linked and modified, even if the filtration membranes manufactured in Example 1 and Example 2 have small differences in each morphological parameter, the flux of the filtration membrane manufactured in Example 1 was significantly lower than that of the filtration membrane manufactured in Example 2. This indicates that for cellulose-based filtration membranes, the void structure of the filtration membrane before and after pressure application may change greatly, and thus filtration membranes with similar morphological parameters before pressure application may exhibit completely different performance during actual use.

[0154] In Examples 2 to 7, through appropriate adjustment of the manufacturing process, it was ensured that the filtration membrane not only had a good virus filtration and removal effect but also had a high flux. When actually used, a filtration membrane with a higher flux or a filtration membrane with a higher LRV can be selected as needed. For a filtration membrane with a relatively low but higher than 5 LRV, such as that in Example 7 or Example 8, by laminating two layers of the filtration membrane and connecting them in series, a membrane filter with LRV>10 can be obtained and applied to materials with higher filtration requirements. That is, the filtration membrane in this application is not limited to single-layer use. When actually used, according to actual needs, a single-layer filtration membrane can be selected and used, or two layers or more than two layers of filtration membranes can be connected in series to obtain the required virus filtration and removal effect.

[0155] By comparing the technical solutions and each performance parameter of Example 2 and Example 8, it is easy to find that in the manufacturing process of the filtration membrane of Example 8, glycerin was not added when hydrolyzing the cellulose acetate membrane, and the size of the filtration membrane changed significantly before and after hydrolysis compared with Example 2. The thickness of the filtration membrane produced in Example 8 was lower and the occupancy rate of the thickness of the separation layer was close to that of Example 2. However, the filtration membrane produced in Example 8 still had a relatively good virus filtration and removal effect. However, compared with the filtration membrane produced in Example 2, the flux was significantly lower.

[0156] In Example 9, in the manufacturing process of the filtration membrane, by controlling conditions such as the water content and the pre-phase separation time in the pre-phase separation liquid during pre-phase separation, holes with a large average pore diameter were generated on the first outer surface. Generally, a filtration membrane with a larger hole structure is considered to have a smaller resistance to the feed liquid and thus should have a higher flux. However, the filtration membrane produced in Example 9 had a large average pore diameter of the holes, but its flux was low, which is considered to be due to the contraction of the void structure caused by the external pressure when the filtration membrane is used.

[0157] In Examples 10 and 11, by controlling the film thickness, the process conditions during preliminary phase separation, and the process conditions during phase separation and solidification, a filtration membrane with a large thickness and a separation layer thickness occupancy rate reaching about 90% could be manufactured. Although the occupancy rate of the separation layer is large, the average pore diameter of the separation layer is large and the change gradient of the average pore diameter is small. Therefore, its flux can still be maintained at 60 L·h -1 ·m -2 or more, and the logarithmic removal rate of PP7 phage of the filtration membrane can reach LRV > 7. Therefore, the filtration membrane can simultaneously have a good virus filtration and removal effect, a high flux, and a high protein yield.

[0158] In Example 12, by controlling the process conditions during preliminary phase separation, the composition components of the membrane casting solution, and the process conditions during phase separation and solidification, etc., a filtration membrane with a relatively low occupancy rate of the separation layer can be manufactured. At this time, both the porosity of the separation layer and the average pore diameter measured by SEM are large. Although the logarithmic virus removal rate LRV4 is achieved when the filtration membrane is used as a single layer, the flux of the filtration membrane is high. When actually used, according to the characteristics of various materials and the filtration requirements, two layers of the filtration membrane layer can be laminated and connected in series to obtain a virus logarithmic removal rate greater than 7 (i.e., LRV > 7).

[0159] In Comparative Example 1, by extending the water content in the preliminary phase separation liquid, the time of preliminary phase separation, and reducing the content of cellulose acetate in the membrane casting solution, etc., holes with significantly large pore diameters are generated on the first outer surface, and first fibers with small diameters can be generated. The ratio of the average pore diameter of the first holes measured by SEM to the diameter of the first fibers measured by SEM is large. The filtration membrane still has a relatively good virus filtration and removal effect, but its flux is low. This is presumably because the filtration membrane deforms greatly under pressure, resulting in a large collapse in the internal void structure of the filtration membrane. Therefore, a filtration membrane with a high porosity has a lower flux instead.

[0160] In Comparative Example 2, by improving the water content in the preliminary phase-separated liquid and removing pore-forming agents and the like in the film-casting solution, the osmotic resistance in the film thickness direction of the coagulation bath was increased. Therefore, the separation layer of the produced filtration membrane clearly has a high change gradient of the SEM-measured average pore diameter. The asymmetric separation layer still has a good virus filtration and removal effect, but the presence of the small pore diameter region causes a low flux of the filtration membrane.

[0161] In addition, a pressure resistance test was performed on each sample of the examples, and the pressure resistance of each was greater than 30 psi. Under the action of a pressure of 30 psi, the filtration membrane was stable with respect to the raw material liquid and could perform rapid filtration. In the integrity test, the filtration membrane further received a pressure of 50 psi, and the membrane pores were still intact. This indicates that the filtration membranes of the examples in this application can operate normally for a long time under a large pressure of 30 psi, greatly improving the problem that the current cellulose-based filtration membranes cannot withstand high pressures.

[0162] This specific example only interprets this application and does not limit this application. After reading this specification, those skilled in the art can make modifications that do not contribute creatively to this example as needed, but as long as they are within the scope of the claims of this application, they will be protected by the patent law.

Claims

1. A high-flux virus-removing cellulose filtration membrane, comprising a porous body having a non-directional meandering passage therein. One surface of the porous body is a first outer surface, and the other surface of the porous body is a second outer surface. The porous body includes a pre-filtration layer and a separation layer for blocking viruses. The SEM-measured average pore diameter of the pre-filtration layer is larger than that of the separation layer. One side of the pre-filtration layer is the first outer surface. The first outer surface includes a plurality of first fibers, and adjacent first fibers are connected to each other to surround and form a first hole. The SEM-measured average pore diameter of the first hole is 300 to 4500 nm, the SEM-measured average diameter of the first fiber is 60 to 600 nm, the porosity of the filtration membrane is 15 to 50%, the PMI average pore diameter of the filtration membrane is 15 to 25 nm, and the flux of the filtration membrane is 35 L·h －１ ·m －２ @ 30 psi or more. A high-flux virus-removing cellulose filtration membrane characterized by the above.

2. The connection site of adjacent first fibers is a node, and the number of first fibers connected to each node is 3 to 8. The ratio of the SEM-measured average pore diameter of the first holes to the SEM-measured average diameter of the first fibers is 4 to 15. The high-flux virus-removing cellulose filtration membrane according to Claim 1.

3. The density of the nodes is 2 to 15 per μm ２ and the average area of the nodes is (0.2 to 2.5) × 10 ６ nm ２ and the area occupancy rate of the nodes is 20 to 45%, and the hole area ratio of the first outer surface is 5 to 40% The high-flux virus-removing cellulose filtration membrane according to Claim 2.

4. The average length of the first fibers between two adjacent nodes is 100 to 1000 nm, and the aspect ratio of the first fibers between two adjacent nodes is 1 to 5. The high-flux virus-removing cellulose filtration membrane according to Claim 2.

5. Each of the first holes is formed by being surrounded by an average of 4 to 15 nodes and the first fibers between the nodes. The size change rate of the first fibers between two adjacent nodes is 5 to 30%. The high-flux virus-removing cellulose filtration membrane according to Claim 2.

6. The high-flux virus-removing cellulose filtration membrane according to Claim 1, wherein the bubble point of the filtration membrane is 0.8 to 1.6 MPa.

7. The second outer surface has second holes. The SEM-measured average pore diameter of the second holes is 25 to 35 nm. The ratio of the SEM-measured average pore diameter of the first outer surface to that of the second outer surface is 10 to 150. The hole area ratio of the second outer surface is 2 to 15%. The high-flux virus-removing cellulose filtration membrane according to Claim 1.

8. The porosity of the preliminary filtration layer is 30 to 70%, the SEM-measured average pore diameter of the preliminary filtration layer is 150 to 500 nm, the SEM-measured average pore diameter of the preliminary filtration layer gradually decreases from near the first outer surface to near the second outer surface, and the rate of decrease in the pore diameter near the first outer surface of the preliminary filtration layer is greater than the rate of decrease in the pore diameter near the second outer surface of the preliminary filtration layer. The high-flux virus-removing cellulose filtration membrane according to claim 1.

9. The preliminary filtration layer includes long support fibers, the support fibers are connected to each other to form the pore structure of the preliminary filtration layer, the SEM-measured average diameter of the support fibers is 60 to 350 nm, and the ratio of the SEM-measured average pore diameter of the preliminary filtration layer to the SEM-measured average diameter of the support fibers is 0.5 to 6. The high-flux virus-removing cellulose filtration membrane according to claim 1.

10. One side of the separation layer is the second outer surface, the thickness of the separation layer is 10 to 60 μm, and the ratio of the thickness of the separation layer to the thickness of the porous body is 40 to 95%. The high-flux virus-removing cellulose filtration membrane according to claim 1.

11. The porosity of the separation layer is 6 to 30%, the SEM-measured average pore diameter of the separation layer is 35 to 85 nm, and the gradient of the SEM-measured average pore diameter change of the separation layer from near the first outer surface to near the second outer surface is 2 nm / μm or less. The high-flux virus-removing cellulose filtration membrane according to claim 10.

12. The separation layer includes long separation fibers, the separation fibers are connected to each other to form the pore structure of the separation layer, the SEM-measured average diameter of the separation fibers is 20 to 50 nm, and the ratio of the SEM-measured average pore diameter of the separation layer to the SEM-measured average diameter of the separation fibers is 1 to 3. The high-flux virus-removing cellulose filtration membrane according to claim 10.

13. The SEM measurement average pore diameter of the first hole is 1000 to 4500 nm, the porosity of the filtration membrane is 25 to 50%, the thickness of the separation layer is 10 to 30 μm, the ratio of the thickness of the separation layer to that of the porous body is 40 to 70%, and the flux of the filtration membrane is 60 to 180 L·h －１ ·m －２ @ 30 psi, characterized in that The high-flux virus-removing cellulose filtration membrane according to any one of claims 1 to 12.

14. The SEM measurement average pore diameter of the first hole is 300 to 2500 nm, the porosity of the filtration membrane is 15 to 45%, the thickness of the separation layer is 20 to 60 μm, the ratio of the thickness of the separation layer to that of the porous body is 60 to 95%, and the flux of the filtration membrane is 35 to 130 L·h －１ ·m －２ @ 30 psi, which is characterized in that The high-flux virus-removing cellulose filtration membrane according to any one of claims 1 to 12.

15. The manufacturing process of the high-flux virus-removing cellulose filtration membrane according to claim 1, Step S1 of manufacturing a membrane casting solution and casting it on a carrier to form a liquid film, wherein the membrane casting solution contains 10 to 30 parts of cellulose acetate, 30 to 60 parts of a first good solvent, 20 to 40 parts of a pore former, and 1 to 5 parts of an inorganic salt. Step S1 wherein the pore former is a poor solvent with a surface tension of 25 dyne / cm or less. Step S2 of performing preliminary phase separation, immersing the liquid film in a preliminary phase separation liquid, performing preliminary phase separation with a preliminary phase separation time of 2 to 10 s to obtain a semi-finished product film, wherein the preliminary phase separation liquid contains a second good solvent and a non-solvent, and the volume occupancy rate of the non-solvent is 30 to 60%. Step S3 of performing phase separation coagulation, immersing the semi-finished product film in a coagulation bath, performing phase separation hardening, setting the temperature of the coagulation bath to 20 to 45°C, the temperature of the coagulation bath being 5 to 15°C higher than the temperature of the carrier, and setting the duration of phase separation coagulation to 20 to 60 s to obtain a formed film, wherein the coagulation bath is water, characterized in that the manufacturing process includes this step.

16. The first good solvent is at least one of acetone, dioxane, dimethylacetamide, N-methylpyrrolidone, acetic acid, propionic acid, butyric acid, and valeric acid. The second good solvent is miscible with the first good solvent. The second good solvent is at least one of acetone, dioxane, dimethylacetamide, N-methylpyrrolidone, acetic acid, propionic acid, butyric acid, and valeric acid. The non-solvent is water. The cation of the inorganic salt is one or more of sodium, potassium, calcium, and magnesium. The anion of the inorganic salt is one or more of sulfate, sulfite, or carbonate, characterized in that The manufacturing process of the high-flux virus-removing cellulose filtration membrane according to Claim 15.

17. The formed film is placed in a sodium hydroxide solution for hydrolysis, and after hydrolysis, it is washed to form a solid film, characterized in that 0.1 to 5 wt% of glycerin is added to the sodium hydroxide solution. The manufacturing process of the high-flux virus-removing cellulose filtration membrane according to Claim 15 or 16.

18. Leave the hydrolyzed solid film in an alkaline environment, crosslink it with a water-soluble crosslinking agent, and after the crosslinking is completed, wash it to obtain the finished product film. Here, the crosslinking agent is at least one of halogenated epoxy, dihaloalkane, and dihaloalcohol, the crosslinking time is 2 to 40 min, and the temperature is 30°C to 80°C, which is characterized in that The manufacturing process of the high-flux virus removal cellulose filtration membrane according to claim 17.

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