WO2023134443A1 - 一种用于含蛋白料液除病毒过滤的过滤装置及进行含蛋白料液除病毒过滤的方法 - Google Patents

一种用于含蛋白料液除病毒过滤的过滤装置及进行含蛋白料液除病毒过滤的方法 Download PDF

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Publication number
WO2023134443A1
WO2023134443A1 PCT/CN2022/142613 CN2022142613W WO2023134443A1 WO 2023134443 A1 WO2023134443 A1 WO 2023134443A1 CN 2022142613 W CN2022142613 W CN 2022142613W WO 2023134443 A1 WO2023134443 A1 WO 2023134443A1
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layer
virus
filter
filtrate
liquid inlet
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PCT/CN2022/142613
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English (en)
French (fr)
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贾建东
杨凯
徐希晨
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杭州科百特过滤器材有限公司
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Publication of WO2023134443A1 publication Critical patent/WO2023134443A1/zh

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D36/00—Filter circuits or combinations of filters with other separating devices
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D29/00—Filters with filtering elements stationary during filtration, e.g. pressure or suction filters, not covered by groups B01D24/00 - B01D27/00; Filtering elements therefor
    • B01D29/50—Filters with filtering elements stationary during filtration, e.g. pressure or suction filters, not covered by groups B01D24/00 - B01D27/00; Filtering elements therefor with multiple filtering elements, characterised by their mutual disposition
    • B01D29/56—Filters with filtering elements stationary during filtration, e.g. pressure or suction filters, not covered by groups B01D24/00 - B01D27/00; Filtering elements therefor with multiple filtering elements, characterised by their mutual disposition in series connection
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor

Definitions

  • the invention relates to the technical field of biological filtration, in particular to a filter device for virus-removing filtration of protein-containing material liquid and a method for performing virus-removal filtration of protein-containing material liquid.
  • recombinant protein and antibody drugs have become an important part of biomedicine due to their wide application in the treatment of various major diseases.
  • recombinant protein drugs are products expressed by genetic engineering technology, which are used to make up for the lack of certain functional proteins in the human body.
  • Antibody drugs such as monoclonal antibodies, are antibodies secreted by a single B lymphocyte clone. Cells can only produce a specific antibody against one antigenic determinant, so it has the characteristics of highly specific physical and chemical properties, single biological activity, and strong binding specificity to antigens. It has achieved great achievements in the field of tumor and autoimmune disease treatment Great progress.
  • domestic recombinant protein and antibody drugs have occupied more than one-third of the biopharmaceutical market, and they are also the fastest growing and most promising development direction in the pharmaceutical field.
  • a cassette filter device is usually used for virus removal and filtration, such as the patent CN112387119A, but the cassette filter is not only complicated to prepare, but also the filter membrane needs to be welded with the shell, here It is easy to cause damage to the filter membrane during the process, thus affecting the final filtration effect.
  • the object to be achieved by the present invention is to provide a filter device for virus removal and filtration of protein-containing material liquid and a method for virus removal and filtration of protein-containing material liquid.
  • the structure is simple, easy to operate, and the virus removal rate is high.
  • a filter device for virus removal and filtration of protein-containing feed liquid comprising:
  • a filter unit which at least includes a filtrate diversion screen and a filter layer arranged on the side of the filtrate diversion screen; a plurality of the filter units are stacked, and a liquid inlet channel is formed between the filter units;
  • An encapsulation layer used for encapsulating and fixing multiple filter units stacked;
  • the liquid inlet channel is used to transport the protein-containing feed liquid to be filtered to the liquid inlet channel;
  • the filtrate channel communicates with the filtrate diversion screen and is used to discharge the protein-containing feed liquid after virus removal;
  • the filter layer includes a virus-removing membrane, the virus-removing membrane has an LRV of not less than 4 for viral impurities, and the protein yield is not lower than 98%, and the virus-removing membrane includes a pre-filter layer and is used to retain viruses, and
  • the separation layer has a pore size smaller than that of the pre-filter layer, and at least one pre-filter layer is located on the surface of the virus-removing membrane away from the filtrate diversion screen.
  • the filter device of the present invention has a plurality of filter units, as well as liquid inlet channels and filtrate channels, wherein the filter units are stacked and sealed by the outer peripheral packaging layer, wherein the liquid inlet channels are only communicated with the liquid inlet channels formed between the filter units , the filtrate channel is only connected with the filtrate diversion screen in the filter unit; when the protein-containing material liquid is filtered for virus removal, the protein-containing material liquid to be filtered can be transported into the liquid inlet channel through the liquid inlet channel.
  • the protein-containing material liquid will be covered with the liquid inlet channel, and the filter layer will be filtered through the filter layer to form a permeate and enter the filtrate diversion screen, which is stacked in the internal filter unit, and both sides of the filtrate diversion screen are A filter layer is provided, and in the outermost filter unit, the filtrate diversion screen can only be provided with a filter layer towards the inside, where the filtrate diversion screen can support the flow channel between the filter layer and the liquid surface. Open, prevent the filter layer from sticking to each other, and give the filter unit a good filtration space. Finally, the permeate is discharged through the filtrate channel connected to the filtrate diversion screen to obtain the target virus-removing protein-containing material liquid.
  • the filter layer of the present invention adopts a virus-removing membrane with an LRV of not less than 4 for virus impurities and a protein yield of not less than 98%.
  • the protein feed liquid has a good virus-removing filtration effect; wherein, the virus-removing membrane includes a pre-filter layer and a separation layer for retaining viruses and having a pore size smaller than the pre-filter layer, and at least one layer of the pre-filter layer is located away from the virus-removing membrane to guide the filtrate
  • the virus-removing membrane includes a pre-filter layer and a separation layer for retaining viruses and having a pore size smaller than the pre-filter layer, and at least one layer of the pre-filter layer is located away from the virus-removing membrane to guide the filtrate
  • the surface of one side of the screen so in the process of use, the protein-containing liquid to be filtered first passes through the pre-filter layer, wherein the pre-filter layer has a larger pore size and can be used to hold dirt, mainly retaining large particles of impurities in the fluid, And it is beneficial to improve the overall filtration speed of the virus removal membrane, so that the time for filtering the protein-containing material liquid is shorter and the time cost is lower.
  • the filtration accuracy of the virus membrane ensures that the virus removal membrane has a high interception effect on viruses. Therefore, at least one pre-filter layer is located on the side of the virus removal membrane away from the filtrate diversion screen. At this time, it is ensured that the liquid inlet surface of the virus removal membrane has a relatively large pore size, a large amount of dirt, and can remove larger particles of impurities in advance. , It is not easy to be clogged and achieves a good filtering effect. Therefore, the invention has simple structure and convenient operation, and has a good virus-removing effect on protein-containing feed liquid.
  • Both the liquid inlet channel and the filtrate channel are located in the filter unit;
  • At least one of the liquid inlet channel and the filtrate channel is arranged on the packaging layer.
  • both the liquid inlet channel and the filtrate channel can be arranged in the filter unit.
  • the liquid inlet channel and the filtrate channel run through the filter unit. Since the protein-containing material liquid is filtered, the permeate will flow to the filtrate channel, so it is far away from the filtrate.
  • the permeate in the filtrate diversion screen of the channel needs to flow to the filtrate diversion screen near the filtrate channel first, which leads to uneven filtration efficiency of the virus removal membrane in each area, and when the liquid inlet channel and the filtrate channel can be set In the filter unit, especially when the liquid inlet channel and/or the filtrate channel are located in the middle of the filter unit, it can make the virus removal membrane filter more evenly and increase the service life of the filter device.
  • liquid inlet channel and the filtrate channel can be arranged in the encapsulation layer, and the liquid inlet channel and/or the filtrate channel are arranged in the encapsulation layer compared to both being arranged in the filter unit, which can prevent the filter unit from being effectively used. area reduction.
  • a liquid inlet diversion screen for supporting the liquid inlet channel is arranged between the filter units.
  • the setting of the liquid inlet diversion screen can support the gap between the filter units and play the role of forming the liquid inlet channel, so that the protein-containing material liquid is transported to the liquid inlet channel more smoothly, and the filtration is more uniform.
  • the filtration of the protein-containing material liquid in the present invention is dead-end filtration, it is necessary to apply a certain pressure to impel the protein-containing material liquid to be filtered from the filter layer.
  • the thickness of the virus-removing membrane of the filter layer is relatively thin, the bonding between the edge section of the virus-removing membrane and the encapsulation layer is not firm, and the protein-containing material liquid easily breaks through the bond between the virus-removing membrane and the encapsulation layer under pressure.
  • a liquid inlet guide is set Screen
  • the adhesive in the encapsulation layer can penetrate into the liquid inlet diversion screen during the encapsulation process, and the encapsulation layer formed by the adhesive that penetrates into the liquid inlet diversion screen can further bond with the surface of the virus removal membrane , can block the impact of the virus-containing feed liquid during the filtration process, and the width of the encapsulation layer formed by the adhesive that penetrates into the liquid-inlet diversion screen is adjustable, so as to ensure a firm bond with the virus-removing membrane; therefore, by carrying out
  • the setting of the liquid diversion screen can increase the sealing between the encapsulation layer and the virus removal membrane, and the virus removal membrane of the present invention is away from the surface of the side of the filtrate diversion screen, that is
  • the virus-removing surface bonded and sealed by the encapsulation layer is a pre-filter layer with a larger pore size. This is because during the bonding process, the pore size is larger, which is conducive to the embedding of the adhesive, thereby further increasing the penetration into the liquid inlet diversion screen. Adhesive sealability of the encapsulation layer to the virus-removing surface.
  • virus-removing membrane separation layer is located on the surface of the virus-removing membrane on the side close to the filtrate diversion screen.
  • the separation layer of the virus removal membrane is close to the side of the filtrate diversion screen.
  • the virus-containing feed liquid first passes through the pre-filtration layer, then flows through the separation layer, and finally reaches the filtrate diversion without going through the pre-filtration layer again.
  • Screen mesh while ensuring good filtration effect, simplifies the structure of the virus removal membrane.
  • the outer side of the pre-filter layer is the first outer surface, the average pore diameter of the first outer surface is 160-440nm, and the pore area ratio of the first outer surface is 0.5-14%;
  • the outer side of the separation layer is the second outer surface, the average pore diameter of the second outer surface is 12-40nm, and the pore area ratio of the second outer surface is 2.5-9%.
  • the average pore diameters of the first outer surface and the second outer surface are different, which not only ensures a faster flow rate and a dirt-holding space for the membrane as a whole, but also has higher filtration precision.
  • the average pore diameter and the pore area ratio of the first outer surface in the present invention have a certain influence on the bonding firmness between the first outer surface of the virus-removing membrane and the encapsulation layer, and the average pore diameter has influenced the adhesion on the encapsulation layer.
  • the degree to which the binder can penetrate into the pre-filter layer, the average pore size of the first outer surface is too small will lead to insufficient penetration, and the bonding force is relatively small; while the pore area ratio of the first outer surface affects the penetration of the adhesive on the packaging layer. If the area ratio of the first outer surface is too small, the adhesive cannot penetrate effectively, and the adhesive force is relatively small.
  • the average pore size of the virus-removing membrane changes continuously in a gradient from the surface area on the side close to the filtrate diversion screen to the surface area on the side away from the filtrate diversion screen, and the average pore size change gradient is 2-5.5 ⁇ m/1 ⁇ m.
  • the average pore size of the virus-removing membrane can change with the thickness gradient, and the specific value of the average pore size gradient can be obtained by the difference/thickness of the average pore size on both sides of the surface, so the unit is ⁇ m (representing the pore size)/1 ⁇ m (representing the thickness),
  • the pore diameter gradually decreases from the surface area on the side away from the filtrate diversion screen towards the surface area on the side close to the filtrate diversion screen, and the average pore size change gradient is 2-5.5 ⁇ m/1 ⁇ m, and the change gradient value is relatively small , illustrates that the membrane pore size of the present invention changes with a small gradient along with the thickness, the membrane pore size will not change too fast, and there will be no too large holes (when the holes of the pre-filter layer are too large, the overall mechanical strength of the membrane will be too low, It is not pressure-resistant, it is easy to be damaged under pressure), then the pre-filter layer can play a certain supporting role for the separation layer at this time, and
  • the average pore diameter of the pre-filter layer is 55-190 nm, and the average pore diameter of the separation layer is 16-23 nm; the ratio of the average pore diameter of the pre-filter layer to the average pore diameter of the separation layer is 4-12.
  • the virus removal membrane cannot achieve a good filtration flux; while the pore size of the separation layer is too large, it is easy to make the separation layer unable to play a good interception effect; It is beneficial to ensure the larger flux and higher retention efficiency of the virus removal membrane.
  • the ratio of the average pore size of the pre-filtration layer to the average pore size of the separation layer is within a limited range, it not only ensures that the filter membrane has a large flux and a long service life; it also ensures that the filter membrane has a high interception efficiency for viruses. meet actual needs. If the ratio is too large or too small, it may easily lead to insufficient filtration precision or too small flux.
  • the thickness of the pre-filter layer accounts for 72-89% of the thickness of the virus-removing membrane, and the porosity is 77-90%; the thickness of the separation layer accounts for 11-28% of the thickness of the virus-removing membrane, and the porosity is 62-78%. %.
  • the thickness of the pre-filtration layer in the virus-removing membrane of the present invention is relatively high, and the porosity is also relatively high, which ensures that the overall membrane has high flux and dirt holding capacity, fast filtration speed, and long service life; the thickness of the separation layer is The proportion is relatively low, and the porosity is also relatively low. On the basis of further ensuring the high flux of the membrane, it can play a sufficient interception effect on viruses and ensure the filtration effect.
  • the thickness of the virus-removing membrane is 45-140 ⁇ m.
  • the thickness of the virus-removing membrane When the thickness of the virus-removing membrane is too small, the mechanical strength of the membrane will be low; at the same time, due to the short filtration time, effective filtration cannot be performed; when the thickness of the membrane is too large, the filtration time will be too long, and the time The cost is too high; the thickness of the virus-removing membrane is within the scope of the present invention, not only has high mechanical strength, but also can perform effective filtration with high filtration efficiency, short filtration time and low time cost.
  • polyethersulfone virus-removing membranes regenerated cellulose virus-removing membranes, cellulose acetate virus-removing membranes or polyvinylidene fluoride virus-removing membranes.
  • the filter layer is a multi-layer virus-removing film
  • each layer of virus-removing film is provided with an encapsulation hole
  • the encapsulation hole is at least partially connected to the liquid inlet channel
  • the multi-layer virus-removal film at least includes the largest encapsulation hole
  • the first virus-removing membrane with the inner diameter and the second virus-removing membrane with the smallest inner diameter of the packaging hole, and the multi-layer virus-removing membranes are stacked to form a radial dislocation area at the packaging hole;
  • a ring-shaped sealing layer is formed in the packaging hole, and the ring-shaped sealing layer covers the inner wall of the liquid inlet channel at the filtrate diversion screen, and the inner wall of the first virus-removing membrane packaging hole and the diameter between the adjacent packaging holes. To the dislocation area, so that each layer of virus-removing membranes and between the filtrate diversion screen and the filter layer form a sealed connection.
  • the multi-layer virus removal film design in order to make the virus removal efficiency higher, the multi-layer virus removal film design can be adopted.
  • a ring-shaped glue seal layer is formed in the packaging hole between the membranes, and the ring-shaped glue seal layer fills the radial dislocation area between adjacent virus removal membranes, and the inner wall of the liquid inlet channel at the filtrate diversion screen, and the second A virus-removing membrane is located on the inner wall of the packaging hole.
  • part of the adhesive penetrates into the filtrate diversion screen to fill the mesh holes of the filtrate diversion screen, and the virus-removal membrane close to the filtrate diversion screen is directly bonded to it , and at the same time, the inner wall of the liquid inlet channel at the filtrate diversion screen is covered with a ring-shaped glue seal layer; since the virus-removing membrane does not penetrate the adhesive, the rest of the virus-removing membrane passes through the radial dislocation area between the packaging holes The filled adhesive forms a package, which firmly adheres adjacent virus-removing membranes. At the same time, a ring-shaped sealing layer is also adhered to the inner wall of the packaging hole of the first virus-removing membrane, which also shows that it has the largest inner diameter of the packaging hole.
  • the side wall of the first virus-removing membrane must be encapsulated with a ring-shaped sealing layer, so that the multi-layer virus-removing membranes can be adhered through the radial dislocation area adhesion, so the ring-shaped sealing layer makes all the virus-removing membranes and A solid bond is formed between the filtrate diversion screens to prevent the unfiltered virus-containing liquid from penetrating through the gaps and ensure a good filtration effect of the virus-removing membrane; the side of the ring-shaped rubber seal layer is sealed with the virus-removing membrane , the upper and lower sides can firmly adhere the adjacent virus-removing membranes, thereby sealing the packaging holes, and ensuring that the protein-containing material liquid to be filtered enters from the liquid inlet channel during filtration.
  • the second virus-removing membrane is located on the side of the filter layer away from the filtrate diversion screen; or, the second virus-removal membrane is located on the side of the filter layer close to the filtrate diversion screen.
  • the second virus-removing film with the largest inner diameter of the packaging hole is located on the outside, so that the adhesive can flow along the packaging hole with a larger inner diameter to the packaging hole with a relatively smaller inner diameter.
  • the second virus-removing membrane with the largest inner diameter of the packaging hole is located on the inner side, avoiding the second virus-removing membrane with the smallest inner diameter of the packaging hole being located on the inner side, causing the second virus-removing membrane to be located in the packaging hole during the scraping process in the packaging hole
  • the rubber layer on the inner wall is scraped off, so that the annular rubber seal layer cannot achieve a good sealing effect, and at the same time, the adhesive can flow along the steps to achieve a better sealing effect.
  • the inner diameter of the packaging hole changes in steps, and it gradually becomes smaller from the side close to the filtrate diversion screen, or it gradually becomes larger from the side closer to the filtrate diversion screen.
  • the ring-shaped sealing layer can cover all the radial dislocation areas.
  • the above-mentioned structural design makes the bonding firmer between all the virus-removing membranes of the filter layer; There is not only a ring-shaped glue seal layer on the side wall between the virus membranes, but also a ring-shaped glue seal layer on the steps of the radial dislocation area, and the adhesion between each virus-removing membrane is more stable. Stable bonding is achieved, and the protein-containing material liquid is not easy to break through the ring-shaped adhesive seal layer, causing the flow channel to penetrate into the packaging hole, so that the permeate is discharged from the filtrate channel connected to the filtrate diversion screen.
  • the filter unit further includes an isolation layer arranged between the filter layer and the filtrate diversion screen.
  • an isolation layer is arranged between the filter layer and the filtrate diversion screen, and the isolation layer plays the role of isolating the filter layer and the filtrate diversion screen, so as to prevent the filtrate diversion screen from being embedded in the filter layer during the filtration process and causing damage to the filter layer.
  • the damage of its membrane hole forms a good protective effect on the filter layer; when filtering, the two sides of the isolation layer can be respectively attached to the filter layer and the filtrate diversion screen, or there can be a gap between the isolation layer and the filter layer, There is also a gap between the isolation layer and the filtrate diversion screen.
  • the isolation layer not only plays the role of isolation, but also plays the role of diversion, that is, the isolation layer cooperates with the filtrate diversion screen to form a two-layer drainage space to reduce back pressure. , Increase the filtration flux, make the filtration smoother and improve the filtration efficiency.
  • the surface roughness of the isolation layer close to the filter layer is 2-25 ⁇ m, and the softness is 100-250 mN.
  • the surface roughness of the isolation layer close to the filter layer is too large to form multiple protrusions.
  • the protrusions are embedded in the pores of the virus removal membrane, which damages the pore structure of the virus removal membrane; or the filter layer is embedded in the adjacent
  • the filtration efficiency is reduced; the selected value of the above surface roughness can reduce the influence on the filter layer under the premise of ensuring the flatness of the surface of the isolation layer.
  • the softness of the isolation layer will also have an impact on the filter layer.
  • the softness of the isolation layer is too small, it will cause hard protrusions to damage the filter layer, while if the softness is too large, it will easily deform, which will easily cause the gap between the filter layer and the isolation layer. Between the folds, affect the filtration efficiency.
  • the thickness of the isolation layer is h1
  • the thickness of the filtrate diversion screen is h2
  • h1:h2 is 1:1-5.
  • the thinner the isolation layer the larger the drainage space and the higher the contribution to the filtration flux.
  • the thickness of the filter device will increase, while if the thickness is too small, it will not be able to achieve a good isolation effect and will easily deform.
  • the filter diversion screen is embedded in the virus removal membrane; the selection of the above thickness ratio can ensure the filtration efficiency while avoiding the excessive thickness of the overall filter device.
  • the thickness of the isolation layer is 80-150 ⁇ m, and the air permeability is 60-160 cc/cm 2 /sec; the thickness of the filtrate diversion screen is 400-650 ⁇ m, and the porosity is 25-35%.
  • the thickness of the isolation layer is within the above value range, which can play a good isolation role, avoid the embedding of the virus removal membrane, and have more drainage space, which increases the filtration flux; if the air permeability is too large, there will be too many pores, which is easy to As a result of the embedding of the filtrate diversion screen, if the air flow is too small, the filtration flux will be reduced; and within the numerical range of the air flow above, when the virus removal filter device is packaged, the adhesive can penetrate well, which is convenient for virus removal filtration Packaging of the device.
  • the thickness and porosity of the filtrate diversion screen can ensure that the filtration flux of the virus removal filter device is in an appropriate range, and at the same time ensure good filtration efficiency.
  • the fiber diameter of the isolation layer is 10-25 ⁇ m, and the grammage is 15-40 g/m 2 .
  • the isolation layer of the present invention has better supporting performance and has a smaller specific surface area, which not only reduces the non-specific adsorption of the isolation layer to proteins, but also reduces the loss caused by repeated collisions between the protein and the fibers of the isolation layer. The probability of living, and during the flow of the permeate, there are fewer eddies formed in the isolation layer, which reduces the shear force on the protein and makes the protein yield and effective protein rate higher.
  • the isolation layer is one or more of non-woven fabric, woven fabric or porous film.
  • the isolation layer is provided with an isolation layer liquid inlet that is at least partially in direct communication with the liquid inlet channel, and the isolation layer is bonded to the filter layer and the filtrate diversion screen through the adhesive layer on the isolation layer.
  • the adhesive layer penetrates into the isolation layer and surrounds the liquid inlet of the isolation layer, and the adhesive layer covers the inner wall of the liquid inlet of the isolation layer, so as to avoid the formation of a gap between the liquid inlet of the isolation layer and the isolation layer.
  • the adhesive layer of the present invention can permeate in the isolation layer, so as to achieve the purpose of bonding with the filter layer and the filtrate diversion screen, and, in order to prevent liquid from entering from the inner wall of the liquid inlet of the isolation layer, the adhesive layer of the present invention is surrounded by
  • the liquid inlet of the isolation layer covers the inner wall of the liquid inlet of the isolation layer, avoiding the formation of a penetrating liquid flow channel from the inner wall of the liquid inlet of the isolation layer between the liquid inlet of the isolation layer and the isolation layer, thereby blocking the liquid from entering from the isolation layer.
  • the liquid exits and enters.
  • a stepped dislocation area is formed between the liquid inlet of the isolation layer and the inner wall of the liquid inlet channel of the filter layer.
  • the setting of the step dislocation area enables the adhesive to fill in the step dislocation area, and the sealing of the isolation layer and the filter layer can also be realized without the adhesive penetrating into the isolation layer, so as to prevent the liquid from flowing between the isolation layer and the filter layer.
  • the gaps flow out to ensure a good filtration effect of the virus-removing membrane.
  • a method for virus-removing filtration of a protein-containing material liquid by using a filter device comprising the following steps:
  • Buffer replacement The buffer is continuously delivered from the liquid inlet channel to the liquid inlet flow channel until it flows out from the filtrate channel of the filter device to form a permeation buffer, so that the buffer is filled with the filter device;
  • Feed liquid continuously transport the protein-containing material liquid from the liquid feed channel to the liquid feed channel;
  • the filter device when the filter device is used to remove virus from the protein-containing feed liquid, it is first necessary to replace the original protective liquid or air in the filter device with the buffer solution, that is, the buffer solution is continuously transported from the liquid inlet channel to the liquid inlet channel until Flow out from the filtrate channel of the filter device, so as to ensure that the buffer can fill the filter device, and then perform the liquid inlet operation.
  • the liquid inlet channels can be simultaneously fed into the liquid, preferably When there are multiple liquid inlet channels, feed the protein-containing material liquid to one liquid inlet channel, and block the rest. To adjust, it is necessary to adjust the liquid inlet pressure of multiple liquid inlet channels to cooperate.
  • liquid inlet pressure in step S2 is 20-40 psi.
  • the filtration flux is greater than 180L/(m 2 *h).
  • the filter device of the present invention is simple in structure, easy to operate, and has a good virus-removing effect on the protein-containing material liquid.
  • the virus-removing membrane adopted includes a pre-filter layer and a separation layer for retaining viruses and has a pore size smaller than the pre-filter layer. There is at least one layer
  • the pre-filtration layer is located on the surface of the virus removal membrane away from the filtrate diversion screen, which not only ensures the efficient retention of viruses by the filter device, but also has a large flux and dirt holding capacity.
  • Fig. 1 is a schematic diagram of the exploded structure of the filter device of the present invention.
  • Fig. 2 is a cross-sectional view of the filter device of the present invention.
  • Fig. 3 is a partial cross-sectional view of the filter unit of the present invention (not including the annular glue seal layer), and the isolation layer is non-woven fabric at this time.
  • Fig. 4 is a partial cross-sectional view of the filter unit of the present invention, at this time, the isolation layer is non-woven fabric.
  • Fig. 5 is a partial cross-sectional view of the filter unit of the present invention (not including the annular glue seal layer), and the isolation layer is a porous membrane at this time.
  • Fig. 6 is a partial sectional view of the filtration unit of the present invention, where the isolation layer is a porous membrane.
  • Fig. 7 is an electron microscopic image of non-woven fabric as the isolation layer of the present invention.
  • Fig. 8 is a partial sectional view of the filter unit of the present invention (not including the annular glue seal layer), and the number of virus-removing membranes is three layers at this time.
  • Fig. 9 is a partial cross-sectional view of the filter unit of the present invention, at this time, the number of virus-removing membranes is three layers.
  • Fig. 10 is a cross-sectional view of the virus-removing filter device of the present invention, at this time, the virus-removing membrane includes a pre-filter layer and a separation layer.
  • Fig. 11 is an electron micrograph of the virus-removing membrane of the present invention including a pre-filter layer and a separation layer.
  • Fig. 12 is a cross-sectional view of the virus-removing filter device of the present invention, at this time, the virus-removing membrane includes two pre-filter layers and a separation layer.
  • Fig. 13 is a schematic diagram of a filtering device according to Example 2 of the present invention.
  • Fig. 14 is a cross-sectional view of the liquid inlet channel of the filter device according to Embodiment 2 of the present invention.
  • Fig. 15 is a cross-sectional view of the filtrate channel of the filtering device of Example 2 of the present invention.
  • Fig. 16 is a schematic diagram of a filtering device according to Embodiment 3 of the present invention.
  • Fig. 17 is a schematic diagram of an exploded structure of a filter device according to Embodiment 5 of the present invention.
  • a filter device for virus removal and filtration of protein-containing feed liquid includes:
  • the liquid inlet diversion screen 1 has a first liquid inlet port 11 and a first filtrate port 12, which are used to guide the fluid to be filtered to permeate along a tangential direction;
  • first liquid inlet 11 and the first filtrate port 12 are respectively provided at both ends of the liquid inlet diversion screen 1, and the inner wall of the first filtrate port 12 passes through the adhesive seal;
  • the filter unit 2 is arranged downstream of the liquid inlet diversion screen 1, and is provided with a second liquid inlet 22 and a second filtrate port 23 at least partly in direct communication with the first liquid inlet 11 and the first filtrate port 12, And the two ends are respectively opened;
  • the filter unit 2 at least includes a filtrate diversion screen 3 and a filter layer 4 arranged on both sides of the filtrate diversion screen 3, and the inner side of the outermost filter unit 2 is provided with a filter layer 4;
  • the liquid inlet channel 101 and the filtrate channel 102 are both arranged in the filter unit, wherein the first liquid inlet port 11 and the second liquid inlet port 22 jointly form the liquid inlet channel 101, and the first filtrate port 12 and the second filtrate port
  • the port 23 forms a filtrate channel 102, the diameter of the first liquid inlet and the second liquid inlet is 11 mm, and the diameter of the first filtrate port and the second filtrate port is 6 mm;
  • a plurality of filter units and the liquid inlet diversion screen 1 are stacked Set and package and fix through the encapsulation layer 103; and the encapsulation layer 103 penetrates into the liquid inlet diversion screen 1, and the encapsulation layer 103 penetrated into the liquid inlet diversion screen 1 is bonded to the first outer surface of the virus removal membrane 41 fixed.
  • the liquid inlet diversion screen 1 may not be provided, and the virus-containing feed liquid can be opened by pressure after being transported into the liquid inlet channel during filtration, thereby completing the filtration.
  • the filter layer 4 includes a virus-removing membrane 41 whose LRV for viral impurities is not lower than 4, and the protein yield is not lower than 98%;
  • the virus-removing membrane 41 includes a pre-filter layer 416 and Separation layer 417, the pore size of the separation layer 417 is smaller than the pore size of the pre-filter layer 416, which is used for interception, at least one layer of pre-filter layer 416 is located on the side of the virus-removing membrane 41 away from the filtrate diversion screen.
  • the virus-removing membrane 41 includes a pre-filter layer 416 and a separation layer 417, the separation layer 417 is positioned at the side close to the filtrate diversion screen 3, and the outside of the pre-filter layer is the first
  • the outer surface, the average pore diameter of the first outer surface is 160-440nm, the pore area ratio of the first outer surface is 0.5-14%
  • the outer side of the separation layer is the second outer surface, the second outer surface
  • the average pore diameter is 12-40nm, and the pore area ratio of the second outer surface is 2.5-9%
  • the average pore diameter of the pre-filter layer is 55-190nm, and the thickness accounts for 72-89% of the thickness of the virus-removing membrane, and the porosity is 77- 90%
  • the average pore diameter of the separation layer is 16-23nm, the thickness accounts for 11-28% of the thickness of the virus-removing membrane, and the porosity is 62-78%
  • the upper side is a pre-filter layer
  • the lower side is a separation layer
  • the overall thickness of the virus-removing membrane is 60 ⁇ m
  • the average pore diameter of the first outer surface is 230 nm
  • the pore area ratio is 10.6%
  • the average pore diameter of the second outer surface is 20.6nm
  • the pore area ratio is 8.4%
  • the average pore diameter change gradient is 3.49 ⁇ m/1 ⁇ m
  • the average pore diameter of the pre-filter layer is 80nm
  • the thickness is 52 ⁇ m
  • the porosity is 81.1%
  • the separation layer The average pore size is 19nm
  • the thickness is 8 ⁇ m
  • the porosity is 74%.
  • the virus-removing membrane 41 includes two pre-filter layers 416 and a separation layer 417, and the separation layer 417 is positioned between the two pre-filter layers 416; A layer 416 is located on the side remote from the isolation layer 21 and a pre-filter layer 416 is located on the side adjacent to the isolation layer 21 .
  • the porosity of the filtrate diversion screen 3 is 25-35%, and its thickness is 400-650 ⁇ m.
  • the filter layer 4 is a single-layer virus-removing film 41 or a multi-layer virus-removing film 41.
  • the two ends of the virus-removing film 41 are respectively provided with packaging holes 411 and conduction ports 412.
  • the packaging holes 411 and the second liquid inlet 22 are at least partly connected. Directly connected.
  • the virus-removing membrane 41 is a PES virus-removing membrane
  • the filter unit 2 includes an isolation layer 21 arranged between the filter layer 4 and the filtrate diversion screen 3 .
  • the thickness of the isolation layer 21 is 80-150 ⁇ m
  • the air permeability is 60-160 cc/cm 2 /sec.
  • the pore diameter close to the filter layer 4 side surface of this isolation layer 21 is defined as d1, and the definition filter layer 4 is close to the isolation layer 21 side, that is, the average aperture on the second outer surface of the virus membrane is d2 in the present embodiment, then d1: d2 is 1000-5000. More specifically, in this embodiment, the pore size of the surface of the isolation layer 21 closer to the filter layer 4 is 20-120 ⁇ m.
  • the softness of the isolation layer 21 is 100-250mN; the surface roughness of the isolation layer 21 close to the filter layer 4 is 2-25 ⁇ m; the isolation layer 21 can be a non-woven fabric with a fiber diameter of 10-25 ⁇ m and a weight of It is 15-40g/m 2 .
  • the isolation layer 21 can also be one of woven cloth or porous film, and the material can be a polymer material, such as PP, PE, PES and the like.
  • the isolation layer 21 is provided with an isolation layer liquid inlet 211 and an isolation layer filtrate port 212 which are at least partly in communication with the second liquid inlet 22 and the second filtrate port 23 respectively.
  • Layer 61 is bonded with the filter layer and the filtrate diversion screen; wherein, the adhesive layer 61 penetrates in the isolation layer and is surrounded by the liquid inlet of the isolation layer, and the adhesive layer covers the inner wall of the liquid inlet of the isolation layer to avoid A penetrating liquid channel that enters from the inner wall of the liquid inlet of the isolation layer is formed between the liquid inlet of the isolation layer and the isolation layer.
  • the width of the adhesive layer is l
  • the diameter of the liquid inlet of the isolation layer is d
  • the diameter of the first liquid inlet is the same
  • the l:d is 1-10:10
  • the liquid inlet of the isolation layer and the second liquid inlet of the filter layer form a step dislocation area, so that the adhesive is filled in the step dislocation The area forms the adhesive layer 61 .
  • the isolation layer 21 is a non-woven fabric, as shown in FIG. Stable bonding of virus removal membrane 41.
  • the isolation layer 21 is a porous film
  • the above-mentioned stepped dislocation region 51 must be provided because the adhesive cannot penetrate into it, as shown in FIG. 5 and FIG. 6 .
  • the virus-removing membrane 41 can be one or more combination of regenerated cellulose virus-removing membrane, cellulose acetate virus-removing membrane or polyvinylidene fluoride virus-removing membrane.
  • the filter layer 4 is a multi-layer virus-removing film 41
  • each layer of the virus-removing film 41 is provided with an encapsulation hole 411 and a conduction port 412, and the encapsulation hole 411 is at least partly in communication with the second liquid inlet 22.
  • the multilayer virus removal film 41 at least includes a first virus removal film 413 with the largest packaging hole inner diameter and a second virus removal film 414 with the smallest packaging hole inner diameter, and the multilayer virus removal film 41 is stacked to form a radial Misplaced area 5.
  • a ring-shaped glue seal layer 6 is formed in the packaging hole, and the ring-shaped glue seal layer 6 covers the inner wall of the second liquid inlet 22, covers the inner wall of the isolation layer liquid inlet 211, and covers the inner wall of the first virus-removing film 413, and The radially misaligned regions 5 between adjacent packaging holes make a sealed connection between the virus-removing membranes 41 of each layer and between the filtrate diversion screen 3 and the filter layer 4 .
  • the filter layer 4 includes two layers of virus-removing membranes 41, specifically the first virus-removing membrane 413 with a larger inner diameter of the packaging hole and the first virus-removing membrane 413 with a smaller packaging hole.
  • a ring-shaped glue seal layer 6 is formed in the packaging hole, and the ring-shaped glue seal layer 6 covers the inner wall of the second liquid inlet 22, covers the inner wall of the isolation layer liquid inlet 211, and covers the first virus-removing film.
  • the conduction port 412 and the second filtrate port 23 are at least partly in communication with each other, and vacuum is drawn against the second filtrate port 23 and the conduction port 412, and the adhesive in the second liquid inlet 22 and the packaging hole 411 is injected. Under the action of negative pressure, it flows along the circumferential direction to form an annular glue seal layer 6 .
  • the number of virus-removing membranes 41 can be three layers, and the first virus-removing membrane 413 with the largest packaging hole inner diameter is located at the most far away from the filtrate diversion screen 3.
  • the second virus-removing membrane 414 with the minimum packaging hole inner diameter is arranged near the filtrate diversion screen 3
  • the third virus-removing membrane 415 is positioned between the first virus-removing membrane 413 and the second virus-removing membrane 414, and its packaging hole inner diameter is It is also smaller than the inner diameter of the packaging hole of the first virus-removing membrane 413 and larger than the inner diameter of the packaging hole of the second virus-removing membrane 414 .
  • the inner diameter of the packaging hole changes in steps, and gradually becomes larger from the side close to the filtrate diversion screen 3 to the outside.
  • the above-mentioned structural design makes the adhesion between all the virus-removing membranes 41 of the filter layer 4 more firm.
  • a ring-shaped glue seal layer 6 is formed in the packaging hole, and the ring-shaped glue seal layer 6 covers the inner wall of the third virus-removing film 415, covers the inner wall of the first virus-removing film 413, and covers the liquid inlet of the isolation layer.
  • the measurement method of the average pore size of the membrane surface can be measured by using computer software (such as Matlab, NIS-Elements, etc.) or manually after using a scanning electron microscope to characterize the membrane structure, and performing corresponding calculations;
  • computer software such as Matlab, NIS-Elements, etc.
  • this direction is the plane direction; if the membrane is in the form of a hollow fiber membrane, then this direction is perpendicular to the radial direction
  • its various characteristics such as pore size
  • the distribution is roughly uniform and basically consistent; therefore, the average pore size of the entire area on the corresponding plane can be reflected by the average pore size of the partial area.
  • the surface of the membrane can be characterized with an electron microscope to obtain the corresponding SEM image. Since the pores on the surface of the membrane are roughly uniform, a certain area can be selected, such as 1 ⁇ m2 (1 ⁇ m times 1 ⁇ m) or 25 ⁇ m 2 (5 ⁇ m multiplied by 5 ⁇ m), the specific area depends on the actual situation, and then use the corresponding computer software or manually measure the pore diameter of all holes on the area, and then calculate to obtain the average pore diameter of the surface; Personnel can also obtain the above parameters through other measurement methods, and the above measurement methods are for reference only.
  • the parameters such as the average pore size, porosity, and thickness of the pre-filtration layer and the separation layer can be divided into the separation layer and the pre-filtration layer by tearing the virus-removing membrane first, and then test the corresponding parameters of the pre-filtration layer, and the average pore size is tested by PMI pore size or by using a scanning electron microscope to characterize the cross-sectional structure of the film, and then use computer software (such as Matlab, NIS-Elements, etc.) or manually measure and measure; of course, those skilled in the art can also use
  • the above parameters are obtained by other measurement methods, and the above measurement methods are for reference only.
  • Softness test refer to the standard ASTM D6828-2002 (2011), test speed: 1.2mm/s.
  • a method for virus-removing filtration of a protein-containing material liquid by using the above-mentioned filter device comprising the following steps:
  • Buffer replacement The buffer is continuously transported from the liquid inlet channel 101 on one side of the filter device, that is, the first liquid inlet 11, into the liquid inlet channel until it flows out from the filtrate channel of the filter device, that is, the second filtrate port 23. infiltrating the buffer so that the buffer fills the filter device;
  • Liquid inlet block the liquid inlet channel on one side, and continuously transport the protein-containing material liquid from the other side into the liquid inlet channel, and the inlet liquid pressure is 20-40psi;
  • the sample is provided with an isolation layer 21;
  • the isolation layer 21 is made of non-woven fabric, the surface roughness of the side close to the filter layer 4 is 3 ⁇ m, the softness is 100 mN, d1:d2 is 1000; l:d is 3:10 , the thickness h1:h2 of the isolation layer 21 is 1:5, wherein h1 is 85 ⁇ m, the thickness h2 of the liquid inlet diversion screen and the filtrate diversion screen is 425 ⁇ m, and the porosity of the filtrate diversion screen is 25%, the isolation layer
  • the air permeability of 21 is 60 cc/cm 2 /sec; the fiber diameter of the isolation layer 21 is 12 ⁇ m, and the weight is 16 g/m 2 .
  • the sample is provided with an isolation layer 21, the isolation layer 21 is made of non-woven fabric, the surface roughness of the side close to the filter layer 4 is 18 ⁇ m, the softness is 118mN, d1:d2 is 1300; l:d is 1:2 , the thickness h1:h2 of the isolation layer 21 is 1:4, wherein h1 is 140 ⁇ m, the thickness h2 of the liquid inlet diversion screen and the filtrate diversion screen is 560 ⁇ m, and the porosity of the filtrate diversion screen is 28%, the isolation layer
  • the air permeability of 21 is 115 cc/cm 2 /sec; the fiber diameter of the isolation layer 21 is 10 ⁇ m, and the grammage is 15 g/m 2 .
  • Sample 3 the sample is provided with an isolation layer 21; the isolation layer 21 is made of non-woven fabric, the surface roughness of the side close to the filter layer 4 is 19 ⁇ m, the softness is 165 mN, d1:d2 is 2100; l:d is 2:5 , the thickness h1:h2 of the isolation layer 21 is 1:4.5, wherein h1 is 142 ⁇ m, the thickness h2 of the liquid inlet diversion screen and the filtrate diversion screen is 639 ⁇ m, and the porosity of the filtrate diversion screen is 30%, the isolation layer
  • the air permeability of 21 is 92 cc/cm 2 /sec; the fiber diameter of the isolation layer 21 is 14 ⁇ m, and the weight is 40 g/m 2 .
  • the sample is provided with an isolation layer 21, the isolation layer 21 is made of non-woven fabric, the surface roughness of the side close to the filter layer 4 is 12 ⁇ m, the softness is 195mN, d1:d2 is 2200; l:d is 3:5 , the thickness h1:h2 of the isolation layer 21 is 1:3.5, wherein h1 is 121 ⁇ m, the thickness h2 of the liquid inlet diversion screen and the filtrate diversion screen is 423.5 ⁇ m, and the porosity of the filtrate diversion screen is 32%.
  • the air permeability of the layer 21 is 124 cc/cm 2 /sec; the fiber diameter of the isolation layer 21 is 17 ⁇ m, and the grammage is 18 g/m 2 .
  • the sample is provided with an isolation layer 21, the isolation layer 21 is made of non-woven fabric, the surface roughness of the side close to the filter layer 4 is 20 ⁇ m, the softness is 220mN, d1:d2 is 3200; l:d is 3:10 , the thickness h1:h2 of the isolation layer 21 is 1:3.8, wherein h1 is 150 ⁇ m, the thickness h2 of the liquid inlet diversion screen and the filtrate diversion screen is 426 ⁇ m, and the porosity of the filtrate diversion screen is 35%, the isolation layer
  • the air permeability of 21 is 152 cc/cm 2 /sec; the fiber diameter of the isolation layer 21 is 18 ⁇ m, and the weight is 36 g/m 2 .
  • the sample is provided with an isolation layer 21, the isolation layer 21 is made of non-woven fabric, the surface roughness of the side close to the filter layer 4 is 25 ⁇ m, the softness is 248mN, d1:d2 is 4300; l:d is 2:5 , the thickness h1:h2 of the isolation layer 21 is 1:3.5, wherein h1 is 138 ⁇ m, the thickness h2 of the liquid inlet diversion screen and the filtrate diversion screen is 570 ⁇ m, and the porosity of the filtrate diversion screen is 27%, the isolation layer
  • the air permeability of 21 is 148 cc/cm 2 /sec; the fiber diameter of the isolation layer 21 is 20 ⁇ m, and the weight is 32 g/m 2 .
  • Embodiment 2 the difference with embodiment 1 is:
  • the liquid inlet channel 101 of the present invention is arranged on the encapsulation layer 103, and the filtrate channel 102 is arranged at the central position of the filter unit 2 and the stacked structure of the liquid inlet diversion screen, wherein the liquid inlet channel 101 and the liquid inlet The diversion screen 1 is connected, while the filter unit 2 on the inner side wall of the liquid inlet channel 101 is sealed by the annular glue seal layer 6, and the liquid inlet diversion screen 1 on the inner side wall of the filtrate channel 102 is sealed by the adhesive penetrating therein.
  • the method for filtering virus-removing protein-containing feed liquid by using the above-mentioned filter device comprises the following steps:
  • buffer replacement the buffer is continuously transported from the liquid inlet channel 10 on one side of the filter device to the liquid inlet flow channel until it flows out from the filtrate channel of the filter device to form a permeation buffer, so that the buffer is filled with the filter device;
  • Feed liquid continuously convey protein-containing material liquid from the liquid feed channel to the liquid feed channel, wherein the liquid feed pressure is 20-40psi;
  • the virus-removing membrane is a PES virus-removing membrane with an overall thickness of 50 ⁇ m, an average pore diameter of the first outer surface of 200 nm, and a pore area ratio of 8.7%, an average pore diameter of the second outer surface of 18.2 nm, and a pore area ratio of
  • the average pore size of the pre-filter layer is 70nm, the thickness is 44 ⁇ m, and the porosity is 78.2%.
  • the average pore size of the separation layer is 17nm, the thickness is 6 ⁇ m, and the porosity is 72.1%. .
  • the isolation layer 21 is set, and the isolation layer 21 is made of non-woven fabric, the surface roughness of which is close to the filter layer 4 side is 8 ⁇ m, the softness is 135mN, d1:d2 is 3800; l:d is 3:10,
  • the thickness h1:h2 of the isolation layer 21 is 1:4.8, wherein h1 is 98 ⁇ m, the thickness h2 of the filtrate diversion screen is 470.4 ⁇ m, the porosity of the filtrate diversion screen is 26%, and the air permeability of the isolation layer 21 is 155cc/cm 2 /sec; the fiber diameter of the isolation layer 21 is 22 ⁇ m, and the grammage is 21 g/m 2 .
  • Embodiment 3 the difference with embodiment 2 is:
  • the liquid inlet channel 101 and the filtrate channel 102 of the present invention are both arranged on the packaging layer 103, wherein the liquid inlet channel 101 communicates with the liquid inlet diversion screen 1, and the filter unit 2 on the inner wall of the liquid inlet channel 101 Then it is sealed by the annular glue seal layer 6 , and the liquid inlet diversion screen 1 on the inner wall of the filtrate channel 102 is also sealed by the adhesive penetrating therein.
  • the virus-removing membrane is a PES virus-removing membrane with an overall thickness of 70 ⁇ m, an average pore diameter of the first outer surface of 260 nm, and a pore area ratio of 12.4%, an average pore diameter of the second outer surface of 22.1 nm, and a pore area ratio of
  • the average pore size of the pre-filter layer is 90nm, the thickness is 60 ⁇ m, and the porosity is 83.4%.
  • the average pore size of the separation layer is 20nm, the thickness is 10 ⁇ m, and the porosity is 75.7%. .
  • the isolation layer 21 is set, and the isolation layer 21 is made of non-woven fabric, the surface roughness of the side close to the filter layer 4 is 10 ⁇ m, the softness is 210mN, d1:d2 is 5000; l:d is 3:10, The thickness h1:h2 of the isolation layer 21 is 1:2.8, wherein h1 is 150 ⁇ m, the thickness h2 of the filtrate diversion screen is 420 ⁇ m, the porosity of the filtrate diversion screen is 33%, and the air permeability of the isolation layer 21 is 160cc/ cm2 /sec; the fiber diameter of the isolation layer 21 is 24 ⁇ m, and the grammage is 25 g/m 2 .
  • Embodiment 4 the difference with embodiment 1 is:
  • the isolation layer 21 does not offer the isolation layer liquid inlet 211 and the isolation layer filtrate port 212, as shown in Figure 17, at this time, the surrounding of the isolation layer can be bonded with the filtrate diversion screen and the filter layer by adhesive.
  • the isolation layer 21 is made of non-woven fabric, the surface roughness of the side close to the filter layer 4 is 15 ⁇ m, the softness is 145 mN, d1:d2 is 1800; l:d is 7:10, the thickness of the isolation layer 21 h1: h2 is 1:3, where h1 is 148 ⁇ m, the thickness of the filtrate diversion screen h2 is 444 ⁇ m, the porosity of the filtrate diversion screen is 29%, and the air permeability of the isolation layer 21 is 85cc/cm 2 /sec; the isolation layer 21 has a fiber diameter of 25 ⁇ m and a grammage of 30 g/m 2 .
  • Embodiment 5 The difference from sample 6 is that this embodiment adopts double-layer CA virus-removing membranes, the average pore diameter of the pre-filter layer is 95nm, and the average pore diameter of the separation layer is 20nm.
  • Example 6 The difference from sample 6 is that the thickness h1:h2 is 1:6, wherein h1 is 70 ⁇ m.
  • Example 7 The difference from sample 6 is that the air permeability of the isolation layer is 40cc/cm 2 /sec.
  • Example 8 The difference from sample 6 is that the fiber diameter of the isolation layer 21 is 7 ⁇ m, and the grammage is 32 g/m 2 .
  • Comparative Example 1 The difference from Sample 6 is that no isolation layer is provided.
  • Comparative Example 2 The difference from Sample 6 is that the roughness is 35 ⁇ m.
  • Comparative Example 3 The difference from Sample 6 is that the softness is 350 mN.
  • the filter devices of the above-mentioned examples and comparative examples were subjected to a virus removal filter test, and the test conditions were to filter a 10 g/L monoclonal antibody protein solution of 7.5 log pfu/ml MVM virus (20 nm in particle size) at a pressure of 30 psi.
  • the virus-removing filter device adopts 8 filter units 2, that is, 16 filter layers 4, and 32 virus-removing membranes 41, and the filter area reaches 0.08m 2 at this time. The results are shown in the table below.
  • Example 6 It can be seen from Example 6 that when the thickness of the isolation layer 21 and the value of h1:h2 are too small, the filtration flux of the filter device is relatively small.
  • Example 7 It can be seen from Example 7 that when the air permeability of the isolation layer is too small, the filtration flux of the filter device is relatively small.
  • Example 8 It can be seen from Example 8 that under the same gram weight, the smaller the fiber diameter, the more eddies formed in the isolation layer, the higher the specific surface area, the greater the protein collision probability, and the relatively low effective protein rate and final protein yield.
  • Comparative Example 1 It can be seen from Comparative Example 1 that the LRV is relatively low when the PES virus removal membrane is used without an isolation layer, indicating that the installation of an isolation layer can protect the membrane pores of the virus removal membrane separation layer well.
  • the virus removal rate LRV of the protein-containing medicinal liquid after filtration is relatively low, indicating that when the softness of the isolation layer 21 is too small, the membrane pores of the separation layer of the virus removal membrane 41 are easily damaged during the test.

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Abstract

本发明公开了一种用于含蛋白料液除病毒过滤的过滤装置及进行含蛋白料液除病毒过滤的方法，涉及生物过滤技术领域，包括：过滤单元，封装层，进液通道，滤液通道，过滤层包括除病毒膜，除病毒膜对于病毒杂质的LRV不低于4，且蛋白收率不低于98％，除病毒膜包括预过滤层和用于截留病毒、且孔径小于预过滤层的分离层，至少有一层预过滤层位于除病毒膜远离滤液导流筛网一侧表面，本发明过滤装置结构简单，操作方便，采用的除病毒膜包括预过滤层和用于截留病毒、且孔径小于预过滤层的分离层，对含蛋白料液具有良好的除病毒效果。

Description

一种用于含蛋白料液除病毒过滤的过滤装置及进行含蛋白料液除病毒过滤的方法 技术领域
本发明涉及生物过滤技术领域，特别是一种用于含蛋白料液除病毒过滤的过滤装置及进行含蛋白料液除病毒过滤的方法。
背景技术
随着社会的发展，重组蛋白和抗体类药物因其在各种重大疾病治疗中的广泛应用，已经成为了生物医药中的重要组成部分。其中，重组蛋白类药物是利用基因工程技术表达的产物，用于弥补人体内某些功能蛋白的缺失，抗体类药物，例如单克隆抗体是由单个B淋巴细胞克隆所分泌的抗体,由于B淋巴细胞只能产生一种专有的、针对一种抗原决定簇的抗体,所以具有理化性质高度专一、生物活性单一、与抗原结合特异性强等特点，在肿瘤和自身免疫疾病治疗领域取得了巨大进展，经过三十多年的发展，目前国内重组蛋白和抗体类药物已经占据生物药物市场的三分之一以上，同时也是医药领域增长速度最快、最有前景的发展方向。
在重组蛋白和抗体类药物生产过程中，需要对含重组蛋白或抗体药液中的的产品蛋白进行分离纯化，分离纯化是重组蛋白和抗体类药物制备技术的关键，其中，除病毒过滤又是分离纯化中的关键步骤，然而目前，现有技术中通常采用盒式的过滤装置进行除病毒过滤，如专利CN112387119A，然而盒式过滤器不但制备复杂，并且过滤膜需要与壳体焊接，在此过程中容易造成过滤膜的破坏，从而影响最终的过滤效果。
发明内容
本发明所要达到的目的是提供一种用于含蛋白料液除病毒过滤的过滤装置 及进行含蛋白料液除病毒过滤的方法，其结构简单，操作简便，同时病毒去除率高。
为了达到上述目的，本发明采用如下技术方案：
一种用于含蛋白料液除病毒过滤的过滤装置，包括：
过滤单元，其至少包括滤液导流筛网和设于滤液导流筛网侧边的过滤层；多个所述过滤单元堆叠设置，且过滤单元之间形成进液流道；
封装层，用于将多个堆叠设置的过滤单元封装固定；
进液通道，用于将待过滤的含蛋白料液输送至进液流道；
滤液通道，与滤液导流筛网连通，用于将除病毒后的含蛋白料液排出；
所述过滤层包括除病毒膜，所述除病毒膜对于病毒杂质的LRV不低于4，且蛋白收率不低于98％，所述除病毒膜包括预过滤层和用于截留病毒、且孔径小于预过滤层的分离层，至少有一层预过滤层位于除病毒膜远离滤液导流筛网一侧表面。
本发明过滤装置具有多个过滤单元，以及进液通道和滤液通道，其中过滤单元堆叠设置并通过外周的封装层进行密封，其中，进液通道仅和过滤单元之间形成的进液流道连通，滤液通道则仅和过滤单元内的滤液导流筛网连通，；在含蛋白料液进行除病毒过滤时，可将待过滤的含蛋白料液通过进液通道输送至进液流道内，此时，含蛋白料液将铺满进液通道，并通过过滤层进行除病毒过滤后形成渗透液进入滤液导流筛网，其中堆叠设置于内部的过滤单元中，滤液导流筛网两侧均设置有过滤层，而设置于最外侧的过滤单元中，滤液导流筛网可以只朝内侧设置过滤层，此处滤液导流筛网的设置能够将过滤层出液面之间的流道撑开，防止过滤层出液面侧之间贴合，给予了过滤单元良好的过滤空间，最后渗透液通过和滤液导流筛网连接的滤液通道排出后得到目标除病毒含 蛋白料液。
同时，为了满足本发明过滤层能够具有良好的除病毒效果，过滤层采用对于病毒杂质的LRV不低于4、且蛋白收率不低于98％的除病毒膜，此时得到的除病毒含蛋白料液具有良好的除病毒过滤效果；其中，除病毒膜包括预过滤层和用于截留病毒、且孔径小于预过滤层的分离层，至少有一层预过滤层位于除病毒膜远离滤液导流筛网一侧表面，因此在使用过程中，待过滤的含蛋白料液首先经过预过滤层，其中，预过滤层的孔径较大，可以用作纳污，主要截留流体中的大颗粒杂质，且有利于提高除病毒膜的整体过滤速度，使得含蛋白料液过滤的时间较短，时间成本较低，随后，含蛋白料液经过分离层，其中分离层孔径相对较小，有利于提高除病毒膜的过滤精度，保证了除病毒膜对病毒具有较高的截留作用。因此，至少有一层预过滤层位于除病毒膜远离滤液导流筛网的一侧，此时保证了除病毒膜的进液面孔径相对较大，纳污量大，能预先除去较大颗粒杂质，不易发生堵塞，达到良好的过滤效果。因此，本发明结构简单，操作方便，对含蛋白料液具有良好的除病毒效果。
进一步的，
所述进液通道和滤液通道均设于过滤单元；或
所述进液通道和滤液通道至少有一处设于封装层。
本发明中，进液通道和滤液通道可均设于过滤单元中，此时，进液通道和滤液通道贯穿过滤单元，由于含蛋白料液过滤时，渗透液会流向滤液通道，因此，远离滤液通道的滤液导流筛网中的渗透液需要先流向靠近滤液通道附近的滤液导流筛网中，这就导致各区域除病毒膜过滤效率不均，而当进液通道和滤液通道可均设于过滤单元中，特别是当进液通道和/或滤液通道位于过滤单元中间时，能够使得除病毒膜各处过滤更加均匀，增加过滤装置使用寿命。或者， 也可以将进液通道和滤液通道至少一处设于封装层中，而将进液通道和/或滤液通道设于封装层相比于均设于过滤单元，能够防止过滤单元中有效使用面积的减少。
进一步的，所述过滤单元之间设有用以支撑进液流道的进液导流筛网。
进液导流筛网的设置能够支撑起过滤单元之间的间隙，起到形成进液流道的作用，使得含蛋白料液输送至进液流道更加流畅，过滤也更为均匀。同时，由于本发明中含蛋白料液过滤为死端过滤，因此需要施加一定的压力促使含蛋白料液从过滤层中进行过滤，过滤过程中，进液流道中往往具有较高的压力，该情况下，由于过滤层除病毒膜厚度较薄，因此靠除病毒膜边缘截面和封装层粘结固定并不牢固，含蛋白料液在压力下容易冲破除病毒膜和封装层之间的粘结，形成缝隙，导致含蛋白料液不从除病毒膜过滤，而从除病毒膜和封装层之间的缝隙处透过，从而影响过滤装置的整体过滤效率，本发明中设置了进液导流筛网，在封装层中胶粘剂在封装过程中能够渗透进入至进液导流筛网中，而渗透进入至进液导流筛网中的胶粘剂形成的封装层能够进一步与除病毒膜表面粘结，能够在过滤过程中阻挡含病毒料液的冲击，且该渗透进入进液导流筛网中的胶粘剂形成的封装层宽度可调，从而确保与除病毒膜之间粘结牢固；因此通过进液导流筛网的设置能够增加封装层和除病毒膜之间的密封性，并且，本发明除病毒膜远离滤液导流筛网一侧表面，即与渗透至进液导流筛网内的封装层粘结密封的除病毒表面为具有较大孔径的预过滤层，这是由于在粘结过程中，孔径较大，利于胶粘剂的嵌入，从而进一步增加渗透至进液导流筛网内的封装层与除病毒表面的粘结密封性。
进一步的，所述除病毒膜分离层位于除病毒膜贴近滤液导流筛网一侧表面。
除病毒膜分离层贴近滤液导流筛网一侧，过滤时，含病毒料液先经过预过 滤层的过滤之后，再流经分离层，最后无需再次经过预过滤层的过滤就到达滤液导流筛网，在保证良好的过滤效果的同时，简化除病毒膜的结构。
进一步的，所述预过滤层的外侧为第一外表面，所述第一外表面的平均孔径为160-440nm，第一外表面的孔面积率为0.5-14％；所述分离层的外侧为第二外表面，所述第二外表面的平均孔径为12-40nm，第二外表面的孔面积率为2.5-9％。
本发明中第一外表面和第二外表面的平均孔径不同，既保证了膜整体具有较快的流速和纳污空间，又具有较高的过滤精度。同时，本发明中的第一外表面的平均孔径和孔面积率对除病毒膜的第一外表面和封装层之间的粘结牢固度具有一定的影响，平均孔径影响了封装层上的粘结剂能够渗透入预过滤层的程度，第一外表面平均孔径过小会导致渗透不够，粘结力相对较小；而第一外表面孔面积率则影响封装层上的粘结剂能够渗透的区域大小，若第一外表面孔面积率过小，也会导致粘结剂无法有效渗透，粘结力也相对较小。
进一步的，所述除病毒膜平均孔径从靠近滤液导流筛网一侧表面区域向远离滤液导流筛网一侧表面区域连续梯度变化，平均孔径变化梯度为2-5.5μm/1μm。
除病毒膜的平均孔径是可以随着厚度变化梯度变化的，平均孔径变化梯度具体数值可以通过两侧表面平均孔径之差/厚度获得，因此单位为μm(代表孔径)/1μm(代表厚度)，在本发明中，孔径从远离滤液导流筛网一侧表面区域朝靠近滤液导流筛网一侧表面区域逐渐变小，平均孔径变化梯度为2-5.5μm/1μm，其变化梯度值较小，说明本发明的膜孔径随厚度是小梯度变化，膜孔径不会变化过快，也不存在过大的孔洞(当预过滤层的孔洞过大时，会导致膜整体的机械强度过低，不耐压，在压力作用下很容易损坏)，那么此时预过滤层能 够对分离层起到一定的支撑作用，膜整体具有不错的机械强度，耐压，在较大压力下不容易损坏；并且能保证除病毒膜对病毒的高效截留，除病毒膜还具有较快的通量，且具有较大的纳污量。
进一步的，所述预过滤层的平均孔径为55-190nm，分离层的平均孔径为16-23nm；所述预过滤层的平均孔径和分离层的平均孔径之比为4-12。
预过滤层的孔径过小使得除病毒膜无法达到良好的过滤通量；而分离层的孔径过大容易使得分离层无法起到良好的截留作用；因此预过滤层和分离层孔径的上述数值设置有利于保证除病毒膜较大的通量和较高的截留效率。
预过滤层的平均孔径和分离层的平均孔径之比在限定范围内时，不但保证了滤膜具有较大的通量，较长的使用寿命；而且保证了滤膜对病毒具有高截留效率，满足实际应该的需求。而其比值过大或过小，容易导致过滤精度不够或者通量过小。
进一步的，所述预过滤层厚度占除病毒膜厚度的72-89％，孔隙率为77-90％；所述分离层厚度占除病毒膜厚度的11-28％，孔隙率为62-78％。
本发明除病毒膜中预过滤层的厚度占比较高，且孔隙率也相对较高，保证了膜整体的具有较高的通量和纳污量，过滤速度快，使用寿命长；分离层厚度占比相对较低，且孔隙率也相对较低，在进一步保证膜高通量的基础上，能够对病毒起到足够的截留作用，保证过滤效果。
进一步的，所述除病毒膜的厚度为45-140μm。
当除病毒膜的厚度过小时，其膜的机械强度就会较低；同时由于过滤时间过短，就无法进行有效的过滤；当膜的厚度过大时，其过滤时间就会过长，时间成本过大；除病毒膜厚度在本发明范围内，不仅具有较高的机械强度，而且能够进行有效的过滤且过滤效率较高，过滤时间较短，时间成本较低。
进一步的，聚醚砜除病毒膜、再生纤维素除病毒膜、醋酸纤维素除病毒膜或聚偏氟乙烯除病毒膜中的一种或多种。
进一步的，所述过滤层为多层除病毒膜，每层除病毒膜上开设有与封装孔，该封装孔与所述进液通道至少部分连通，多层除病毒膜至少包括具有最大封装孔内径的第一除病毒膜和具有最小封装孔内径的第二除病毒膜，多层除病毒膜堆叠进而在封装孔处形成径向错位区域；
所述封装孔内形成环状胶封层，该环状胶封层覆盖滤液导流筛网处进液通道的内壁，及第一除病毒膜封装孔的内壁和相邻封装孔之间的径向错位区域，以使得各层除病毒膜之间以及滤液导流筛网和过滤层之间形成密封连接。
本发明中，为了使得除病毒效率更高，可以采用多层除病毒膜设计，在固定封装多层除病毒膜时，特别是当进液通道设于过滤单元中的情况下，多层除病毒膜之间通过在封装孔内形成环状胶封层，该环状胶封层填充相邻除病毒膜之间的径向错位区域，和滤液导流筛网处进液通道的内壁，以及第一除病毒膜位于封装孔的内侧壁，具体的，部分粘合剂渗透进入滤液导流筛网，填充滤液导流筛网的网孔，靠近滤液导流筛网的除病毒膜直接与其粘接，同时在滤液导流筛网处的进液通道内壁包覆环状胶封层；由于除病毒膜不会渗透粘合剂，因此其余的除病毒膜通过封装孔之间的径向错位区域内填充的粘合剂形成封装，将相邻除病毒膜牢牢粘附，同时在第一除病毒膜的封装孔内侧壁也粘附有环状胶封层，其也说明了具有最大封装孔内径的第一除病毒膜侧壁必须封装有环状胶封层，才能通过径向错位区域粘附的方式将多层除病毒膜粘附起来，因此环状胶封层使得所有的除病毒膜和滤液导流筛网之间形成稳固的粘合作用，避免未过滤的含病毒料液从缝隙中透过，保证除病毒膜良好的过滤效果；环状胶封层的侧边和除病毒膜密封，其上下两边能将相邻的除病毒膜牢牢粘附，从而将 封装孔内封堵，保证过滤时待过滤的含蛋白料液从进液流道进入。
进一步的，所述第二除病毒膜位于过滤层远离滤液导流筛网一侧；或者，所述第二除病毒膜位于过滤层靠近滤液导流筛网一侧。
具有最大封装孔内径的第二除病毒膜位于外侧，使得粘合剂可以顺着内径较大的封装孔流向内径相对较小的封装孔，环状胶封层的制作更加简单，粘合结构更加稳固；具有最大封装孔内径的第二除病毒膜位于内侧，避免具有最小封装孔内径的第二除病毒膜位于内侧，导致在封装孔内进行刮胶处理时将第二除病毒膜位于封装孔内侧壁的胶层刮除，导致环状胶封层无法实现良好的密封作用，同时也可以达到粘合剂顺着阶梯流动实现更好的密封作用的功能。
进一步的，所述封装孔的内径呈阶梯变化，其自靠近滤液导流筛网一侧向外逐渐变小，或者，其自靠近滤液导流筛网一侧向外逐渐变大。
保证环状胶封层可以覆盖到所有的径向错位区域，上述结构设计使得过滤层的所有除病毒膜之间粘结牢固性更高；由于封装孔的内径呈阶梯变化，使得所有相邻除病毒膜之间不仅在侧壁上具有环状胶封层，而且在径向错位区域的台阶上也具有环状胶封层，各个除病毒膜之间粘合更加稳固，由于在两个方向均实现稳固的粘接，含蛋白料液不容易冲破环状胶封层导致流道渗透进入封装孔，使得渗透液均从与滤液导流筛网连通的滤液通道排出。
进一步的，所述过滤单元还包括设于过滤层和滤液导流筛网之间的隔离层。
过滤装置在过滤过程中，在待过滤液体的较大压力之下，滤液导流筛网容易嵌入过滤层中，对过滤层的膜孔径造成损坏，容易导致过滤层对病毒去除率的下降，同时也影响了除病毒过滤装置的整体使用寿命。本发明在过滤层和滤液导流筛网之间设置隔离层，该隔离层起到了隔离过滤层和滤液导流筛网的作用，避免滤液导流筛网在过滤过程中嵌入过滤层中导致对其膜孔的损坏，对过 滤层形成良好的保护作用；在过滤时，隔离层两侧可以分别与过滤层和滤液导流筛网贴合，也可以是隔离层和过滤层之间存在间隙、隔离层和滤液导流筛网之间也存在间隙，隔离层不仅起到隔离作用，还起到导流的作用，即隔离层配合滤液导流筛网形成两层的排液空间，降低背压，增加了过滤通量，使得过滤更加顺畅，过滤效率提高。
进一步的，所述隔离层贴近过滤层一侧表面粗糙度为2-25μm，柔软度为100-250mN。
隔离层贴近过滤层一侧的表面粗糙度过大会形成多个突起，在过滤过程中受压的前提下，突起嵌入除病毒膜孔中，损伤除病毒膜的孔结构；或者过滤层嵌入相邻突起之间，造成过滤效率降低；上述表面粗糙度的选值可以保证隔离层表面的平整度的前提下，降低对过滤层的影响。同时，隔离层的柔软度对过滤层也会产生影响，隔离层的柔软度偏小则会导致坚硬的突起损伤过滤层，而柔软度偏大则容易产生变形，容易造成过滤层和隔离层之间的褶皱，影响过滤效率。
进一步的，隔离层的厚度为h1，所述滤液导流筛网的厚度为h2，h1:h2为1:1-5。
隔离层的厚度越大则排液空间越大，对过滤通量的贡献越高，但厚度过大容易导致过滤装置的厚度增加，而厚度过小则无法起到良好的隔离作用，容易发生形变导致过滤导流筛网嵌入除病毒膜中；上述厚度比例的选择可以保证过滤效率的同时避免整体过滤装置厚度过大。
进一步的，所述隔离层的厚度为80-150μm，透气量为60-160cc/cm 2/sec；所述滤液导流筛网的厚度为400-650μm，孔隙率为25-35％。
隔离层的厚度在上述数值范围内，可以起到良好的隔离作用，避免除病毒 膜的嵌入，而且具有更多的排液空间，增加了过滤通量；透气量过大则孔隙过多，容易造成滤液导流筛网的嵌入，透气量过小则会减小过滤通量；而且在上述透气量的数值范围内，在除病毒过滤装置封装时，粘合剂能够良好渗透，便于除病毒过滤装置的封装。同时，滤液导流筛网的厚度和孔隙率设置可以保证除病毒过滤装置的过滤通量处于合适的范围，同时保证良好的过滤效率。
进一步的，所述隔离层的纤维直径为10-25μm，克重为15-40g/m 2。
采用直径较粗但纤维密度较低的组合，达到隔离层的透气度，继而保证除病毒过滤装置的过滤通量，以及方便除病毒过滤装置的粘合封装；相比于采用直径较细但纤维密度较大的方案，本发明的隔离层支撑性能更好，同时具有更小的比表面积，不但减小隔离层对蛋白质的非特异性吸附，同时能够减小蛋白质与隔离层的纤维反复碰撞导致失活的概率，并且渗透液流动过程中，在隔离层内形成的涡流而已更少，降低了蛋白受到的剪切力，使得蛋白收率和有效蛋白率更高。
进一步的，所述隔离层为无纺布、织布或多孔膜中的一种或多种。
进一步的，所述隔离层上开设有与进液通道至少部分正对连通的隔离层进液口，所述隔离层通过隔离层上的胶粘层与过滤层和滤液导流筛网粘结。
进一步的，所述胶粘层渗透于隔离层内，并围设于隔离层进液口，且胶粘层覆盖隔离层进液口内壁，以避免隔离层进液口和隔离层之间形成从隔离层进液口内壁进入的贯通液体流道。
本发明胶粘层可以渗透于隔离层内，从而达到与过滤层和滤液导流筛网粘结的目的，并且，为了防止液体从隔离层进液口内壁进入，本发明胶粘层围设于隔离层进液口，且覆盖隔离层进液口内壁，避免隔离层进液口和隔离层之间形成从隔离层进液口内壁进入的贯通液体流道，从而阻断了液体从隔离层进液口 出进入。
进一步的，所述隔离层进液口与过滤层进液通道内壁处形成阶梯错位区域。
采用阶梯错位区域的设置使得粘合剂能够在阶梯错位区域填充，在胶粘剂不渗透入隔离层的情况下也能实现隔离层和过滤层的封装，避免料液从隔离层和过滤层之间的缝隙流出，保证除病毒膜良好的过滤效果。
一种采用过滤装置进行含蛋白料液除病毒过滤的方法，包括以下步骤：
S1：缓冲液置换：缓冲液从进液通道持续输送至进液流道内，直至从过滤装置滤液通道处流出形成渗透缓冲液，从而使得缓冲液充满过滤装置；
S2：进液：将含蛋白料液从进液通道持续输送至进液流道内；
S3：过滤：含蛋白料液通过进液导流筛网沿切线方向渗透，并通过过滤单元内的过滤层，形成除病毒渗透液；
S4：排液：除病毒渗透液沿滤液导流筛网流动并从滤液通道处排出，得到除病毒后的含蛋白料液。
本发明在采用过滤装置对含蛋白料液进行除病毒过滤时，首先需要通过缓冲液对过滤装置内原先的保护液或空气进行置换，即将缓冲液从进液通道持续输送至进液流道内直至从过滤装置滤液通道处流出，从而保证缓冲液能够充满过滤装置，随后进行进液操作，在进液之前，若过滤装置具有多处进液通道，可对进液通道同时进行进液，优选为在具有多处进液通道时，向一处进液通道输送含蛋白料液，其余几处进行封堵，这是由于当多处进液通道同时进液时，会导致过滤装置整体通量不易调整，需要调节多处进液通道的进液压力进行配合，同时，甚至也会出现某处进液通道由于进液压力过小，发生含蛋白料液回流的现象产生。随后，当含蛋白料液通过过滤单元内的过滤层后，形成除病毒渗透液，除病毒渗透液沿滤液导流筛网流动并从滤液通道处排出得到除病毒后 的含蛋白料液。采用本发明过滤装置进行除病毒过滤操作简便，具有较高的效率。
进一步的，步骤S2中所述进液压力为20-40psi。
进一步的，过滤通量大于180L/(m 2*h)。
本发明过滤装置结构简单，操作方便，对含蛋白料液具有良好的除病毒效果，采用的除病毒膜包括预过滤层和用于截留病毒、且孔径小于预过滤层的分离层，至少有一层预过滤层位于除病毒膜远离滤液导流筛网一侧表面，不但能保证过滤装置对病毒的高效截留，还具有较大的通量和纳污量。
附图说明
下面结合附图对本发明作进一步说明：
图1为本发明过滤装置的分解结构示意图。
图2为本发明过滤装置的剖视图。
图3为本发明过滤单元(不包括环状胶封层)的部分剖视图，此时隔离层是无纺布。
图4为本发明过滤单元的部分剖视图，此时隔离层是无纺布。
图5为本发明过滤单元(不包括环状胶封层)的部分剖视图，此时隔离层是多孔膜。
图6为本发明过滤单元的部分剖视图，此时隔离层是多孔膜。
图7为本发明隔离层为无纺布的电镜图。
图8为本发明过滤单元(不包括环状胶封层)的部分剖视图，此时除病毒膜数量为三层。
图9为本发明过滤单元的部分剖视图，此时除病毒膜数量为三层。
图10为本发明除病毒过滤装置的剖视图，此时除病毒膜包括一个预过滤层 和一个分离层。
图11为本发明除病毒膜包括一个预过滤层和一个分离层的电镜图。
图12为本发明除病毒过滤装置的剖视图，此时除病毒膜包括两个预过滤层和一个分离层。
图13为本发明实施例2过滤装置示意图。
图14为本发明实施例2过滤装置进液通道处剖视图。
图15为本发明实施例2过滤装置滤液通道处剖视图。
图16为本发明实施例3过滤装置示意图。
图17为本发明实施例5过滤装置的分解结构示意图。
其中，101-进液通道，102-滤液通道，103-封装层，1-进液导流筛网，11-第一进液口，12-第一滤液口，121-第二凹槽结构，2-过滤单元，21-隔离层，211-隔离层进液口，212-隔离层滤液口，22-第二进液口，23-第二滤液口，3-滤液导流筛网，311-第一凹槽结构，4-过滤层，41-除病毒膜，411-封装孔，412-导通口，413-第一除病毒膜，414-第二除病毒膜，415-第三除病毒膜，416-预过滤层，417-分离层，5-径向错位区域，51-阶梯错位区域，6-环状胶封层，61-胶粘层。
具体实施方式
为了能够更清楚地理解本发明的上述目的、特征和优点，下面结合附图和具体实施方式对本发明进行进一步的详细描述。需要说明的是，在不冲突的情况下，本申请的实施例及实施例中的特征可以相互组合。
在下面的描述中阐述了很多具体细节以便于充分理解本发明，但是，本发明还可以采用其他不同于在此描述的其他方式来实施，因此，本发明的保护范围并不受下面公开的具体实施例的限制。
实施例1：
如图1所示，一种用于含蛋白料液除病毒过滤的过滤装置，包括：
进液导流筛网1，具有第一进液口11和第一滤液口12，其用于引导待过滤流体沿切线方向渗透；
在本实施例中，进液导流筛网1的两端分别设有第一进液口11和第一滤液口12，第一滤液口12内壁通过渗透于进液导流筛网1内的粘合剂密封；
过滤单元2，设置在进液导流筛网1的下游，开设有与第一进液口11和第一滤液口12至少部分正对连通的第二进液口22和第二滤液口23，且两端分别开设；过滤单元2至少包括滤液导流筛网3和设于滤液导流筛网3两侧的过滤层4，最外侧的过滤单元2中朝内的一侧设置过滤层4；
本实施例中，进液通道101和滤液通道102均设于过滤单元，其中，第一进液口11和第二进液口22共同形成进液通道101，第一滤液口12和第二滤液口23形成滤液通道102，第一进液口、第二进液口的直径为11mm，第一滤液口、第二滤液口的直径为6mm；多个过滤单元和进液导流筛网1堆叠设置并通过封装层103封装固定；且封装层103渗透入进液导流筛网1中，渗透入进液导流筛网1中的封装层103与除病毒膜41的第一外表面粘结固定。
当然，在其余实施例中也可以不设置进液导流筛网1，过滤时含病毒料液在输送进入进液流道后能够通过压力将进液流道撑开，从而完成过滤。
本实施例中，过滤层4包括除病毒膜41，所述除病毒膜对于病毒杂质的LRV不低于4，且蛋白质收率不低于98％；除病毒膜41又包括预过滤层416和分离层417，分离层417的孔径小于预过滤层416的孔径，其用于截留，至少有一层预过滤层416位于除病毒膜41远离滤液导流筛网的一侧。
具体如图10所示，此时除病毒膜41包括一个预过滤层416和一个分离层417，分离层417位于贴近滤液导流筛网3的一侧，所述预过滤层的外侧为第一 外表面，所述第一外表面的平均孔径为160-440nm，第一外表面的孔面积率为0.5-14％；所述分离层的外侧为第二外表面，所述第二外表面的平均孔径为12-40nm，第二外表面的孔面积率为2.5-9％；其中预过滤层的平均孔径为55-190nm，厚度占除病毒膜厚度的72-89％，孔隙率为77-90％，分离层的平均孔径为16-23nm，厚度占除病毒膜厚度的11-28％，孔隙率为62-78％；所述预过滤层的平均孔径和分离层的平均孔径之比为4-12，且除病毒膜平均孔径从靠近滤液导流筛网一侧表面区域向远离滤液导流筛网一侧表面区域连续梯度变化，平均孔径变化梯度为2-5.5μm/1μm，除病毒膜的整体厚度为45-140μm。
再结合图11所示，本实施例中，上侧为预过滤层，下侧为分离层，除病毒膜的整体厚度为60μm，第一外表面的平均孔径为230nm，孔面积率为10.6％，第二外表面的平均孔径为20.6nm，孔面积率为8.4％，平均孔径变化梯度为3.49μm/1μm；预过滤层的平均孔径为80nm，厚度为52μm，孔隙率为81.1％，分离层的平均孔径为19nm，厚度为8μm，孔隙率为74％。
在其他实施例中，如图12所示，此时除病毒膜41包括两个预过滤层416和一个分离层417，分离层417位于两个预过滤层416之间；此时其中一个预过滤层416位于远离隔离层21的一侧，一个预过滤层416位于贴近隔离层21的一侧。
在本实施例的过滤单元中，滤液导流筛网3的孔隙率为25-35％，其厚度为400-650μm。
过滤层4为单层除病毒膜41或者为多层除病毒膜41，除病毒膜41的两端分别开设有封装孔411和导通口412，封装孔411与第二进液口22至少部分正对连通。
本实施例中，如图1-4所示，除病毒膜41为PES除病毒膜，过滤单元2包 括设置在过滤层4和滤液导流筛网3之间的隔离层21。定义该隔离层21的厚度为h1，上述滤液导流筛网3的厚度为h2，则h1:h2为1:1-5。更具体的，在本实施例中隔离层21的厚度为80-150μm，透气量为60-160cc/cm 2/sec。
定义该隔离层21的贴近过滤层4一侧表面的孔径为d1，定义过滤层4贴近隔离层21一侧，即本实施例中除病毒膜第二外表面的平均孔径为d2，则d1:d2为1000-5000。更具体的，在本实施例中隔离层21更贴近过滤层4一侧表面的孔径为20-120μm。
该隔离层21的柔软度为100-250mN；该隔离层21贴近过滤层4一侧表面粗糙度为2-25μm；该隔离层21可以是无纺布，其纤维直径为10-25μm，克重为15-40g/m 2。隔离层21也可以是织布或多孔膜中的一种，材质可为聚合物材料，例如PP、PE、PES等。
隔离层21上开设有分别与第二进液口22和第二滤液口23至少部分正对连通的隔离层进液口211和隔离层滤液口212，所述隔离层通过隔离层上的胶粘层61与过滤层和滤液导流筛网粘结；其中，胶粘层61渗透于隔离层内，并围设于隔离层进液口，且胶粘层覆盖隔离层进液口内壁，以避免隔离层进液口和隔离层之间形成从隔离层进液口内壁进入的贯通液体流道，同时，所述胶粘层的围设宽度为l，隔离层进液口的直径为d，并与第一进液口直径相同，所述l:d为1-10:10，且也可以是隔离层进液口与过滤层第二进液口处形成阶梯错位区域，使得胶粘剂填充于阶梯错位区域形成胶粘层61。本实施例中，隔离层21为无纺布时，如图7所示，此时胶粘剂可以渗透进入无纺布，可采用渗透于隔离层内的胶粘层或设置阶梯错位区域51实现其与除病毒膜41的稳固粘接。其余实施例中，当隔离层21为多孔膜时，由于胶粘剂无法渗透进入，其必须设置上述阶梯错位区域51，如图5、图6所示。
在其余实施例中，除病毒膜41可以为再生纤维素除病毒膜、醋酸纤维素除病毒膜或聚偏氟乙烯除病毒膜中的一种或几种联用。
在本实施例中，过滤层4为多层除病毒膜41，每层除病毒膜41上开设有封装孔411和导通口412，封装孔411与第二进液口22至少部分正对连通，多层除病毒膜41至少包括具有最大封装孔内径的第一除病毒膜413和具有最小封装孔内径的第二除病毒膜414，多层除病毒膜41堆叠进而在封装孔处形成径向错位区域5。
封装孔内形成环状胶封层6，该环状胶封层6覆盖第二进液口22的内壁，覆盖隔离层进液口211的内壁，及覆盖第一除病毒膜413的内壁、和相邻封装孔之间的径向错位区域5，以使得各层除病毒膜41之间以及滤液导流筛网3和过滤层4之间形成密封连接。
具体的，如图3、图4所示，在本实施例中，过滤层4包括两层除病毒膜41，具体是具有较大封装孔内径的第一除病毒膜413和具有较小封装孔内径的第二除病毒膜414，其中第一除病毒膜413位于靠近滤液导流筛网3的内侧，第二除病毒膜414位于远离滤液导流筛网3的外侧。
如图4所示，封装孔内形成环状胶封层6，该环状胶封层6覆盖第二进液口22的内壁，覆盖隔离层进液口211的内壁，覆盖第一除病毒膜413的内壁，及覆盖第一除病毒膜413和第二除病毒膜414的径向错位区域5，以使得第一除病毒膜413和第二除病毒膜414之间以及滤液导流筛网3和第一除病毒膜413之间形成密封连接。
封装时，导通口412和第二滤液口23至少部分正对连通，对着第二滤液口23和导通口412抽真空，注入第二进液口22和封装孔411内的粘合剂在负压的作用下，沿周向流动形成环状胶封层6。
当然，在其余实施例中，如图8、图9所示，除病毒膜41的数量可以为三层，具有最大封装孔内径的第一除病毒膜413位于远离滤液导流筛网3的最外侧，具有最小封装孔内径的第二除病毒膜414靠近滤液导流筛网3设置，第三除病毒膜415位于第一除病毒膜413和第二除病毒膜414之间，其封装孔内径也小于第一除病毒膜413的封装孔内径、大于第二除病毒膜414的封装孔内径。
换句话说，封装孔的内径呈阶梯变化，其自靠近滤液导流筛网3一侧向外逐渐变大。上述结构设计使得过滤层4的所有除病毒膜41之间粘结牢固性更高。
如图9所示，封装孔内形成环状胶封层6，该环状胶封层6覆盖第三除病毒膜415的内壁，覆盖第一除病毒膜413的内壁，覆盖隔离层进液口211的内壁，及覆盖第三除病毒膜415和第一除病毒膜413的径向错位区域，覆盖第三除病毒膜415和第二除病毒膜414的径向错位区域。以使得第二除病毒膜414和第三除病毒膜415之间，第三除病毒膜415和第一除病毒膜413之间，隔离层21和第一除病毒膜413之间，以及滤液导流筛网3和隔离层21之间形成密封连接。
其中：膜表面平均孔径的测量方式可以通过使用扫描电子显微镜对膜结构进行形貌表征后，再利用计算机软件(如Matlab、NIS-Elements等)或手工进行测量，并进行相应计算；在膜的制备过程中，在垂直于膜厚度方向上(如果膜是平板膜形态，则该方向是平面方向；如果膜是中空纤维膜形态，则该方向是垂直于半径方向)，其各项特征如孔径分布是大致均匀的，基本保持一致；所以可以通过在相应平面上部分区域的平均孔径大小，来反映该平面上整体的平均孔径大小。在实际进行测量时，可以先用电子显微镜对膜表面进行表征，获得相应的SEM图，而由于膜表面孔洞大致是均匀的，因此可以选取一定的面积，例如1μm 2(1μm乘以1μm)或者25μm 2(5μm乘以5μm)，具体面积大小视实际情况而定，再用相应计算机软件或者手工测出该面积上所有孔洞 的孔径，然后进行计算，获得该表面的平均孔径；当然本领域技术人员也可以通过其他测量手段获得上述参数，上述测量手段仅供参考。预过滤层和分离层平均孔径、孔隙率，厚度等参数可以通过先将除病毒膜撕开，分成分离层和预过滤层，再对预过滤层进行相应参数测试，其中平均孔径采用PMI孔径测试仪进行测试；或者通过使用扫描电子显微镜对膜截面结构进行形貌表征后，再利用计算机软件(如Matlab、NIS-Elements等)或手工进行测量后计算测得；当然本领域技术人员也可以通过其他测量手段获得上述参数，上述测量手段仅供参考。
粗糙度测试：用ContourGT-X三维光学轮廓仪(Bruker,Geman)测试，在6×6毫米的表面区域内，扫描三个大小约为0.65×0.45毫米表面区域(区域大小由恒定的5倍放大率和使用扫描显微镜的自动对焦定义)，取n＝6个线性轨道(每个200μm)，轮廓过滤器：截止波长λs＝0.8μm，λc＝0.08mm，测量粗糙度，计算平均值。
柔软度测试：参照标准ASTM D6828-2002(2011)，测试速度：1.2mm/s。
一种采用上述过滤装置进行含蛋白料液除病毒过滤的方法，包括以下步骤：
S1：缓冲液置换：缓冲液从过滤装置一侧的进液通道101，即第一进液口11持续输送至进液流道内，直至从过滤装置滤液通道，即第二滤液口23处流出形成渗透缓冲液，从而使得缓冲液充满过滤装置；
S2：进液：封堵一侧的进液通道，将含蛋白料液从另一侧进液通道持续输送至进液流道内，其中进液压力为20-40psi；
S3：过滤：含蛋白料液通过进液导流筛网沿切线方向渗透，并通过过滤单元内的过滤层，形成除病毒渗透液；
S4：排液：除病毒渗透液沿滤液导流筛网流动并从滤液通道处排出，得到 除病毒后的含蛋白料液。
在本实施例结构的过滤装置在除病毒过滤的具体应用中，取7个试样，分别为：
试样1，试样设置隔离层21；隔离层21选用无纺布，其贴近过滤层4一侧表面粗糙度为3μm，柔软度为100mN，d1：d2为1000；l:d为3:10，隔离层21的厚度h1：h2为1:5，其中h1为85μm，进液导流筛网和滤液导流筛网厚度h2为425μm，滤液导流筛网的孔隙率为25％，隔离层21透气量为60cc/cm 2/sec；隔离层21的纤维直径为12μm，克重为16g/m 2。
试样2，试样设置隔离层21，隔离层21选用无纺布，其贴近过滤层4一侧表面粗糙度为18μm，柔软度为118mN，d1：d2为1300；l:d为1:2，隔离层21的厚度h1：h2为1:4，其中h1为140μm，进液导流筛网和滤液导流筛网厚度h2为560μm，滤液导流筛网的孔隙率为28％，隔离层21透气量为115cc/cm 2/sec；隔离层21的纤维直径为10μm，克重为15g/m 2。
试样3，试样设置隔离层21；隔离层21选用无纺布，其贴近过滤层4一侧表面粗糙度为19μm，柔软度为165mN，d1：d2为2100；l:d为2:5，隔离层21的厚度h1：h2为1:4.5，其中h1为142μm，进液导流筛网和滤液导流筛网厚度h2为639μm，滤液导流筛网的孔隙率为30％，隔离层21透气量为92cc/cm 2/sec；隔离层21的纤维直径为14μm，克重为40g/m 2。
试样4，试样设置隔离层21，隔离层21选用无纺布，其贴近过滤层4一侧表面粗糙度为12μm，柔软度为195mN，d1：d2为2200；l:d为3:5，隔离层21的厚度h1：h2为1:3.5，其中h1为121μm，进液导流筛网和滤液导流筛网厚度h2为423.5μm，滤液导流筛网的孔隙率为32％，隔离层21透气量为124cc/cm 2/sec；隔离层21的纤维直径为17μm，克重为18g/m 2。
试样5，试样设置隔离层21，隔离层21选用无纺布，其贴近过滤层4一侧表面粗糙度为20μm，柔软度为220mN，d1：d2为3200；l:d为3:10，隔离层21的厚度h1：h2为1:3.8，其中h1为150μm，进液导流筛网和滤液导流筛网厚度h2为426μm，滤液导流筛网的孔隙率为35％，隔离层21透气量为152cc/cm 2/sec；隔离层21的纤维直径为18μm，克重为36g/m 2。
试样6，试样设置隔离层21，隔离层21选用无纺布，其贴近过滤层4一侧表面粗糙度为25μm，柔软度为248mN，d1：d2为4300；l:d为2:5，隔离层21的厚度h1：h2为1:3.5，其中h1为138μm，进液导流筛网和滤液导流筛网厚度h2为570μm，滤液导流筛网的孔隙率为27％，隔离层21透气量为148cc/cm 2/sec；隔离层21的纤维直径为20μm，克重为32g/m 2。
实施例2：与实施例1的区别在于：
如图13-15所示：本发明进液通道101设于封装层103上，滤液通道102设于过滤单元2和进液导流筛网堆叠结构的中心位置，其中进液通道101和进液导流筛网1连通，而进液通道101内侧壁的过滤单元2则通过环状胶封层6密封，滤液通道102内侧壁的进液导流筛网1通过渗透其中的粘合剂密封。
采用上述过滤装置进行含蛋白料液除病毒过滤的方法，包括以下步骤：
S1：缓冲液置换：缓冲液从过滤装置一侧的进液通道10持续输送至进液流道内，直至从过滤装置滤液通道处流出形成渗透缓冲液，从而使得缓冲液充满过滤装置；
S2：进液：将含蛋白料液从进液通道持续输送至进液流道内，其中进液压力为20-40psi；
S3：过滤：含蛋白料液通过进液导流筛网沿切线方向渗透，并通过过滤单元内的过滤层，形成除病毒渗透液；
S4：排液：除病毒渗透液沿滤液导流筛网流动并从滤液通道处排出，得到除病毒后的含蛋白料液。
本实施例中，除病毒膜为PES除病毒膜，整体厚度为50μm，第一外表面的平均孔径为200nm，孔面积率为8.7％，第二外表面的平均孔径为18.2nm，孔面积率为6.9％，平均孔径变化梯度为3.64μm/1μm；预过滤层的平均孔径为70nm，厚度为44μm，孔隙率为78.2％，分离层的平均孔径为17nm，厚度为6μm，孔隙率为72.1％。
该实施例中，设置隔离层21，隔离层21选用无纺布，其贴近过滤层4一侧表面粗糙度为8μm，柔软度为135mN，d1：d2为3800；l:d为3:10，隔离层21的厚度h1：h2为1:4.8，其中h1为98μm，滤液导流筛网厚度h2为470.4μm，滤液导流筛网的孔隙率为26％，隔离层21透气量为155cc/cm 2/sec；隔离层21的纤维直径为22μm，克重为21g/m 2。
实施例3：与实施例2的区别在于：
如图16所示：本发明进液通道101和滤液通道102均设于封装层103上，其中进液通道101和进液导流筛网1连通，而进液通道101内侧壁的过滤单元2则通过环状胶封层6密封，滤液通道102内侧壁的进液导流筛网1同样通过渗透其中的粘合剂密封。
本实施例中，除病毒膜为PES除病毒膜，整体厚度为70μm，第一外表面的平均孔径为260nm，孔面积率为12.4％，第二外表面的平均孔径为22.1nm，孔面积率为8.9％，平均孔径变化梯度为3.4μm/1μm；预过滤层的平均孔径为90nm，厚度为60μm，孔隙率为83.4％，分离层的平均孔径为20nm，厚度为10μm，孔隙率为75.7％。
该实施例中，设置隔离层21，隔离层21选用无纺布，其贴近过滤层4一侧 表面粗糙度为10μm，柔软度为210mN，d1：d2为5000；l:d为3:10，隔离层21的厚度h1：h2为1:2.8，其中h1为150μm，滤液导流筛网厚度h2为420μm，滤液导流筛网的孔隙率为33％，隔离层21透气量为160cc/cm 2/sec；隔离层21的纤维直径为24μm，克重为25g/m 2。
实施例4：与实施例1的区别在于：
隔离层21上没有开设隔离层进液口211和隔离层滤液口212，如图17所示，此时，隔离层周围可通过胶粘剂与滤液导流筛网和过滤层粘结。
该实施例中，隔离层21选用无纺布，其贴近过滤层4一侧表面粗糙度为15μm，柔软度为145mN，d1：d2为1800；l:d为7:10，隔离层21的厚度h1：h2为1:3，其中h1为148μm，滤液导流筛网厚度h2为444μm，滤液导流筛网的孔隙率为29％，隔离层21透气量为85cc/cm 2/sec；隔离层21的纤维直径为25μm，克重为30g/m 2。
实施例5：与试样6的区别在于，本实施例采用双层CA除病毒膜，预过滤层的平均孔径为95nm，分离层的平均孔径为20nm。
实施例6：与试样6的区别在于，厚度h1：h2为1:6，其中h1为70μm。
实施例7：与试样6的区别在于，隔离层透气量为40cc/cm 2/sec。
实施例8：与试样6的区别在于，隔离层21的纤维直径为7μm，克重为32g/m 2。
对比例1：与试样6的区别在于，不设置隔离层。
对比例2：与试样6的区别在于，所述粗糙度为35μm。
对比例3：与试样6的区别在于，所述柔软度为350mN。
将上述实施例和对比例的过滤装置在进行除病毒过滤试验，试验条件为7.5log pfu/ml MVM病毒(粒径20nm)的10g/L单抗蛋白质溶液在30psi压力下 进行过滤。其中除病毒过滤装置采用8个过滤单元2，也就是16个过滤层4，32张除病毒膜41，此时过滤面积达到0.08m 2。结果如下表所示。
Figure PCTCN2022142613-appb-000001
上表可知，本发明实施例对于含蛋白料液均具有较好的除病毒过滤效果。
由实施例6可知，当隔离层21的厚度和h1:h2的值过小时，过滤装置过滤通量相对较小。
由实施例7可知，当隔离层透气量过小时，过滤装置过滤通量相对较小。
由实施例8可知，在相同克重下，纤维直接越小，隔离层内形成的涡流更多，且比表面积较高，蛋白碰撞概率越大，有效蛋白率和最终蛋白收率相对较低。
由对比例1可知，未设置隔离层，采用PES除病毒膜时LRV相对较低，说明设置隔离层能够对除病毒膜分离层膜孔起到良好的保护作用。
由对比例2可知，过滤后含蛋白药液的病毒去除率LRV相对较低，说明当隔离层21的表面粗糙度过大时，除病毒膜41在试验过程中分离层膜孔容易损坏。
由对比例3可知，过滤后含蛋白药液的病毒去除率LRV相对较低，说明当隔离层21的柔软度过小时，除病毒膜41在试验过程中分离层膜孔容易损坏。
以上已详细描述了本发明的较佳实施例，但应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改。这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (24)

  1. 一种用于含蛋白料液除病毒过滤的过滤装置，其特征在于：包括：
    过滤单元，其至少包括滤液导流筛网和设于滤液导流筛网侧边的过滤层；多个所述过滤单元堆叠设置，且过滤单元之间形成进液流道；
    封装层，用于将多个堆叠设置的过滤单元封装固定；
    进液通道，用于将待过滤的含蛋白料液输送至进液流道；
    滤液通道，与滤液导流筛网连通，用于将除病毒后的含蛋白料液排出；
    所述过滤层包括除病毒膜，所述除病毒膜对于病毒杂质的LRV不低于4，且蛋白收率不低于98％，所述除病毒膜包括预过滤层和用于截留病毒、且孔径小于预过滤层的分离层，至少有一层预过滤层位于除病毒膜远离滤液导流筛网一侧表面。
  2. 根据权利要求1所述的过滤装置，其特征在于，
    所述进液通道和滤液通道均设于过滤单元；或
    所述进液通道和滤液通道至少有一处设于封装层。
  3. 根据权利要求1所述的过滤装置，其特征在于，所述过滤单元之间设有用以支撑进液流道的进液导流筛网。
  4. 根据权利要求1所述的过滤装置，其特征在于，所述除病毒膜分离层位于除病毒膜贴近滤液导流筛网一侧表面。
  5. 根据权利要求1-4任一所述的过滤装置，其特征在于，所述预过滤层的外侧为第一外表面，所述第一外表面的平均孔径为160-440nm，第一外表面的孔面积率为0.5-14％；所述分离层的外侧为第二外表面，所述第二外表面的平均孔径为12-40nm，第二外表面的孔面积率为2.5-9％。
  6. 根据权利要求1-4任一所述的过滤装置，其特征在于，所述除病毒膜平 均孔径从靠近滤液导流筛网一侧表面区域向远离滤液导流筛网一侧表面区域连续梯度变化，平均孔径变化梯度为2-5.5μm/1μm。
  7. 根据权利要求1所述的过滤装置，其特征在于，所述预过滤层的平均孔径为55-190nm，分离层的平均孔径为16-23nm；所述预过滤层的平均孔径和分离层的平均孔径之比为4-12。
  8. 根据权利要求1所述的过滤装置，其特征在于，所述预过滤层厚度占除病毒膜厚度的72-89％，孔隙率为77-90％；所述分离层厚度占除病毒膜厚度的11-28％，孔隙率为62-78％。
  9. 根据权利要求1所述的过滤装置，其特征在于，所述除病毒膜的厚度为45-140μm。
  10. 根据权利要求1所述的过滤装置，其特征在于，所述除病毒膜包括聚醚砜除病毒膜、再生纤维素除病毒膜、醋酸纤维素除病毒膜或聚偏氟乙烯除病毒膜中的一种或多种。
  11. 根据权利要求2所述的过滤装置，其特征在于，所述过滤层为多层除病毒膜，每层除病毒膜上开设有与封装孔，该封装孔与所述进液通道至少部分连通，多层除病毒膜至少包括具有最大封装孔内径的第一除病毒膜和具有最小封装孔内径的第二除病毒膜，多层除病毒膜堆叠进而在封装孔处形成径向错位区域；
    所述封装孔内形成环状胶封层，该环状胶封层覆盖滤液导流筛网处进液通道的内壁，及第一除病毒膜封装孔的内壁和相邻封装孔之间的径向错位区域，以使得各层除病毒膜之间以及滤液导流筛网和过滤层之间形成密封连接。
  12. 根据权利要求11所述的过滤装置，其特征在于，所述第二除病毒膜位于 过滤层远离滤液导流筛网一侧；或者，所述第二除病毒膜位于过滤层靠近滤液导流筛网一侧。
  13. 根据权利要求12所述的过滤装置，其特征在于，所述封装孔的内径呈阶梯变化，其自靠近滤液导流筛网一侧向外逐渐变小，或者，其自靠近滤液导流筛网一侧向外逐渐变大。
  14. 根据权利要求1或2所述的过滤装置，其特征在于，所述过滤单元还包括设于过滤层和滤液导流筛网之间的隔离层。
  15. 根据权利要求14所述的过滤装置，其特征在于，所述隔离层贴近过滤层一侧表面粗糙度为2-25μm，柔软度为100-250mN。
  16. 根据权利要求14所述的过滤装置，其特征在于，隔离层的厚度为h1，所述滤液导流筛网的厚度为h2，h1:h2为1:1-5。
  17. 根据权利要求14所述的过滤装置，其特征在于，所述隔离层的厚度为80-150μm，透气量为60-160cc/cm 2/sec；所述滤液导流筛网的厚度为400-650μm，孔隙率为25-35％。
  18. 根据权利要求14所述的过滤装置，其特征在于，所述隔离层为无纺布、织布或多孔膜中的一种或多种。
  19. 根据权利要求14所述的过滤装置，其特征在于，所述隔离层上开设有与进液通道至少部分正对连通的隔离层进液口，所述隔离层通过隔离层上的胶粘层与过滤层和滤液导流筛网粘结。
  20. 根据权利要求19所述的过滤装置，其特征在于，所述胶粘层渗透于隔离层内，并围设于隔离层进液口，且胶粘层覆盖隔离层进液口内壁，以避免隔离层进液口和隔离层之间形成从隔离层进液口内壁进入的贯通液体流道。
  21. 根据权利要求19所述的过滤装置，其特征在于，所述隔离层进液口与过滤层进液通道内壁处形成阶梯错位区域。
  22. 一种采用权利要求1-21任一所述过滤装置进行含蛋白料液除病毒过滤的方法，其特征在于，包括以下步骤：
    S1：缓冲液置换：缓冲液从进液通道持续输送至进液流道内，直至从过滤装置滤液通道处流出形成渗透缓冲液，从而使得缓冲液充满过滤装置；
    S2：进液：将含蛋白料液从进液通道持续输送至进液流道内；
    S3：过滤：含蛋白料液通过进液导流筛网沿切线方向渗透，并通过过滤单元内的过滤层，形成除病毒渗透液；
    S4：排液：除病毒渗透液沿滤液导流筛网流动并从滤液通道处排出，得到除病毒后的含蛋白料液。
  23. 根据权利要求22所述的含蛋白料液除病毒过滤方法，其特征在于，步骤S2中进液压力为20-40psi。
  24. 根据权利要求22所述的含蛋白料液除病毒过滤方法，其特征在于，过滤通量大于180L/(m 2*h)。
PCT/CN2022/142613 2022-01-14 2022-12-28 一种用于含蛋白料液除病毒过滤的过滤装置及进行含蛋白料液除病毒过滤的方法 WO2023134443A1 (zh)

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