Low-dissolution deep filter paperboard, preparation method, virus filtration system and filtration method thereof

Abstract

The present application relates to the field of filter paperboard, and specifically to a low-dissolution deep filter paperboard, a preparation method, a virus filtration system and a filtration method thereof. The low-dissolution deep filter paperboard comprises fibers, a filter aid and a binder. The deep filter paperboard has a liquid inlet surface for receiving a liquid to be filtered and a liquid outlet surface for discharging a permeated liquid. The deep filter paperboard contains a relatively low content of positive charges. The deep filter paperboard has a reduced degree of hydrophobicity. The deep filter paperboard also has the following properties: taking an effective filtration area of ​​23 cm 2 The deep filter paperboard is washed with ultrapure water at a flow rate of 600LMH at room temperature. When the washing volume reaches 60L / m 2 In the above, the ammonium ion concentration Q in the washing solution is less than 50 ppb. The present application has the effect of taking into account both good protein aggregate removal ability and extremely low charged impurity drop degree.

Description

Technical Field

[0001] The present invention relates to the field of deep filter paperboard, and more particularly to a low-dissolution deep filter paperboard, a preparation method, a virus filtering system and a filtering method thereof. Background Art

[0002] In addition to the required low-molecular-weight proteins such as immunoglobulins (IgG) or monoclonal antibodies, protein solutions derived from plasma, cell culture, tissue extracts, secretions, and artificial synthesis inevitably contain high-molecular-weight proteins such as protein trimers or high-molecular-weight protein aggregates. High-molecular-weight protein aggregates are toxic and are easily regarded as foreign matter during the treatment of patients, causing the body's immune system to react; or leading to abnormal cell function and death, affecting organ function and nerve centers. Therefore, this part of the protein aggregates must be removed to avoid adverse reactions to the protein solution on patients.

[0003] Secondly, protein aggregates, due to their relatively larger size, also have a negative impact on the filtration stage of the protein solution. The protein solution needs to be treated for virus removal during the purification process to prevent unwanted viruses from entering the protein solution and causing adverse reactions to the patient. Especially at the end of the process, the protein solution needs to be treated for virus removal again to improve the overall virus clearance rate. However, for the virus removal filter, since the filtration pore size of the virus removal filter is very small, protein aggregates are easily trapped in the virus removal filter and clog the virus removal filter. Even at a low aggregate concentration of 0.01-0.1%, the virus removal filter will be quickly clogged, causing the virus removal filtration efficiency of the virus removal filter to decrease and reducing the durability of the virus removal filter.

[0004] Traditional methods for removing protein aggregates from protein solutions include gel chromatography, size exclusion chromatography, or filtration with ultrafiltration membranes, all of which are relatively costly.

[0005] EMD Millipore's US patent publication number US7118675B2 discloses a method for removing protein aggregates and viruses from a protein solution, including filtering the protein solution through one or more layers of an adsorptive depth filter, a charged or surface-modified microporous membrane, or a small chromatographic medium bed in a normal flow filtration operation mode in the first step to produce a permeate flow without protein aggregates. The protein permeate flow without aggregates can then be filtered through one or more ultrafiltration membranes to intercept viral particles with a retention level of at least 3LRV and allow the protein solution without aggregates and viruses to pass through it.

[0006] In the above method, it is disclosed that the deep filter paperboard can be used to remove protein aggregates, and the deep filter paperboard can adsorb and retain protein aggregates in the protein solution through hydrophobic interaction and electrostatic adsorption.

[0007] Hydrophobic interaction refers to the interaction between non-polar molecules, which tend to aggregate together to minimize the contact area between them and water. The surface of the flow channel in the paperboard is partially exposed to hydrophobic groups, which are hydrophobic. Therefore, the adsorption effect of the paperboard on protein aggregates can be enhanced by increasing the hydrophobic effect. However, the compatibility of hydrophobic groups with the filtered biological materials is poor, especially when the hydrophobicity is too strong, it is easy to cause damage to the biological materials after filtering through the paperboard. Therefore, the hydrophobicity control of the deep filter paperboard should not be too strong, and moderate is enough.

[0008] Positive charge adsorption refers to the interaction between positive and negative charges. Usually, the positive charge in the cardboard comes from the groups or functional groups on the surface of the cardboard, such as amine groups; therefore, the adsorption effect of the cardboard on protein aggregates can be enhanced by increasing the content of positive charge on the cardboard.

[0009] Common depth filter sheets used for protein aggregate adsorption usually have a certain degree of hydrophobicity and a high positive charge.

[0010] However, the inventors found in the process of studying the adsorption performance of deep filter paperboard that excessive positive adsorption will make it easy for the paperboard to shed positively charged impurities. Positively charged impurities will fall off or dissolve from the paperboard and enter the filtration flow through the paperboard, and enter the protein solution at the rear end of the paperboard, which may have an adverse effect on the subsequent use of the protein solution. Even if the positive charge of the deep filter paperboard is reduced, positively charged impurities will still be dissolved, and in the field of biological detection, even a very small amount of positively charged impurities dissolved will affect the final detection results.

[0011] Therefore, it is hoped to provide a deep filter paperboard that can solve the problem of impurity dissolution from the deep filter paperboard and maintain a good protein aggregate adsorption effect. Summary of the invention

[0012] In view of the problems existing in the prior art, the object of the present invention is to provide a low-dissolution deep filter paperboard, a preparation method, a virus filtration system and a filtration method thereof.

[0013] To achieve the above object, the present invention provides the following technical solutions:

[0014] A low dissolution deep filter paperboard comprises fibers, a filter aid and a binder. The deep filter paperboard has a liquid inlet surface for receiving a liquid to be filtered and a liquid outlet surface for discharging a permeated liquid.

[0015] The deep filter paperboard contains positive charges, and the degree of positive charge is controlled as follows:

[0016] When the effective filtration area is 13cm 2 After the deep filter paperboard is rinsed with ultrapure water, a soap yellow dye solution with a concentration of 50ppm is supplied. When the absorbance of the permeate at a wavelength of 418nm rises to 0.05A, the total volume of the permeate is 30-135ml;

[0017] The deep filter paperboard has hydrophobicity, and the degree of hydrophobicity is controlled as follows:

[0018] A 0.5 g / L IvIg protein solution was supplied from the feed surface to the deep filter paperboard, and the IvIg protein was captured by the deep filter paperboard, and filtered at 100 L / m 2 , the reduction range C of IvIg protein concentration in the filtered solution compared with the initial concentration is 2% to 20%;

[0019] The deep filter paperboard also has the following properties:

[0020] Take the effective filtration area as 23cm 2 The deep filter paperboard is washed with ultrapure water at a flow rate of 600LMH at room temperature. When the washing volume reaches 60L / m 2 Above, the ammonium ion concentration Q in the rinse solution is less than 50 ppb.

[0021] The charged impurities that fall off from the deep filter paperboard may come from a variety of components added to the paperboard, including wet strength resins, charge additives, etc. When the fluid passes through the deep filter paperboard, these components are prone to partial fall off due to mechanical impact of the fluid or interaction with certain components in the fluid. The fall off may be fragments of these components that are not firmly bound.

[0022] In order to improve the shedding of charged impurities in the deep filter paperboard and prevent them from affecting the fluid being filtered, the present application designs the charge and hydrophilicity of the deep filter paperboard, so that when the deep filter paperboard is used in a virus pre-filtration scenario, the amount of charged impurities shedding in the deep filter paperboard can be reduced, and at the same time, its adsorption and interception effect on protein aggregates can be enhanced.

[0023] Specifically, the present application controls the overall charged component content of the deep filter paperboard at a lower level, so that the amount of charged impurities that are easily dissolved or detached is also reduced. When the soap yellow dye passes through the deep filter paperboard, since the soap yellow dye carries a negative charge, the soap yellow dye will be adsorbed by the deep filter paperboard through the principle of positive adsorption. When the deep filter paperboard still has a positive charge, the soap yellow content in the permeate flowing out from the liquid outlet of the deep filter paperboard is almost 0. When the absorbance of the permeate flowing out of the liquid outlet of the deep filter paperboard at a wavelength of 418nm rises to 0.05A, it means that the positive charge in the deep filter paperboard is basically neutralized by the soap yellow component, so that the soap yellow appears in the permeate. Therefore, the positive charge content originally carried by the deep filter paperboard can be displayed by measuring the total volume of the permeate. The present application controls the total positive charge of the deep filter paperboard by controlling the total volume of the soap yellow dye permeate to be 30 to 150 ml to reduce the amount of charged impurities that fall off.

[0024] However, the total positive charge content of the deep filter paperboard is low, which will make the deep filter paperboard have a lower positive adsorption effect on impurities such as protein aggregates, resulting in poor filtration effect of the deep filter paperboard when filtering biological products such as protein solutions.

[0025] Therefore, on the other hand, the present application controls the hydrophobicity of the deep filter paperboard within a certain range so that the deep filter paperboard has a good adsorption effect on impurities such as protein aggregates, which can compensate for the weakening of the filtration effect caused by the low charge of the deep filter paperboard, and at the same time will not cause excessive adsorption of the required monoclonal antibodies and other substances, resulting in a reduced yield.

[0026] In the present application, the hydrophobicity of the deep filter paperboard is tested by using an IvIg protein solution. Because the pH of the IvIg protein solution is set to 7.0, and the isoelectric point PL of the IvIg protein used is about 7.0, the IvIg protein solution is basically electrically neutral, and the hydrophobicity of the IvIg protein is caused by the structure of the protein itself, so the hydrophobicity still exists. When the IvIg protein solution passes through the deep filter paperboard, the IvIg protein will only be adsorbed and retained by the hydrophobic interaction of the deep filter paperboard itself, and will not produce positive adsorption. Therefore, the strength of the hydrophobic adsorption in the deep filter paperboard can be reflected according to the reduction in the concentration of the IvIg protein compared to the initial concentration. The present application controls the hydrophobicity of the deep filter paperboard by controlling the reduction in the concentration of the IvIg protein in the filtered solution to C by 5% to 20% compared to the initial concentration. When the hydrophobicity of the deep filter paperboard meets the above range, the hydrophobicity of the deep filter paperboard will not be too strong to reduce the yield of proteins such as antibodies. At the same time, the hydrophobicity of the deep filter paperboard can make up for the problem of reduced adsorption and interception capacity of the deep filter paperboard due to reduced charge.

[0027] Secondly, the present application can also improve the flushing effect of the deep filter paperboard when it is flushed before use by controlling the hydrophobicity of the deep filter paperboard within the above range, so that the charged impurities in the deep filter paperboard are more easily flushed out of the paperboard. However, the hydrophobicity cannot be too low or too high. For the deep filter paperboard with extremely low hydrophobicity, the charged impurities flushed from the upstream of the deep filter paperboard during the flushing stage will be re-adsorbed on the paperboard downstream of the paperboard, so that the charged impurities inside the paperboard cannot be completely discharged under the conventional flushing process and flushing amount. The charged impurities that are not completely flushed out of the paperboard are still easy to enter the rear end of the filtration, causing adverse effects on the subsequent use of the filtered liquid; for the deep filter paperboard with higher hydrophobicity, the interaction between the flushing water and the paperboard is stronger during the flushing stage due to the excessive hydrophobicity inside the paperboard, and the more charged impurities will be flushed out of the paperboard at the position with higher hydrophobicity, so it is still difficult to flush to a lower level of charged impurity content under the conventional flushing process and flushing amount.

[0028] By controlling the hydrophobicity of the deep filter paperboard within the scope of the present application, the charged impurities washed down from the upstream of the paperboard are not easily attached to the downstream of the paperboard when passing through the downstream of the paperboard, because the charged impurities in the water flow are usually more hydrophilic. At the same time, because the hydrophobicity of the deep filter paperboard is not too high, the amount of charged impurity fragments washed off the paperboard is not high. Through the cooperation of the above two aspects, the deep filter paperboard can have a very low level of charged impurity dissolution when filtering the liquid under the conventional flushing process and flushing amount.

[0029] Finally, within the above-mentioned hydrophobicity and charge range, when the deep filter paperboard of the present application is rinsed with pure water, when the flushing volume reaches 60L / m 2 After that, the ammonium ion concentration in the flushing liquid can be reduced to below 10ppb, which is at an extremely low level. At such a low ammonium ion concentration level, the content of positively charged impurities in the permeate of the deep filter paperboard will basically not affect its application or detection in any field.

[0030] Furthermore, the deep filter paperboard is divided into a first area, a second area and a third area in a thickness direction from the liquid inlet surface to the liquid outlet surface at equal distances;

[0031] The overall tightness of the deep filter paperboard is 0.3-0.4 g / cm 3 The tightness of the first area is t1, the tightness of the second area is t2, and the tightness of the third area is t3. t1, t2 and t3 increase successively, and the deviation of t2, t3 and t1 is 0.1-15%.

[0032] The higher the tightness of the deep filter paperboard, the more complicated and tortuous the flow path in the deep filter paperboard will be. When the filtered fluid passes through the deep filter paperboard, the contact area between the filtered fluid and the deep filter paperboard will be higher or the contact time will be longer, which can improve the adsorption effect of the deep filter paperboard on impurities such as protein aggregates in the filtered fluid. However, too high a tightness will cause the flow rate of the fluid to decrease too much, resulting in a significant reduction in the filtration efficiency. In this application, the tightness of the deep filter paperboard is controlled to be 0.3-0.4g / cm 3 range, taking into account the removal effect and filtration efficiency of the deep filter paperboard on impurities such as protein aggregates.

[0033] Secondly, the first area, the second area and the third area of ​​the deep filter paperboard of the present application are divided from the liquid inlet surface to the liquid outlet surface according to the thickness direction of the deep filter paperboard. The tightness t1, t2 and t3 of the first area, the second area and the third area of ​​the deep filter paperboard increase successively, indicating that the tightness of the deep filter paperboard has a gradient increasing trend along the thickness direction. The advantage of such a setting is that there is more space at the front end of the deep filter paperboard, which can provide more space for the interception of impurities; the flow channel at the rear end of the deep filter paperboard is more intricate, and the contact between the filtered fluid at the rear end of the deep filter paperboard and the deep filter paperboard is more sufficient or the contact time is longer, which can provide a better removal effect on impurities such as protein aggregates. In summary, the gradual increase in the tightness of the deep filter paperboard in the thickness direction can not only ensure a better removal effect on protein aggregates, but also enable the deep filter paperboard to have more pre-filtration space, and secondly, the flow rate of the filtered fluid through the paperboard can also be improved to a certain extent.

[0034] The present application also controls that the tightness variation deviation of the deep filter paperboard in the thickness direction should not be too large. The calculation method of the tightness deviation in the present application is: The deviation of t2, t3 and t1 is 0.1-15%. If the tightness difference between the front and rear ends of the deep filter paperboard is too large, the rear end of the deep filter paperboard will be subjected to a stronger force of the fluid, and there will be more nodes where charged impurity fragments can fall off. Therefore, the rear end of the deep filter paperboard is more likely to fall off charged impurity fragments, making it difficult for the deep filter paperboard to be reduced to a lower level under the specified flushing volume.

[0035] Furthermore, the deep filter paperboard is divided into a first area, a second area and a third area in a thickness direction from the liquid inlet surface to the liquid outlet surface at equal distances;

[0036] The first area, the second area and the third area are respectively supplied with 0.5 g / L of IvIg protein solution and filtered at 100 L / m 2 Afterwards, the decreases in the concentrations of IvIg proteins in the filtered solutions compared to the initial concentrations were C1, C2, and C3, respectively; C1, C2, and C3 increased in turn;

[0037] C1:C2:C3 is 1:1~2:1.5~3.

[0038] The first area, the second area and the third area of ​​the deep filter paperboard of the present application are divided from the liquid inlet surface to the liquid outlet surface according to the thickness direction of the deep filter paperboard, and C1, C2 and C3 respectively represent the concentration reduction amplitude of each area when filtering the IvIg protein solution. The greater the reduction amplitude of the IvIg protein concentration, the higher the hydrophobicity of the area; conversely, the lower the hydrophobicity. The increase of C1, C2 and C3 in sequence indicates that the hydrophobicity of the deep filter paperboard of the present application increases in a gradient in the thickness direction. The enhanced gradient of hydrophobicity makes the charged impurities that fall off from the front end of the deep filter paperboard during the flushing process of the deep filter paperboard more strongly repelled by the hydrophobic effect at the rear end of the deep filter paperboard, thereby making it more difficult for the charged impurities to reattach to the deep filter paperboard at the rear end of the deep filter paperboard, thereby improving the flushing effect of the deep filter paperboard during the flushing stage, so that the deep filter paperboard can be flushed to the required cleanliness under the conventional flushing process and flushing amount.

[0039] If the hydrophobicity gradient of the deep filter paperboard is reduced, the hydrophobicity of the rear end of the deep filter paperboard is lower, and the charged impurities falling from the front end of the deep filter paperboard are easily re-adsorbed onto the deep filter paperboard at the rear end of the deep filter paperboard, resulting in that under the conventional flushing process and flushing volume, it is difficult for the flushing water to flush the charged impurities in the deep filter paperboard to an extremely low level.

[0040] Moreover, the higher the hydrophobicity, the more hydrophobic adsorption sites there are in the deep filter paperboard; conversely, the fewer the hydrophobic adsorption sites. The values ​​of C1, C2, and C3 increase successively, that is, the number of hydrophobic adsorption sites in the first region, the second region, and the third region increases successively, and the number of protein aggregates that can be adsorbed by hydrophobic action also increases. This makes the rear end of the deep filter paperboard more capable of hydrophobic adsorption of impurities such as protein aggregates. When the filtered fluid passes through the rear end of the deep filter paperboard, the concentration of impurities such as protein aggregates contained therein is usually at a lower level, especially in the above-mentioned 0.3-0.4 g / cm 3In the tightness range and tightness gradient change, the concentration of protein aggregates passing through the rear end of the deep filter paperboard is extremely low, but this part of protein aggregates cannot be ignored. Therefore, the hydrophobic adsorption capacity of the rear end of the deep filter paperboard is stronger, and there are more hydrophobic action sites, so the adsorption and retention effect of protein aggregates is higher, and the protein aggregates in the filtered fluid at extremely low concentrations can be effectively adsorbed as much as possible, thereby improving the filtering effect and filtering accuracy of the deep filter paperboard, and further enhancing the removal effect of the deep filter paperboard for impurities such as protein aggregates. At the same time, since the front end of the deep filter paperboard is not highly hydrophobic, the front end of the deep filter paperboard can provide more pre-filtration effects, avoiding the premature adsorption and accumulation of impurities such as protein aggregates on the deep filter paperboard, resulting in a decrease in the adsorption capacity of the deep filter paperboard.

[0041] The variation range of the hydrophobicity of the deep filter paperboard in the thickness direction of the present application needs to be controlled within a certain range. If the variation range is too large, due to the low hydrophobicity of the overall deep filter paperboard, it is easy to cause the hydrophobicity of the front end of the deep filter paperboard to be very low, and the hydrophobicity of the rear end to be too strong, so that the utilization rate of the front end becomes low, and the interaction between the rear end of the deep filter paperboard and the flushing water is stronger, resulting in the shedding of more charged impurities. Under conventional flushing processes and flushing volumes, it is more difficult for the deep filter paperboard to achieve a low level of charged impurity drop, and more flushing water may be required to reduce the amount of charged impurities dropped from the deep filter paperboard to a stable value.

[0042] If the change in hydrophobicity is too small, that is, the hydrophobicity of the front end of the deep filter paperboard is not much different from that of the back end, it is easy for the deep filter paperboard to reach a stage of strong adsorption too quickly in the thickness direction, which is equivalent to impurities such as protein aggregates easily accumulating and gathering at the front end of the deep filter paperboard too quickly, making the pre-filtration area of ​​the deep filter paperboard narrower and reducing the adsorption retention capacity for protein aggregates.

[0043] Furthermore, the deep filter paperboard is divided into a first region, a second region and a third region in a thickness direction from a liquid inlet surface to a liquid outlet surface at equal distances; when a soap yellow dye solution with a concentration of 50 ppm is supplied to the first region, the second region and the third region, when the absorbance of the permeate at a wavelength of 418 nm rises to 0.05A, the total volumes of the permeate are V1, V2 and V3 respectively;

[0044] The deviation between V2, V3 and V1 is 0 to 35%.

[0045] The first area, the second area and the third area of ​​the deep filter paperboard of the present application are divided from the liquid inlet surface to the liquid outlet surface according to the thickness direction of the deep filter paperboard, and V1, V2 and V3 respectively represent the volume of the permeate after the positive charges in each area are neutralized. The larger the volume of the permeate, the higher the amount of positive charges originally contained in the area.

[0046] This application controls the gradient variation of the positive charge of the deep filter paperboard in the thickness direction within a certain range, and its deviation should not be too large or too small. The calculation method of the positive charge deviation in this application is: The purpose of the present application to control the deviation of the deep filter paperboard is to reduce the amount of positively charged impurities falling from the deep filter paperboard to a stable low level under a conventional flushing process. If the deviation between the positive charge content on the first area, the second area and the third area of ​​the deep filter paperboard is too large, it is easy to cause excessive amount of charged impurities falling from the local area of ​​the deep filter paperboard, and it is impossible to achieve a low degree of charged impurity shedding under a conventional flushing process and flushing amount.

[0047] Furthermore, the deep filter paperboard is divided into a first region, a second region and a third region in a thickness direction from the liquid inlet surface to the liquid outlet surface at equal distances; the filter aid content in the first region accounts for B1, the filter aid content in the second region accounts for B2, and the filter aid content in the third region accounts for B3; B1, B2 and B3 increase in sequence;

[0048] B1:B2:B3 is 1:1.2~2:2~3.

[0049] In the deep filter paperboard of the present application, diatomaceous earth mainly plays the role of reducing filtration resistance, increasing filtration speed and clarity; and can also improve the strength, toughness and bending resistance of the deep filter paperboard.

[0050] The fine fiber content of the deep filter paperboard is expected to be higher on the side of the liquid outlet than on the side of the liquid inlet, because the more fine fibers there are on the side of the rear end of the deep filter paperboard, the tighter the fibers are entangled, which makes the fluid encounter greater resistance when passing through the rear end of the deep filter paperboard, and the greater the force between the fluid and the rear end of the deep filter paperboard, and the rear end of the deep filter paperboard is more likely to drop charged impurity fragments, resulting in the deep filter paperboard charged impurity shedding amount is not easy to reduce to a low level. Diatomaceous earth filter aids can effectively reduce the problem of too tight entanglement between fibers, reduce the force between the rear end of the deep filter paperboard and the filtered fluid, and avoid excessive drop of charged impurities.

[0051] Secondly, the proportion of diatomaceous earth filter aid in the thickness direction of the deep filter paperboard increases gradually, which can make the pore complexity of the deep filter paperboard increase in the thickness direction. The closer to the liquid outlet, the higher the pore complexity. When the filtered fluid containing protein aggregate impurities passes through the rear end of the deep filter paperboard, the better the protein aggregates are adsorbed and retained. Therefore, the level of impurities such as protein aggregates in the filtered fluid after filtering through the deep filter paperboard can be reduced to the desired level that does not affect subsequent use. In addition, diatomaceous earth has a filtering effect, especially when the above 0.3-0.4 g / cm 3 In the case of tightness range and tightness gradient change, since the rear end of the deep filter paperboard is tighter, increasing the proportion of diatomaceous earth at the rear end can, to a certain extent, reduce the flow rate attenuation of the filtered fluid when it passes through the rear end, and can further improve the filtration efficiency without basically affecting the filtration effect.

[0052] Furthermore, when the effective filtration area is 0.45 cm 2 The deep filter paperboard is rinsed with ultrapure water and the flushing volume reaches 100L / m 2 The rinse water is mixed with the DNA standard sample, and the mixed solution is the DNA test sample; the DNA content ratio between the DNA test sample and the DNA standard sample is 0.7-1; wherein the DNA standard sample is a 20% vol DNA aqueous solution.

[0053] Through DNA testing method, the deep filter paperboard flushing volume of this application is tested to reach 100L / m 2 The content of positively charged substances in the rinse liquid after washing. The results show that the amount of positively charged impurities falling off the deep filter paperboard is close to 0. This shows that after washing a certain amount of water in the deep filter paperboard, very few positively charged impurities fall off, and the adsorption of protein aggregates is mainly caused by positively charged substances. Therefore, the deep filter paperboard of the present application has a better adsorption effect on protein aggregates. In addition, this also shows that the deep filter paperboard has a better purity and contains fewer impurities in the filtered fluid.

[0054] Furthermore, ultrapure water was passed through a filter with an effective filtration area of ​​23 cm at a constant pressure of 100 kPa and 20 °C. 2 The deep filter paperboard has a flow rate of not less than 0.2 L / min.

[0055] Furthermore, the dry bursting strength of the deep filter paperboard is 400-700 kPa, and the wet bursting strength is 100-300 kPa.

[0056] Within the above-mentioned dry and wet burst resistance ranges, the deep filter paperboard can have good mechanical strength and good wet strength, making the deep filter paperboard more suitable for filtering scenarios of biological liquids.

[0057] Furthermore, the fiber comprises one or more hydrophobic fibers selected from the group consisting of polyacrylonitrile fibers, polyolefin fibers, polyester fibers, and hydrophobically modified natural fibers.

[0058] Furthermore, the monomer of the binder is a water-soluble monomer, and the binder becomes a water-insoluble polymer after being heated and polymerized.

[0059] Further, the binder comprises a water-soluble synthetic polymer based on urea or melamine-formaldehyde polymer, a polyaminopolyamide-epichlorohydrin polymer or a glyoxylated polyacrylamide resin.

[0060] Furthermore, the filter aid is selected from one or more of diatomaceous earth particles, hydrophobically modified diatomaceous earth particles, silicon dioxide, perlite and silicate.

[0061] Furthermore, the filter aid has a D 50 The particle size is controlled to be 1-40 μm, and the pore size of the filter aid is controlled to be 20-600 nm.

[0062] A virus filtration system using the low-dissolution deep filter paperboard comprises a deep filter and a virus removal filter which are assembled in sequence along the filtering direction of the system; the deep filter paperboard serves as the filter medium of the deep filter.

[0063] Furthermore, a layer of nylon membrane is arranged between the deep filter and the virus removal filter, and the pore size of the nylon membrane is 0.1 to 0.4 μm and the thickness is 100 to 300 μm.

[0064] A method for preparing a low-dissolution deep filter paperboard comprises the following steps:

[0065] S1: beating, selecting fibers for beating, and controlling the beating degree to be 30-70°SR to obtain fiber slurry;

[0066] S2: Mixing, firstly, the binder is divided into two equal parts, one of which is added to the fiber slurry, stirred at a speed of 50-100 rpm for 2-3 hours, and the pH is adjusted to 7-10, then the filter aid is added to the fiber slurry, stirred at a speed of 20-50 rpm for 0.5-1 hour, and finally the other binder is added to the fiber slurry, stirred at a speed of 40-50 rpm for 0.5-1 hour, and the pH is adjusted to 7-10 to obtain a mixed slurry;

[0067] S3: Forming, spreading the mixed slurry on the screen, and using vacuum to suck the side of the screen where the mixed slurry is not spread to obtain a predetermined shape of the initial finished product; the vacuum degree is controlled to -100 to -10kpa;

[0068] S4: Drying: Dry the finished product until the moisture content is no more than 5%;

[0069] S5: Punching, cutting the primary finished product into finished products;

[0070] Wherein, the fiber raw material in step S1 includes hydrophobic fibers and / or the filter aid includes hydrophobically modified diatomaceous earth particles.

[0071] In order to reduce the amount of charged impurities falling off the deep filter paperboard in the present application, the amount of binder used is reduced, and at the same time, some hydrophobic materials, such as hydrophobic fibers or hydrophobically modified diatomaceous earth filter aids, are added, so that the deep filter paperboard can take into account both lower charged impurity falling off and better protein aggregate removal ability.

[0072] However, since the binder also has the effect of improving the wet strength of the paperboard, if the traditional preparation method is used, the bonding strength between the components of the deep filter paperboard will be reduced, and the wet strength of the paperboard will be reduced. Therefore, the present application divides the mixing and stirring in step S2 into three stages to maximize the mixing effect between the binder and other components, thereby enhancing the bonding effect of the binder, improving the wet strength of the paperboard at a lower binder dosage, and making the mechanical properties of the paperboard still reach a better level.

[0073] Specifically, for the binder, the bonding process of the binder can be mainly divided into stages A, B, and C, wherein stage A is the stage when the binder just begins to enter the mixed system, at which time the binder is in a completely fluid state and can be well dispersed in the mixed system. Therefore, the present application first mixes the binder in stage A with the pulped fiber slurry, so that the fibers and the binder can be fully and well blended, and part of the binder penetrates into the fibers. After adjusting the pH, the binder gradually changes to stage B due to changes in the environment in the mixed system under the influence of environmental factors. Stage B refers to a state in which the binder is in a semi-cured state, the molecules of the binder have not yet been completely cross-linked to form a solid, and the binder molecules will be adsorbed by the fiber surface; and since the fibers and the binder have already had good contact and mixing, when entering stage B, the binder that has already had good contact with the fibers will form a stronger connection with the fibers and will not be easily broken up. Then, the filter aid is added. At this time, the binder in the mixed system is basically in the B stage. The added filter aid will adsorb the binder molecules on its surface. That is to say, the filter aid will be connected with the fiber through the bridging effect of the binder molecules in the B stage during the mixing process. Although the connection is not stable at this time, the trend always exists. Finally, the present application adds the remaining binder, so that the binder in the A stage forms a blended mixture with the fiber and the filter aid that have already formed a connection trend, and through the subsequent pH adjustment, this part of the binder added later also enters the B stage, further stabilizing the connection state between the fiber and the filter aid, and at the same time bridging the different fibers, so that the binder in the final mixed slurry is evenly distributed between each fiber and fiber, fiber and filter aid, and filter aid and filter aid.

[0074] The mixed slurry is then subsequently formed and dried, so that the binder enters the fully cured C stage, so that the mechanical properties of the deep filter paperboard can be achieved at a higher level at a lower binder dosage.

[0075] Further, the binder comprises a water-soluble synthetic polymer based on urea or melamine-formaldehyde polymer, a polyaminopolyamide-epichlorohydrin polymer or a glyoxylated polyacrylamide resin.

[0076] After the above-mentioned adhesive components are cross-linked in the paperboard, the positively charged amino groups will be exposed on the chain segments, so that the impurity components such as negatively charged protein aggregates passing through the deep filtration paperboard can be positively adsorbed by the paperboard.

[0077] Furthermore, in step S3, the molding stage is divided into a high vacuum stage and a low vacuum stage. The vacuum degree of the high vacuum stage is controlled to be -60 to -50 kPa, and the time of the high vacuum stage is 1 to 2 minutes; the vacuum degree of the low vacuum stage is controlled to be -30 to -10 kPa, and the time of the low vacuum stage is 5 to 10 minutes.

[0078] During the forming process of step S3, the vacuum suction stage is divided into two stages, firstly a short high vacuum suction and then a long low vacuum suction. The purpose of this is to prepare a deep filter paperboard with a tightness gradient distribution from the liquid inlet surface to the liquid outlet surface and a diatomaceous earth proportion gradient distribution in a relatively low increase range in the thickness direction of the deep filter paperboard, so as to improve the deep filter paperboard's ability to remove impurities such as protein aggregates, reduce the amount of charged impurities falling and achieve a better paperboard washing efficiency.

[0079] Furthermore, in the drying process of step S4, the drying temperature is controlled to be 120-200° C., and the drying time is 5-8 hours.

[0080] Furthermore, the drying process in step S4 is divided into a rapid heating stage, a slow heating stage and a constant temperature stage. The heating rate in the rapid heating stage is controlled to be 5-10°C / min, and the low heating stage is entered when the temperature is increased to 10-15°C away from the drying set temperature; the heating rate in the slow heating stage is controlled to be 1-2°C / min, and the constant temperature stage is entered after the temperature is increased to the drying set temperature.

[0081] During the drying process of step S4, the binder mainly undergoes a C-stage change, that is, cross-linking to form a stable three-dimensional network structure. The present application divides the heating stage of the drying process into a rapid heating stage and a slow heating stage. In the rapid heating stage, the cross-linking and curing of the binder on the surface of the deep filter paperboard can be improved, thereby reducing the loss of paperboard strength caused by excessive binder escaping from the paperboard during the drying process. The slow heating stage can make the temperature inside and outside the paperboard rise slowly, and the temperature difference between the inside and outside will not become larger and larger, so that the cross-linking and curing of the binder proceeds smoothly and orderly, and cross-linking and curing are carried out from the outside to the inside, so that the deep filter paperboard is bonded more stably and has higher strength.

[0082] A filtration method for removing protein aggregates and viruses in a fluid using the low-dissolution deep filter paperboard, comprising the following steps:

[0083] A1: Use a deep filter paperboard that is rinsed with ultrapure water until the conductivity of the rinse fluid is less than 30 μS / cm to filter the fluid containing protein aggregates and / or viruses;

[0084] A2: The filtrate from step A1 is then passed through at least one virus filter with a molecular weight cutoff of 50 to 150 kD;

[0085] Before performing step A1, the virus content in the fluid does not exceed 0.1%.

[0086] In summary, the present invention has the following beneficial effects:

[0087] First, the deep filter paperboard of the present application is designed by designing the charge amount and hydrophilicity and hydrophobicity of the deep filter paperboard.

[0088] It can not only make the charged impurity drop amount of the deep filter paperboard stable at a lower level, but also maintain or enhance the adsorption and retention capacity of the deep filter paperboard for protein aggregates.

[0089] Second, the present application also controls the hydrophobicity of the deep filter paperboard in the thickness direction to be distributed in a gradient manner, controls the deviation of the charge of the paperboard in the thickness direction to be low, and controls the tightness to increase in a low gradient in the thickness direction of the paperboard, so as to obtain a deep filter paperboard with better effect on flushing and removing charged impurities and better adsorption and retention of impurities such as protein aggregates. BRIEF DESCRIPTION OF THE DRAWINGS

[0090] Figure 1 is a bar graph of Vmax of Examples 1 to 18 and Comparative Examples 1 to 3;

[0091] Figure 2 It is a bar graph of the lowest values ​​of ammonium ion concentration in the flushing solutions of Examples 1 to 18 and Comparative Examples 1 to 3. DETAILED DESCRIPTION

[0092] In order to more clearly understand the above-mentioned purpose, features and advantages of the present invention, the present invention is further described in detail below in conjunction with the accompanying drawings and specific embodiments. It should be noted that the embodiments of the present application and the features in the embodiments can be combined with each other without conflict.

[0093] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein. Therefore, the protection scope of the present invention is not limited to the specific embodiments disclosed below.

[0094] Example

[0095] Example 1

[0096] A deep filter paperboard is prepared from 50.5% by mass of fiber, 0.5% by mass of a binder and 49% by mass of a diatomaceous earth filter aid, and has a liquid inlet surface for receiving a liquid to be filtered and a liquid outlet surface for discharging a permeated liquid.

[0097] The fibers include natural cotton fibers and polyacrylonitrile hydrophobic fibers in a mass ratio of 5:1; the diatomaceous earth includes 50% by mass of hydrophobically modified diatomaceous earth, and the D 50 The particle size is controlled to be 40 μm, the pore size of the filter aid is controlled to be 100 nm; and the binder is a polyamino polyamide-epichlorohydrin polymer.

[0098] The specific preparation steps are as follows:

[0099] A method for preparing a deep filter paperboard comprises the following steps:

[0100] S1: beating, mixing and beating the fibers, and controlling the beating degree to 70°SR to obtain a fiber slurry;

[0101] S2: Mixing: first, the binder is divided into two equal parts, one of which is added to the fiber slurry and stirred at a speed of 100 rpm for 2 hours, and the pH is adjusted to 8. Then, the filter aid is added to the fiber slurry and stirred at a speed of 50 rpm for 0.5 hours. Finally, the other binder is added to the fiber slurry and stirred at a speed of 40 rpm for 0.5 hours. After adjusting the pH to 7, a mixed slurry is obtained;

[0102] S3: Forming, spreading the mixed slurry on the screen, and using vacuum to suck the side of the screen where the mixed slurry is not spread to obtain a pre-formed primary product; the vacuum suction stage is divided into two stages, first a short period of high vacuum suction, and then a long period of low vacuum suction. The purpose of doing this is to prepare a deep filter paperboard in which the tightness gradient distribution from the liquid inlet surface to the liquid outlet surface and the diatomaceous earth proportion gradient distribution are both at a lower increase in the thickness direction of the deep filter paperboard, so as to improve the deep filter paperboard's ability to remove impurities such as protein aggregates, a lower amount of charged impurities falling, and a better paperboard washing efficiency. The vacuum degree of the high vacuum stage in step S3 is preferably -60 to -50 kpa, and the time of the high vacuum stage is preferably 1 to 2 min; the vacuum degree control of the low vacuum stage is preferably -30 to -10 kpa, and the time of the low vacuum stage is preferably 5 to 10 min. In this embodiment, the vacuum degree in the high vacuum stage is preferably -60 kPa, and the time of the high vacuum stage is preferably 1 min; the vacuum degree control in the low vacuum stage is preferably -30 kPa, and the time of the low vacuum stage is preferably 10 min.

[0103] S4: Drying, shaping and drying the primary finished product until the moisture content is no more than 5%; during the drying process, the binder mainly undergoes the C stage change, that is, cross-linking to form a stable three-dimensional network structure. The present application divides the heating stage of the drying process into a rapid heating stage and a slow heating stage. In the rapid heating stage, the cross-linking and curing of the binder on the surface of the deep filter paperboard can be improved, thereby reducing the loss of paperboard strength caused by excessive binder escaping from the paperboard during the drying process. The slow heating stage can make the temperature inside and outside the paperboard rise smoothly, and the temperature difference between the inside and outside will not become larger and larger, so that the cross-linking and curing of the binder proceeds smoothly and orderly, and the cross-linking and curing is carried out from the outside to the inside, so that the deep filter paperboard is bonded more stably and has higher strength. Specifically, the drying process in step S4 is divided into a rapid heating stage, a slow heating stage and a constant temperature stage. The heating rate in the rapid heating stage is preferably 5-10°C / min, and the slow heating stage is entered when the temperature rises to 10-15°C from the drying setting temperature; the heating rate in the slow heating stage is preferably 1-2°C / min, and the constant temperature stage is entered after the temperature rises to the drying setting temperature. The drying temperature is preferably controlled at 120-200°C, and the drying time is preferably controlled at 5-8h.

[0104] In this embodiment, the heating rate in the rapid heating stage is preferably 10°C / min, and when the temperature rises to 10°C from the drying setting temperature, the slow heating stage is entered; the heating rate in the slow heating stage is preferably 2°C / min, and after the temperature rises to the drying setting temperature, the constant temperature stage is entered. The drying temperature control is preferably 130°C, and the drying time control is preferably 6h.

[0105] S5: Punching, cutting the primary finished product into finished products.

[0106] Example 1 also discloses a virus filtration system using a deep filter paperboard, including a deep filter and a virus removal filter assembled in sequence along the filtration direction of the system; the filter medium of the deep filter sequentially adopts the filter paperboard prepared above.

[0107] Example 1 also discloses a method for removing protein aggregates and viruses from a fluid using a deep filter paperboard, comprising the following steps:

[0108] A1: Select deep filter paper washed with ultrapure water source 100L / m 2 , and then filtering the fluid containing protein aggregates and / or viruses; the pressure is 30 psi and the temperature is 25° C. wherein the content of viruses in the fluid does not exceed 0.1%.

[0109] A2: The filtrate after filtering in step A2 is then passed through a virus filter with a molecular weight cutoff of 150 kd.

[0110] The structural parameters of the prepared deep filter paperboard were tested as follows:

[0111] Overall tightness test: Cut the prepared deep filter paperboard into round pieces, the thickness of the sample paperboard is 3.6mm and the diameter is 47mm. Use an analytical balance to measure the mass of the sample paperboard as M, and calculate V through the thickness and diameter of the sample paperboard. The overall tightness is

[0112] Layered tightness test: Cut the sample paperboard into three equal parts along the thickness direction, and divide them into the first area, the second area and the third area from the liquid inlet surface to the liquid outlet surface. Measure the mass of each area as m1, m2 and m3 respectively. The tightness of the three areas is

[0113] Overall hydrophobicity test: using The intravenous human immunoglobulin (pH 4) was used as the IvIg protein stock solution, which was diluted with physiological saline to prepare a 0.5 g / L IvIg protein solution with a pH of 7 (the isoelectric point of the IvIg protein solution is 7). Then, the sample paperboard was clamped with a clamp, and the IvIg protein solution was then supplied to the sample paperboard from the liquid inlet side. The filtration rate was 120 LMH and the filtration rate was 100 L / m 2 After that, the concentration c of the IvIg protein solution in the filtrate was measured, and the overall hydrophobicity

[0114] Layered hydrophobicity test: the sample paperboard was cut into three equal parts along the thickness direction, and divided into the first area, the second area and the third area from the liquid inlet surface to the liquid outlet surface. Each area was supplied with the above 0.5g / L IvIg protein solution, and the filtration speed was controlled to be 120LMH, and the filtration rate was 100L / m 2 After that, the concentrations of IvIg protein solution c1, c2, and c3 in the filtrate were measured respectively;

[0115] Overall charge test: Cut the prepared deep filter paperboard into disc-shaped samples with a thickness of 3.6 mm and a diameter of 47 mm. Use negatively charged soap yellow dye as a standard reagent and add water to make a 50 ppm solution. Supply a 50 ppm soap yellow dye solution at a constant rate of 5 ml / min. When the absorbance of the permeate at 430 nm drops to 0.05 A, measure the total volume V of the permeate soap yellow dye solution.

[0116] Layered charge test: The prepared deep filter paperboard is cut into disc-shaped samples, and then cut into three equal parts along the thickness direction, and divided into the first area, the second area and the third area from the liquid inlet surface to the liquid outlet surface; the thickness of each area is 1.2mm and the diameter is 47mm.

[0117] Negatively charged soap yellow dye is used as a standard reagent, and water is added to prepare a 50ppm solution. The 50ppm soap yellow dye solution is supplied at a constant rate of 5ml / min. When the absorbance of the permeated liquid at 430nm drops to 0.05A, the total volume of the permeated soap yellow dye solution is measured to be V1, V2 and V3 respectively.

[0118] The overall diatomite filter aid ratio is tested according to the following method: the prepared deep filter paperboard is cut into disc-shaped samples, the thickness of the sample paperboard is 3.6 mm, and the diameter is 47 mm. The mass of the sample paperboard is measured as M. The sample paperboard is placed in a muffle furnace at 575±25℃ and burned to constant weight (3h), and weighed as m'.

[0119] The filter aid ratio is calculated according to the following formula:

[0120] The proportion of layered diatomite filter aid was tested according to the following method: the prepared deep filter paperboard was cut into disc-shaped samples with a thickness of 3.6 mm and a diameter of 47 mm. The sample paperboard was cut into three equal parts along the thickness direction, and divided into the first area, the second area and the third area from the liquid inlet surface to the liquid outlet surface, and the mass of each area was measured as m1, m2, and m3 respectively. Each area was placed in a muffle furnace at 575±25℃ and burned to constant weight (3h), and weighed as m1', m2', and m3'.

[0121] The filter aid ratio is calculated according to the following formula:

[0122] By changing the raw material ratios, stirring process parameters, vacuum suction process parameters in the molding process, and process parameters in the drying process in the preparation process, deep filter paperboards with different structural properties in Examples 2 to 18 and Comparative Examples 1 to 3 were prepared.

[0123] Specifically, the overall hydrophobicity of the deep filter paperboard can be controlled by controlling the proportion of hydrophobic fibers and the proportion of hydrophobically modified diatomaceous earth in the raw materials.

[0124] By controlling the amount of binder added and the process parameters of the drying process, the overall charge and mechanical properties of the deep filter paperboard can be regulated.

[0125] By controlling the amount of diatomaceous earth added and the vacuum suction process parameters, the density distribution, hydrophobicity distribution and charge distribution in the thickness direction of the paperboard can be regulated.

[0126] The specific results of each embodiment are as follows:

[0127] Table 1

[0128]

[0129]

[0130] Table 2

[0131]

[0132] Table 3

[0133]

[0134] In the preparation process of the deep filter paperboard of Comparative Examples 1-2, in the mixing stage of step S2, the binder and the filter aid are added to the fiber slurry at the same time, and then stirred and mixed for 3 hours.

[0135] Performance Test:

[0136] (1) Test of ammonium ion concentration in the flushing liquid: The effective filtration area of ​​the deep filter paperboard assembled using the various embodiments and comparative examples in this application is 23 cm 2 The syringe filter is then flushed with ultrapure water at a rate of 600LMH, with each flushing being 20L / m 2 After the flushing water is added, the ammonium ion concentration in the flushing liquid of the filter is tested and recorded. Finally, the change of the ammonium ion concentration in the flushing liquid with the flushing amount is obtained by using software fitting, and the final stable level and the flushing amount required to reach an ammonium ion concentration of 50ppb are recorded.

[0137] (2) Protein aggregate retention performance test: Preparation of protein aggregate feed standard solution: IgG aggregate solution (SeraCare 5% human gamma globulin, purchased from SeraCare, Inc., CAT#HS-9000), phosphate buffer (10 g / L Difeo FA buffer, pH 7.2, from Fisher Scientific, Cat#DF 2314150) and EDTA (10 mmol / L ethylenediaminetetraacetic acid disodium calcium salt, from Sigma Aldrich, CAT#ED2SC) were mixed to obtain the initial feed solution, and the initial feed solution was passed through a PLCXK membrane (PLCXK membrane is a cellulose ultrafiltration membrane with a nominal molecular weight of 1000 kDaltons, available from Millipore, Bedford, Massachusetts) to remove 90% of the protein aggregates to obtain a protein aggregate feed solution with a concentration of 10% of the original.

[0138] A conventional constant flow virus filter was used without any aggregate removal step using a 13.5 cm2 of NFP virus filters selectively remove aggregates from protein solutions during normal flow (NFF) filtration.

[0139] The effective filtration area of ​​the deep filter paperboard assembled using the various embodiments and comparative examples of this application is 4.5×10 -4 m 2 The protein solution was then filtered using a 13.5 cm2 deep filter supplied by Millipore Corporation in Bedford, Massachusetts. NFP filters were used for virus removal steps.

[0140] The measured retention capacity Vmax of the virus filter is used as a measure of the ability of the deep filter paperboard to remove protein aggregates. The stronger the removal ability, the larger the Vmax.

[0141] (3) Flow rate test: Assemble the deep filter paperboard into the filter and obtain 4.5×10 -4 m 2 The effective filtration area of ​​the deep filter; the double-layer filter was filtered with an ultrapure water source at a constant pressure of 100 kPa and 20°C, and the filtration speed in each embodiment and comparative example was measured.

[0142] (4) Burst strength test: The test was performed using the NPD-02 fully automatic burst strength tester.

[0143] (5) DNA test: Take 10 ng CHO DNA and add flushing volume to 100 L / m 2 The ultrapure water source rinse solution was added to 5 ml to obtain the test sample; the test sample was treated with resDNASEQ TM The quantitative CHO DNA kit was used to detect the CHO DNA content in the test sample.

[0144] (6) Protein yield test: A 0.5 wt% IgG protein standard solution was used to supply an effective filtration area of ​​23 cm 2 The deep filter paperboard filter has a flow rate of 600LMH. When the supply is 100L / m 2 Afterwards, the concentration of IgG protein in the permeate was tested, and the changes in the content of IgG protein before and after were recorded. The yield = 100% × (IgG protein front end - IgG protein back end) / IgG protein front end. The test results are shown in the following table:

[0145] Table 4

[0146]

[0147] Table 5

[0148]

[0149]

[0150] The applicant also prepared Comparative Example 4, which differed from Example 1 only in that in step S2, the binder and the filter aid were added to the fiber slurry at the same time, and then stirred and mixed for 3 hours. After testing its mechanical properties, it was found that the dry burst strength of the paperboard was less than 400 kPa, and the wet burst strength was less than 100 kPa.

[0151] Conclusion: Reference Figure 1 and Figure 2 By comparing the overall hydrophobicity, charge, ammonium ion concentration and DNA test results of Examples 1 to 17 and Comparative Examples 1 to 3, it can be clearly seen that within the hydrophobicity range and charge range regulated by the present application, the amount of charged impurities dropped from the paperboard can be significantly reduced. Figure 1 As shown, by comparing the values ​​of Vmax, it is found that the hydrophobicity and charge of the paperboard do not affect the adsorption effect of the paperboard on protein aggregates separately. There is a certain correlation between the hydrophobicity and charge of the paperboard. When the hydrophobicity and charge meet the range of this application, the adsorption effect on protein aggregates is significantly improved. Moreover, from the yield test results of IgG protein, it can be seen that excessive hydrophobicity will lead to a decrease in its yield. Therefore, the hydrophobicity of the deep filtration paperboard cannot be increased as much as possible, but should be within a reasonable range, that is, the scope of this application.

[0152] According to the data comparison between Example 1 and Examples 8 and 9, it can be seen that when the tightness of the deep filter paperboard does not meet the range disclosed in the present application, it is difficult to balance the adsorption capacity of the paperboard for impurities such as protein aggregates and the filtration efficiency. In addition, it is difficult to reduce the amount of charged impurities dropped from the deep filter paperboard to an extremely low level.

[0153] According to the data comparison between Example 1 and Example 10, the tightness of the deep filter paperboard shows a decreasing trend in the thickness direction, which makes it impossible to reduce the amount of charged impurities falling from the deep filter paperboard to a low level, and the flow rate cannot reach a very high level, and the adsorption amount of protein aggregates cannot be comparable to that of Example 1.

[0154] According to the data comparison between Example 1 and Example 11, the range of the gradient increase of the tightness of the deep filter paperboard in the thickness direction cannot be too large, otherwise the charged impurities falling from the rear end will increase, so that the amount of charged impurities falling from the deep filter paperboard cannot be reduced to a low level. In addition, due to the excessive tightness of the rear end of the deep filter paperboard, the filtration efficiency of the deep filter paperboard will be low.

[0155] According to the data comparison between Example 1 and Example 12, it can be seen that the hydrophobicity of the deep filter paperboard decreases gradually in the thickness direction, which makes it easy for the charged impurities falling from the front end of the deep filter paperboard to be re-adsorbed onto the deep filter paperboard at the rear end of the deep filter paperboard, resulting in that under the conventional flushing process and flushing amount, it is difficult for the flushing water to flush the charged impurities in the deep filter paperboard to an extremely low level.

[0156] According to the data comparison between Example 1 and Examples 13 and 14, it can be seen that the hydrophobicity of the deep filter paperboard increases gradually in the thickness direction and the range of change is too large, which easily causes the hydrophobicity of the front end of the deep filter paperboard to be very low, and the hydrophobicity of the rear end is too strong, which makes the utilization rate of the front end low, and the interaction between the rear end of the deep filter paperboard and the flushing water is stronger, resulting in more charged impurities falling off. Under the conventional flushing process and flushing volume, it is more difficult for the deep filter paperboard to achieve a low level of charged impurity falling. The hydrophobicity of the deep filter paperboard increases gradually in the thickness direction and the range of change is too small, which easily causes the deep filter paperboard to reach a stage of strong adsorption too quickly in the thickness direction, which is equivalent to impurities such as protein aggregates being easily accumulated and aggregated at the front end of the deep filter paperboard too quickly, making the pre-filtration area of ​​the deep filter paperboard narrower, and reducing the adsorption and retention capacity of protein aggregates.

[0157] According to the data comparison between Example 1 and Example 15, it can be seen that the charge of the deep filter paperboard increases gradually in the thickness direction and the range of change is too large, which easily leads to excessive amount of charged impurities falling off locally in the deep filter paperboard, and it is impossible to achieve a lower degree of charged impurity shedding under the conventional flushing process and flushing amount.

[0158] According to the data comparison between Example 1 and Example 16, the proportion of diatomaceous earth in the deep filter paperboard decreases gradually in the thickness direction, which will make the resistance encountered by the fluid when passing through the rear end of the deep filter paperboard still relatively large, and the force between the fluid and the rear end of the deep filter paperboard is greater. The rear end of the deep filter paperboard is more likely to drop charged impurity fragments, resulting in the charged impurity shedding amount of the deep filter paperboard not being easy to reduce to a low level.

[0159] According to the data comparison between Example 1 and Example 17, when the tightness of the deep filter paperboard is low, even if the proportion of diatomaceous earth in the thickness direction increases gradually, it does not significantly help to reduce the level of charged impurities falling from the deep filter paperboard, and the level of charged impurities falling from the deep filter paperboard still cannot reach a lower level.

[0160] As for the adsorption capacity of protein aggregates, when the total charge, layered charge, overall hydrophobicity, layered hydrophobicity, overall tightness, layered tightness, overall diatomaceous earth content and layered diatomaceous earth content of the paperboard all meet the scope of this application, the higher the total charge, the lower the deviation of the layered charge gradient distribution, the higher the overall hydrophobicity, the greater the amplitude of the hydrophobicity gradient distribution, the higher the overall tightness, the greater the amplitude of the tightness gradient distribution, the higher the overall diatomaceous earth content and the greater the amplitude of the diatomaceous earth proportion gradient distribution, the more beneficial it is for the adsorption of protein aggregates.

[0161] This specific embodiment is merely an explanation of the present invention and is not a limitation of the present invention. After reading this specification, those skilled in the art may make non-creative modifications to the present embodiment as needed. However, as long as they are within the scope of the claims of the present invention, they are protected by the patent law.

Claims

1. A low-dissolution deep filter paperboard, comprising fibers, filter aids and a binder, wherein the deep filter paperboard has a liquid inlet surface for receiving a liquid to be filtered and a liquid outlet surface for discharging a permeated liquid, characterized in that: The deep filter paperboard contains positive charges, and the degree of positive charge is controlled as follows: When the effective filtration area is 13cm 2 After the deep filter paperboard is rinsed with ultrapure water, a soap yellow dye solution with a concentration of 50ppm is supplied. When the absorbance of the permeate at a wavelength of 418nm rises to 0.05A, the total volume V of the permeate is 30-135ml; The deep filter paperboard is hydrophobic, and the degree of hydrophobicity is controlled as follows: A 0.5 g / L IvIg protein solution was supplied from the feed surface to the deep filter paperboard, and the IvIg protein was captured by the deep filter paperboard, and filtered at 100 L / m 2 , the reduction of IvIg protein concentration in the filtered solution compared with the initial concentration is 2-20%; The deep filter paperboard also has the following properties: Take the effective filtration area as 23cm 2 The deep filter paperboard is washed with ultrapure water at a flow rate of 600LMH at room temperature. When the washing volume reaches 60L / m 2 Above, the ammonium ion concentration Q in the rinse solution is less than 50 ppb.

2. The low dissolution depth filter paperboard according to claim 1, characterized in that: The deep filter paperboard is divided into a first area, a second area and a third area in a thickness direction, equidistant from the liquid inlet surface to the liquid outlet surface; The overall tightness of the deep filter paperboard is 0.3-0.4 g / cm 3 The tightness of the first area is t1, the tightness of the second area is t2, the tightness of the third area is t3, and the deviations of t2, t3 and t1 are 0.1-15%.

3. The low dissolution depth filter paperboard according to claim 1, characterized in that: The deep filter paperboard is divided into a first area, a second area and a third area in a thickness direction, equidistant from the liquid inlet surface to the liquid outlet surface; The first area, the second area and the third area are respectively supplied with 0.5 g / L of IvIg protein solution and filtered at 100 L / m 2 Afterwards, the decreases in the concentrations of IvIg proteins in the filtered solutions compared to the initial concentrations were C1, C2, and C3, respectively; C1, C2, and C3 increased in turn; C1:C2:C3 is 1:1~2:1.5~3.

4. The low dissolution depth filter paperboard according to claim 1, characterized in that: The deep filter paperboard is divided into a first area, a second area and a third area in a thickness direction, equidistant from the liquid inlet surface to the liquid outlet surface; When the first region, the second region and the third region are supplied with a soap yellow dye solution with a concentration of 50 ppm, when the absorbance of the permeate at a wavelength of 418 nm rises to 0.05A, the total volumes of the permeate are V1, V2 and V3 respectively; The deviation between V2, V3 and V1 is 0 to 35%.

5. The low dissolution depth filter paperboard according to claim 1, characterized in that: The deep filter paperboard is equally divided into a first region, a second region and a third region from the liquid inlet surface to the liquid outlet surface in the thickness direction; the filter aid content in the first region accounts for B1, the filter aid content in the second region accounts for B2, and the filter aid content in the third region accounts for B3; B1:B2:B3 is 1:1.2-2:2-3.

6. The low dissolution depth filter paperboard according to claim 1, characterized in that: When the effective filtration area is 0.45cm 2 The deep filter paperboard is rinsed with ultrapure water and the flushing volume reaches 100L / m 2 The rinse water after washing is mixed with the DNA standard sample, and the mixed solution is the DNA test sample; the DNA content ratio between the DNA test sample and the DNA standard sample is 0.7-1; wherein, the DNA standard sample is a 20% vol DNA aqueous solution.

7. The low dissolution depth filter paperboard according to claim 1, characterized in that: At a constant pressure of 100 kPa and 20°C, ultrapure water is passed through an effective filtration area of ​​23 cm 2 The deep filter paperboard has a flow rate of not less than 0.2 L / min.

8. The low dissolution depth filter paperboard according to claim 1, characterized in that: The dry bursting strength of the deep filter paperboard is 400-700 kPa, and the wet bursting strength is 100-300 kPa.

9. The low dissolution depth filter paperboard according to claim 1, characterized in that: The fibers include hydrophobic fibers selected from one or more of polyacrylonitrile fibers, polyolefin fibers, polyester fibers, and hydrophobically modified natural fibers.

10. The low dissolution depth filter paperboard according to claim 1, characterized in that: The monomer of the binder is a water-soluble monomer, and the binder becomes a water-insoluble polymer after being heated and polymerized.

11. The low dissolution depth filter paperboard according to claim 10, characterized in that: The binder comprises a water-soluble synthetic polymer based on urea or melamine-formaldehyde polymers, polyaminopolyamide-epichlorohydrin polymers or glyoxylated polyacrylamide resins.

12. The low dissolution depth filter paperboard according to claim 1, characterized in that: The filter aid is selected from one or more of diatomaceous earth particles, hydrophobically modified diatomaceous earth particles, silicon dioxide, perlite and silicate.

13. The low dissolution depth filter paperboard according to claim 12, characterized in that: The D of the filter aid 50 The particle size is controlled to be 1-40 μm, and the pore size of the filter aid is controlled to be 20-600 nm.

14. A virus filtration system using the low-dissolution depth filter paperboard according to any one of claims 1 to 13, characterized in that: It comprises a deep filter and a virus removal filter which are assembled in sequence along the filtering direction of the system; the deep filter paperboard serves as the filtering medium of the deep filter.

15. A virus filtration system using the deep filter paperboard according to claim 14, characterized in that: A layer of nylon membrane is arranged between the deep filter and the virus removal filter. The pore size of the nylon membrane is 0.1 to 0.4 μm and the thickness is 100 to 300 μm.

16. A method for preparing the low dissolution depth filter paperboard according to any one of claims 1 to 13, characterized in that: The following steps are involved: S1: beating, selecting fibers for beating, and controlling the beating degree to be 30-70°SR to obtain fiber slurry; S2: Mixing, firstly, the binder is divided into two equal parts, one of which is added to the fiber slurry, stirred at a speed of 50-100 rpm for 1-2 hours, and the pH is adjusted to 7-10, then the filter aid is added to the fiber slurry, stirred at a speed of 20-50 rpm for 1-2 hours, and finally the other binder is added to the fiber slurry, stirred at a speed of 100-200 rpm for 2-3 hours, and the pH is adjusted to 7-10 to obtain a mixed slurry; S3: Forming, spreading the mixed slurry on the screen, and using vacuum to suck the side of the screen where the mixed slurry is not spread to obtain a predetermined shape of the initial finished product; the vacuum degree is controlled to be -100 to -10kPa; S4: Drying: Dry the finished product to a moisture content of no more than 5%; S5: Punching, cutting the primary finished product into finished products; Wherein, the fiber raw material in step S1 includes hydrophobic fibers and / or the filter aid includes hydrophobically modified diatomaceous earth particles.

17. The method for preparing a depth filter paperboard according to claim 16, wherein the binder comprises a water-soluble synthetic polymer based on urea or melamine-formaldehyde polymer, a polyaminopolyamide-epichlorohydrin polymer or a glyoxylated polyacrylamide resin.

18. The method for preparing a deep filter paperboard according to claim 16, characterized in that: In step S3, the molding stage is divided into a high vacuum stage and a low vacuum stage. The vacuum degree of the high vacuum stage is controlled to be -60 to -50 kPa, and the time of the high vacuum stage is 1 to 2 minutes; the vacuum degree of the low vacuum stage is controlled to be -30 to -10 kPa, and the time of the low vacuum stage is 5 to 10 minutes.

19. The method for preparing a deep filter paperboard according to claim 16, characterized in that: In the drying process of step S4, the drying temperature is controlled to be 120-200° C. and the drying time is 5-8 hours.

20. The method for preparing a deep filter paperboard according to claim 16, characterized in that: The drying process in step S4 is divided into a rapid heating stage, a slow heating stage and a constant temperature stage. The heating rate in the rapid heating stage is controlled to be 5-10°C / min, and the low heating stage is entered when the temperature is increased to 10-15°C away from the drying set temperature; the heating rate in the slow heating stage is controlled to be 1-2°C / min, and the constant temperature stage is entered after the temperature is increased to the drying set temperature.

21. A filtration method for removing protein aggregates and viruses in a fluid using the low-dissolution depth filter paperboard according to any one of claims 1 to 13, characterized in that: The following steps are involved: A1: Use a deep filter paperboard that is rinsed with ultrapure water until the conductivity of the rinse fluid is less than 30 μS / cm to filter the fluid containing protein aggregates and / or viruses; A2: The filtrate from step A1 is then passed through at least one virus filter with a molecular weight cutoff of 50 to 150 kD; Before performing step A1, the virus content in the fluid does not exceed 0.1%.

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