Tangential flow filtering device with cleaning device, perfusion culture system and perfusion culture method

Abstract

The invention discloses a tangential flow filtering device with a cleaning device and a perfusion culture system and method.The tangential flow filtering device comprises a hollow fiber column assembly, a pressure detection meter, a first diaphragm pump and a second diaphragm pump, the hollow fiber column assembly comprises a hollow fiber column and a sleeve, and the sleeve is arranged outside the hollow fiber column in a sleeving mode; a waste liquid cavity is formed between the inner wall of the sleeve and the hollow fiber column; a first butt-joint port and a second butt-joint port are formed in the upper end and the lower end of the hollow fiber column assembly respectively, and a first liquid outlet and a second liquid outlet are formed in the upper end side wall and the lower end side wall of the hollow fiber column assembly respectively; the first diaphragm pump is in butt joint with the second butt joint opening, the second diaphragm pump is in butt joint with the second liquid outlet, and the pressure detection meter is connected with the waste liquid cavity through the second liquid outlet. The blockage condition of the hollow fiber column is judged by monitoring the pressure change of the liquid outlet through the pressure detection meter, and liquid is driven by the second diaphragm pump to perform back flushing on the hollow fiber column, so that the smoothness of the hollow fiber column is ensured.

Description

Technical Field

[0001] This invention relates to the field of biopharmaceuticals, and in particular to a tangential flow filtration device with a cleaning unit, a perfusion culture system, and a method. Background Technology

[0002] In recent years, the biopharmaceutical industry has frequently used hollow fiber perfusion culture to obtain high-density cell culture results. Perfusion culture technology can obtain high-density, highly viable cells and enable continuous harvesting of cell products. A key component in the perfusion culture process is the hollow fiber. A hollow fiber column is composed of many tiny hollow fibers, whose sidewalls have uniform pore sizes and biocompatible groups on their surfaces. The pore size of the fiber column sidewalls can be adjusted to meet different separation and purification requirements. The fiber column has an external, fixed shell to anchor the fibers and maintain structural stability.

[0003] Existing common perfusion devices cannot monitor hollow fiber blockage online; they can only infer whether the hollow fibers are blocked by comparing the concentrations of the target product in the reactor and the effluent through offline sampling. Once the hollow fibers become blocked, the test or production batch must be terminated, resulting in a significant decrease in production efficiency, which has certain drawbacks. Summary of the Invention

[0004] The purpose of this invention is to provide a tangential flow filtration device with a cleaning unit, a perfusion culture system and method, so as to realize online monitoring of hollow fiber blockage and reverse flushing of hollow fibers to ensure unobstructed flow of hollow fibers.

[0005] To solve the above-mentioned technical problems, the present invention provides a tangential flow filtration device with a cleaning device, comprising: a hollow fiber column assembly, a pressure gauge, a first diaphragm pump, and a second diaphragm pump;

[0006] The hollow fiber column assembly includes several hollow fiber columns and a sleeve. The sleeve is fitted over the outside of the several hollow fiber columns, and a waste liquid cavity is formed between the inner wall of the sleeve and the several hollow fiber columns.

[0007] The hollow fiber column assembly has a first pair of interfaces and a second pair of interfaces at its upper and lower ends, respectively. The first pair of interfaces and the second pair of interfaces are interconnected with the fluid channels of the hollow fiber columns. The upper and lower sidewalls of the hollow fiber column assembly have a first drain port and a second drain port, respectively. The first drain port and the second drain port are interconnected with the waste liquid chamber.

[0008] The first diaphragm pump is sealed to the second interface, the second diaphragm pump is sealed to the second drain port, and the pressure gauge is connected to the waste liquid chamber of the hollow fiber column assembly through the second drain port. The pressure gauge is used to detect the change in liquid pressure in the waste liquid chamber in real time.

[0009] When the change in liquid pressure in the waste liquid chamber is higher than the set value, the first diaphragm pump operates normally and the hollow fiber column assembly performs normal filtration.

[0010] When the liquid pressure change value in the waste liquid chamber is lower than the set value, the second diaphragm pump starts to work, driving the liquid in the waste liquid chamber to backwash the hollow fiber column.

[0011] Furthermore, both the first diaphragm pump and the second diaphragm pump include a rigid spherical shell and an elastic bladder. The elastic bladder is disposed inside the rigid spherical shell, and a pressure regulating cavity is formed between the outer wall of the elastic bladder and the inner wall of the rigid spherical shell. The elastic bladder contracts or expands according to the pressure change of the pressure regulating cavity.

[0012] The elastic bulb cavity of the first diaphragm pump is interconnected with the fluid channels of the hollow fiber columns, and the elastic bulb cavity of the second diaphragm pump is interconnected with the waste liquid cavity.

[0013] Furthermore, the bottom of the rigid spherical shell is provided with a base, and the base is provided with a vent hole, through which an external air pump assembly is connected to the air pressure regulating chamber.

[0014] Furthermore, both the first diaphragm pump and the second diaphragm pump include a connecting pipe. The connecting pipe is disposed at the end of the rigid spherical shell away from the base. The lower ends of the two connecting pipes are respectively sealed and connected to the open ends of the two elastic spherical bags. The upper end of the connecting pipe of the first diaphragm pump is sealed and connected to the second interface of the hollow fiber column assembly. The upper end of the connecting pipe of the second diaphragm pump is sealed and connected to the second drain port of the hollow fiber column assembly. An impregnation hole is provided on the side wall of the connecting pipe for connecting a wetting tube.

[0015] Furthermore, it also includes a T-type equal diameter tee, the first end of which is sealed and connected to the adapter pipe of the second diaphragm pump via an L-shaped elbow, the second end of which is sealed and connected to the second drain port, and the third end of which is connected to the pressure gauge.

[0016] Furthermore, the elastic balloon is provided with an internal support column, which is used to fix the upper and lower ends of the elastic balloon.

[0017] Furthermore, the first interface is connected to the main pipeline, which is used to connect to the bioreactor; the first drain outlet is connected to the drain pipe, which is used to discharge waste liquid from the waste liquid chamber.

[0018] In a second aspect, the present invention discloses a perfusion culture system, comprising: a first air pump assembly, a second air pump assembly, a bioreactor, a control unit, and the aforementioned tangential flow filtration device with a cleaning device;

[0019] The bioreactor is connected to the first pair of interfaces of the hollow fiber column assembly via a main pipeline.

[0020] The first diaphragm pump of the tangential flow filter device and the first air pump assembly form an axial drive unit, and the second diaphragm pump of the tangential flow filter device and the second air pump assembly form a radial drive unit.

[0021] The pressure gauges of the first air pump assembly, the second air pump assembly, and the tangential flow filter are all connected to the control unit. The control unit controls the working state of the axial drive unit and the radial drive unit based on the pressure changes in the waste liquid chamber detected by the pressure gauges.

[0022] When the pressure gauge detects that the liquid pressure change in the waste liquid chamber is higher than the set value, the axial drive unit works normally to drive the liquid in the hollow fiber column assembly to flow back and forth, thereby achieving tangential filtration.

[0023] When the pressure gauge detects that the liquid pressure change in the waste liquid chamber is lower than the set value, the radial drive unit starts to work to drive the liquid in the waste liquid chamber to backwash the hollow fiber column of the hollow fiber column assembly.

[0024] Thirdly, the present invention discloses a perfusion culture method, comprising:

[0025] Provide the above-mentioned perfusion culture system;

[0026] The axial drive unit pushes the liquid inside the hollow fiber column to flow back and forth along the axial direction. During this process, fresh liquid is added to the bioreactor while waste liquid is discharged from the hollow fiber column assembly, thereby achieving continuous tangential filtration of the liquid inside the reactor.

[0027] When the pressure gauge detects that the liquid pressure change in the waste liquid chamber is lower than the set value, the fiber column of the hollow fiber column assembly is reverse-flushed through the radial drive unit.

[0028] The working process of the axial drive unit includes:

[0029] Step S11: Inflate the rigid spherical shell with air through the first air pump assembly to compress the elastic bladder of the first diaphragm pump, causing the elastic bladder of the first diaphragm pump to contract. The liquid inside the elastic bladder flows into the hollow fiber column of the hollow fiber column assembly through the second pair of interfaces.

[0030] Step S12: The rigid spherical shell is evacuated by the first air pump assembly, causing the elastic bladder of the first diaphragm pump to expand. The liquid in the hollow fiber column flows into the elastic bladder through the second pair of interfaces.

[0031] Step S13: Repeat steps S11-S12 continuously.

[0032] Furthermore, the operation of the radial drive unit includes:

[0033] Step S21: Inflate the rigid spherical shell with air through the second air pump assembly to compress the elastic bladder of the second diaphragm pump, causing the elastic bladder of the second diaphragm pump to contract. The liquid in the elastic bladder flows into the waste liquid chamber through the second drain port and drives the liquid in the waste liquid chamber to backwash the hollow fiber column.

[0034] Step S22: The rigid spherical shell is evacuated by the second air pump assembly, causing the elastic bladder of the second diaphragm pump to expand, and the liquid in the hollow fiber column assembly flows tangentially into the elastic bladder of the second diaphragm pump again through the second drain port.

[0035] Step S23 involves continuously repeating steps S21-S22.

[0036] Compared with the prior art, the present invention has at least the following beneficial effects:

[0037] This invention monitors the pressure change at the waste liquid outlet of the waste liquid chamber using a pressure gauge, thereby determining the blockage of the hollow fiber column. It also drives the liquid to flow in reverse through the hollow fiber column online via a second diaphragm pump, clearing and cleaning the micropores on the hollow fiber column in reverse, ensuring the unobstructed flow of the hollow fiber column, and thus improving the efficiency of perfusion culture. Attached Figure Description

[0038] Figure 1 This is a schematic diagram of the overall structure of the tangential flow filter device with a cleaning unit according to the present invention;

[0039] Figure 2 This is a cross-sectional structural schematic diagram of the tangential flow filter device with a cleaning unit according to the present invention;

[0040] Figure 3 This is a schematic diagram of the fiber column assembly structure of the tangential flow filter device with cleaning device of the present invention;

[0041] Figure 4 This is a schematic diagram of the immersion state structure of the perfusion culture system of the present invention;

[0042] Figure 5 This is a schematic diagram of the production state structure of the perfusion culture system of the present invention;

[0043] Figure 6 This is a schematic diagram of the cleaning state structure of the perfusion culture system of the present invention. Detailed Implementation

[0044] The tangential flow filtration device with cleaning apparatus, perfusion culture system, and method of the present invention will now be described in more detail with reference to the schematic diagrams, which illustrate preferred embodiments of the invention. It should be understood that those skilled in the art can modify the invention described herein while still achieving the advantageous effects of the invention. Therefore, the following description should be understood as being of general knowledge to those skilled in the art and is not intended to limit the invention.

[0045] The invention is described more specifically by way of example in the following paragraphs with reference to the accompanying drawings. The advantages and features of the invention will become clearer from the following description. It should be noted that the drawings are in a very simplified form and use non-precise proportions, and are only used to facilitate and clarify the illustration of the embodiments of the invention.

[0046] Example 1

[0047] like Figures 1 to 3 As shown, an embodiment of the present invention proposes a tangential flow filtration device with a cleaning device, comprising: a hollow fiber column 3 assembly, a pressure gauge 1, a first diaphragm pump, and a second diaphragm pump.

[0048] Specifically, the hollow fiber column 3 assembly includes several hollow fiber columns 3 and a sleeve 4. The sleeve 4 is sleeved on the outside of the several hollow fiber columns 3, and a waste liquid cavity 5 is formed between the inner wall of the sleeve 4 and the several hollow fiber columns 3.

[0049] The hollow fiber column 3 assembly has a first pair of interfaces and a second pair of interfaces at its upper and lower ends, respectively. Both the first and second pairs of interfaces are interconnected with several fluid channels of the hollow fiber columns 3. A first drain port and a second drain port are respectively provided on the upper and lower sidewalls of the hollow fiber column 3 assembly, and both are interconnected with the waste liquid chamber 5. The first pair of interfaces is connected to the main pipeline 6, which is used to connect to the bioreactor; the first drain port is connected to the drain pipe 14, which is used to discharge waste liquid from the waste liquid chamber 5.

[0050] The first diaphragm pump is sealed to the second interface, the second diaphragm pump is sealed to the second drain port, and the pressure gauge 1 is connected to the waste liquid chamber 5 of the hollow fiber column 3 assembly through the second drain port. The pressure gauge 1 is used to detect the liquid pressure change of the second drain port in real time, thereby obtaining the change value of the liquid pressure in the waste liquid chamber 5.

[0051] During operation, the first and second diaphragm pumps adjust their operating status based on the real-time readings from pressure gauge 1. Specifically:

[0052] When the liquid pressure change value in the waste liquid chamber 5 is higher than the set value, the first diaphragm pump works normally, and the hollow fiber column 3 assembly performs normal filtration.

[0053] When the liquid pressure change value in the waste liquid chamber 5 is lower than the set value, the second diaphragm pump starts to work, driving the liquid in the waste liquid chamber 5 to backwash the hollow fiber column 3.

[0054] Furthermore, both the first diaphragm pump and the second diaphragm pump include a rigid spherical shell 7 and an elastic balloon 2. The elastic balloon 2 is disposed inside the rigid spherical shell 7, and the inner cavity of the elastic balloon 2 is interconnected with the fluid channels of the plurality of hollow fiber columns 3 or the waste liquid chamber 5. A pressure regulating chamber (not shown) is formed between the outer wall of the elastic balloon 2 and the inner wall of the rigid spherical shell 7. The elastic balloon 2 contracts or expands according to the pressure change of the pressure regulating chamber.

[0055] Specifically, the bottom of the rigid spherical shell 7 is provided with a base 8, and the base 8 is provided with a vent hole 9. The external air pump assembly is connected to the air pressure regulating chamber through the vent hole 9.

[0056] In this embodiment, the air pump assembly is connected to the air pressure regulating chamber through the vent 9, and switches between the contracted and inflated states of the elastic balloon 2 by changing the air pressure in the air pressure regulating chamber, specifically:

[0057] When the air pump assembly inflates the pressure regulating chamber through the vent 9, the pressure inside the pressure regulating chamber increases. When the pressure inside the pressure regulating chamber is greater than the pressure inside the elastic balloon 2, the elastic balloon 2 contracts under the pressure of the external pressure.

[0058] When the air pump assembly draws air out of the pressure regulating chamber through the vent 9, the air pressure inside the pressure regulating chamber decreases. The air pressure inside the pressure regulating chamber is less than the pressure inside the elastic bladder, and the elastic bladder 2 expands under the pressure of the internal pressure.

[0059] To prevent the elastic balloon 22 from blocking the outlet when it contracts, an internal support column 10 is provided on the elastic balloon 2, which is used to fix the upper and lower ends of the elastic balloon 2.

[0060] In one specific embodiment, both the first diaphragm pump and the second diaphragm pump further include a connecting pipe 11. The connecting pipe 11 is disposed at the end of the rigid spherical shell 7 away from the base 8. The lower ends of the two connecting pipes 11 are respectively sealed and connected to the open ends of the two elastic balloons 2. The upper end of the connecting pipe 11 of the first diaphragm pump is sealed and connected to the second interface of the hollow fiber column 3 assembly. The upper end of the connecting pipe 11 of the second diaphragm pump is sealed and connected to the second drain port of the hollow fiber column 3 assembly. An impregnation hole is provided on the side wall of the connecting pipe 11 for connecting the wetting tube 12.

[0061] When connecting and installing the transfer pipe 11, waste liquid chamber 5, and pressure gauge 1, a T-type equal diameter tee 13 is used. The first end of the T-type equal diameter tee 13 is sealed and connected to the transfer pipe 11 of the second diaphragm pump via an L-shaped elbow, the second end of the T-type equal diameter tee 13 is sealed and connected to the second drain port, and the third end of the T-type equal diameter tee 13 is connected to the pressure gauge 1.

[0062] Example 2

[0063] As shown in the figure, the present invention discloses a perfusion culture system, including: a first air pump assembly, a second air pump assembly, a bioreactor, a control unit, and the aforementioned tangential flow filter with a cleaning device.

[0064] Specifically, the bioreactor is connected to the first pair of interfaces of the hollow fiber column 3 assembly via the main pipeline 6.

[0065] The first diaphragm pump of the tangential flow filter and the first air pump assembly form an axial drive unit, and the second diaphragm pump of the tangential flow filter and the second air pump assembly form a radial drive unit.

[0066] The pressure gauge 1 of the first air pump assembly, the second air pump assembly, and the tangential flow filter device are all connected to the control unit. The control unit controls the working state of the axial drive unit and the radial drive unit based on the pressure change in the waste liquid chamber 5 detected by the pressure gauge 1. Specifically:

[0067] When the pressure gauge 1 detects that the liquid pressure change in the waste liquid chamber 5 is higher than the set value, the axial drive unit works normally to drive the liquid in the hollow fiber column 3 assembly to flow back and forth, thereby achieving tangential filtration.

[0068] When the pressure gauge 1 detects that the liquid pressure change value in the waste liquid chamber 5 is lower than the set value, the radial drive unit starts to work to drive the liquid in the waste liquid chamber 5 to backwash the hollow fiber column 3 of the hollow fiber column 3 assembly.

[0069] Example 3

[0070] This invention discloses a perfusion culture method, using the perfusion culture system in Example 2, comprising the following steps:

[0071] The axial drive unit pushes the liquid inside the hollow fiber column 3 to flow back and forth along the axial direction. During this process, new liquid is added to the bioreactor while waste liquid is discharged from the hollow fiber column 3 assembly, thereby achieving continuous tangential filtration of the liquid inside the bioreactor.

[0072] When the pressure gauge 1 detects that the liquid pressure change value in the waste liquid chamber 5 is lower than the set value, the fiber column 3 of the hollow fiber column 3 assembly is reverse-flushed through the radial drive unit.

[0073] The working process of the axial drive unit includes:

[0074] Step S11: Inflate the rigid spherical shell 7 with air through the first air pump assembly to compress the elastic bladder 2 of the first diaphragm pump, causing the elastic bladder 2 of the first diaphragm pump to contract. The liquid inside the elastic bladder 2 flows into the hollow fiber column 3 of the hollow fiber column 3 assembly through the second pair of interfaces.

[0075] Step S12: The rigid spherical shell 7 is evacuated by the first air pump assembly, causing the elastic bladder 2 of the first diaphragm pump to expand. The liquid in the hollow fiber column 3 flows into the elastic bladder 2 through the second pair of interfaces.

[0076] Step S13: Continuously cycle through steps S11-S12 until the liquid pressure change value in the waste liquid chamber 5 is lower than the set value.

[0077] The operation process of the radial drive unit includes:

[0078] In step S21, the rigid spherical shell 7 is inflated by the second air pump assembly to compress the elastic bladder 2 of the second diaphragm pump, causing the elastic bladder 2 of the second diaphragm pump to contract. The liquid in the elastic bladder 2 flows into the waste liquid chamber 5 through the second drain port, and drives the liquid in the waste liquid chamber 5 to backwash the hollow fiber column 3.

[0079] In step S22, the rigid spherical shell 7 is evacuated by the second air pump assembly, causing the elastic bladder 2 of the second diaphragm pump to expand, so that the liquid in the hollow fiber column 3 assembly flows tangentially into the elastic bladder 2 of the second diaphragm pump again through the second drain port.

[0080] Step S23: Continuously cycle through steps S21-S22 until the liquid pressure change value in the waste liquid chamber 5 is higher than the set value.

[0081] The specific workflow and steps involved in biopharmaceutical development are as follows:

[0082] (1) Pre-connect the pipelines and related supporting devices using aseptic connection methods.

[0083] (2) Figure 4 As shown, the inlet end of the wetting tube 12 is connected to the immersion bottle using a sterile connector, and the outlet end of the drain tube 14 is connected to the collection bag. A peristaltic pump pumps the culture medium from the immersion bottle into the hollow fiber column 3 until it is full of liquid. Excess wetting fluid will flow from the drain tube 14 into the collection bottle, ensuring the entire device is filled with liquid. Afterward, the end of the wetting tube 12 is welded shut, the Robert clamp between the two elastic balloons 2 is closed, and the wetting fluid bag is removed.

[0084] (3) Biological culture. For example... Figure 5 As shown, the first air pump assembly alternately pumps and inflates, driving the elastic balloon 2 connected to the hollow fiber column 3 to cyclically expand and contract. When the first air pump assembly pumps air, the elastic balloon 2 expands, drawing liquid from the bioreactor into the elastic balloon 2. When the first air pump assembly inflates, the elastic balloon 2 contracts, pushing the culture medium into the hollow fiber column 3. The culture medium in the hollow fiber column 3 flows into the bioreactor, while simultaneously, a peristaltic pump draws liquid filtered through the fiber from the drain pipe 14. Liquid in the replenishment bottle is continuously pumped into the bioreactor by the peristaltic pump. This ensures that fresh liquid always enters the bioreactor, while some liquid is filtered through the hollow fiber column 3 and discharged through the drain pipe 14, thus achieving liquid replacement within the bioreactor and maintaining the cultured target material in a favorable growth environment. During the culture process, the culture medium flows back and forth along the axial direction of the hollow fiber column 3. Under the action of transmembrane pressure, some liquid and small molecules pass through the micropores to become filtrate, which enters the waste liquid chamber 5.

[0085] (4) Equipment cleaning. For example... Figure 6As shown, during perfusion culture, the hollow fiber column 3 is prone to blockage due to high-density cell proliferation. When blockage is imminent, abnormal liquid flow occurs inside the hollow fiber column 3, causing internal pressure changes to differ from normal operating conditions. The internal pressure of the waste liquid chamber 5 is monitored using pressure gauge 1. If the pressure change detected by pressure gauge 1 is lower than the programmed value, the control program indicates impending blockage. The clamp on the waste liquid pipe is closed, and simultaneously, the control program activates the second air pump assembly. The second air pump assembly alternately pumps and inflates, driving the elastic balloon 2 connected to the waste liquid chamber 5 to cyclically contract and expand. When the elastic balloon 2 contracts, it pushes the culture medium into the waste liquid chamber 5, which backflushes and cleans the hollow fiber column 3. When the elastic balloon 2 expands, it draws the culture medium from inside the waste liquid chamber 5 into the elastic balloon 2, preparing for the next backflushing. This backflushing is repeated until the pressure change inside the waste liquid chamber 5 returns to normal, resolving the blockage.

[0086] Compared with the prior art, the present invention has at least the following beneficial effects:

[0087] This invention uses a pressure gauge to monitor pressure changes at the waste liquid outlet to determine the blockage of the hollow fiber column. A second diaphragm pump drives the liquid to flow backward through the hollow fiber column online, effectively cleaning and unblocking the micropores and ensuring unobstructed flow, thereby improving production efficiency.

[0088] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A tangential flow filtration device with belt cleaning device, characterized in that The utility model relates to a hollow fiber column assembly, pressure detection table, first diaphragm pump and second diaphragm pump are included. The hollow fiber column assembly includes a plurality of hollow fiber columns and a sleeve, the sleeve is sleeved outside the plurality of hollow fiber columns, and a waste liquid cavity is formed between the inner wall of the sleeve and the plurality of hollow fiber columns. The upper and lower ends of the hollow fiber column assembly are respectively provided with a first connecting port and a second connecting port, the first connecting port and the second connecting port are communicated with the fluid channels of the plurality of hollow fiber columns, and the upper and lower end side walls of the hollow fiber column assembly are respectively provided with a first liquid discharge port and a second liquid discharge port, which are communicated with the waste liquid cavity. The first diaphragm pump is sealingly connected with the second connecting port, the second diaphragm pump is sealingly connected with the second liquid discharge port, the pressure detection table is connected with the waste liquid cavity of the hollow fiber column assembly through the second liquid discharge port, and the pressure detection table is used for detecting the change of liquid pressure in the waste liquid cavity in real time. When the liquid pressure change value in the waste liquid cavity is higher than the set value, the first diaphragm pump normally works, and the hollow fiber column assembly normally filters. When the liquid pressure change value in the waste liquid cavity is lower than the set value, the second diaphragm pump starts to work and drives the liquid in the waste liquid cavity to reversely flush the hollow fiber column. The first diaphragm pump and the second diaphragm pump each include a rigid spherical shell and an elastic balloon, the elastic balloon is arranged in the rigid spherical shell, a gas pressure adjusting cavity is formed between the outer wall of the elastic balloon and the inner wall of the rigid spherical shell, and the elastic balloon contracts or expands according to the gas pressure change of the gas pressure adjusting cavity.

2. The tangential flow filtration device with cleaning apparatus of claim 1, wherein, The inner cavity of the elastic balloon of the first diaphragm pump is communicated with the fluid channels of the plurality of hollow fiber columns, and the inner cavity of the elastic balloon of the second diaphragm pump is communicated with the waste liquid cavity. The bottom of the rigid spherical shell is provided with a base, the base is provided with a ventilation hole, and an external air pump assembly is communicated with the gas pressure adjusting cavity through the ventilation hole.

3. The tangential flow filtration device with cleaning apparatus of claim 2, wherein, The first diaphragm pump and the second diaphragm pump each include an adapter pipe, the adapter pipe is arranged at the end of the rigid spherical shell away from the base, the lower ends of the two adapter pipes are sealingly connected with the opening ends of the two elastic balloons respectively, the upper end of the adapter pipe of the first diaphragm pump is sealingly connected with the second connecting port of the hollow fiber column assembly, the upper end of the adapter pipe of the second diaphragm pump is sealingly connected with the second liquid discharge port of the hollow fiber column assembly, and the side wall of the adapter pipe is provided with a soaking hole for connecting a wetting pipe.

4. The tangential flow filtration device with cleaning apparatus of claim 2, wherein, A T-shaped equal-diameter tee joint is further included, the first end of the T-shaped equal-diameter tee joint is sealingly connected with the adapter pipe of the second diaphragm pump through an L-shaped elbow, the second end of the T-shaped equal-diameter tee joint is sealingly connected with the second liquid discharge port, and the third end of the T-shaped equal-diameter tee joint is connected with the pressure detection table.

5. The tangential flow filtration device with cleaning apparatus of claim 4, wherein, A ball inner support is arranged on the elastic balloon and used for fixing the upper and lower ends of the elastic balloon.

6. The tangential flow filtration device with cleaning apparatus of claim 2, wherein, ​ 7. The tangential flow filtration device with cleaning apparatus of claim 1, wherein, The first interface is connected with a main pipeline, and the main pipeline is used for connecting a bioreactor; the first liquid outlet is connected with a liquid discharge pipeline, and the liquid discharge pipeline is used for discharging waste liquid in the waste liquid cavity.

8. A perfusion culture system, characterized by, The tangential flow filtration device with cleaning device according to any one of claims 1-7, wherein the bioreactor is connected with the first interface of the hollow fiber column assembly through a main pipeline; the first diaphragm pump of the tangential flow filtration device and the first air pump assembly constitute an axial driving unit, and the second diaphragm pump of the tangential flow filtration device and the second air pump assembly constitute a radial driving unit; the first air pump assembly, the second air pump assembly and the pressure detection table of the tangential flow filtration device are connected with the control unit; the control unit controls the working state of the axial driving unit and the radial driving unit according to the pressure change in the waste liquid cavity detected by the pressure detection table; when the pressure change value of the liquid in the waste liquid cavity detected by the pressure detection table is higher than a set value, the axial driving unit works normally to drive the liquid in the hollow fiber column assembly to flow back and forth, thereby realizing tangential filtration; when the pressure change value of the liquid in the waste liquid cavity detected by the pressure detection table is lower than the set value, the radial driving unit starts to work to drive the liquid in the waste liquid cavity to perform reverse flushing on the hollow fiber column of the hollow fiber column assembly. The tangential flow filtration device with cleaning device according to any one of claims 1-7, wherein the bioreactor is connected with the first interface of the hollow fiber column assembly through a main pipeline; the first diaphragm pump of the tangential flow filtration device and the first air pump assembly constitute an axial driving unit, and the second diaphragm pump of the tangential flow filtration device and the second air pump assembly constitute a radial driving unit; the first air pump assembly, the second air pump assembly and the pressure detection table of the tangential flow filtration device are connected with the control unit; the control unit controls the working state of the axial driving unit and the radial driving unit according to the pressure change in the waste liquid cavity detected by the pressure detection table; when the pressure change value of the liquid in the waste liquid cavity detected by the pressure detection table is higher than a set value, the axial driving unit works normally to drive the liquid in the hollow fiber column assembly to flow back and forth, thereby realizing tangential filtration; when the pressure change value of the liquid in the waste liquid cavity detected by the pressure detection table is lower than the set value, the radial driving unit starts to work to drive the liquid in the waste liquid cavity to perform reverse flushing on the hollow fiber column of the hollow fiber column assembly. The tangential flow filtration device with cleaning device according to any one of claims 1-7, wherein the bioreactor is connected with the first interface of the hollow fiber column assembly through a main pipeline; the first diaphragm pump of the tangential flow filtration device and the first air pump assembly constitute an axial driving unit, and the second diaphragm pump of the tangential flow filtration device and the second air pump assembly constitute a radial driving unit; the first air pump assembly, the second air pump assembly and the pressure detection table of the tangential flow filtration device are connected with the control unit; the control unit controls the working state of the axial driving unit and the radial driving unit according to the pressure change in the waste liquid cavity detected by the pressure detection table; when the pressure change value of the liquid in the waste liquid cavity detected by the pressure detection table is higher than a set value, the axial driving unit works normally to drive the liquid in the hollow fiber column assembly to flow back and forth, thereby realizing tangential filtration; when the pressure change value of the liquid in the waste liquid cavity detected by the pressure detection table is lower than the set value, the radial driving unit starts to work to drive the liquid in the waste liquid cavity to perform reverse flushing on the hollow fiber column of the hollow fiber column assembly. The tangential flow filtration device with cleaning device according to any one of claims 1-7, wherein the bioreactor is connected with the first interface of the hollow fiber column assembly through a main pipeline; the first diaphragm pump of the tangential flow filtration device and the first air pump assembly constitute an axial driving unit, and the second diaphragm pump of the tangential flow filtration device and the second air pump assembly constitute a radial driving unit; the first air pump assembly, the second air pump assembly and the pressure detection table of the tangential flow filtration device are connected with the control unit; the control unit controls the working state of the axial driving unit and the radial driving unit according to the pressure change in the waste liquid cavity detected by the pressure detection table; when the pressure change value of the liquid in the waste liquid cavity detected by the pressure detection table is higher than a set value, the axial driving unit works normally to drive the liquid in the hollow fiber column assembly to flow back and forth, thereby realizing tangential filtration; when the pressure change value of the liquid in the waste liquid cavity detected by the pressure detection table is lower than the set value, the radial driving unit starts to work to drive the liquid in the waste liquid cavity to perform reverse flushing on the hollow fiber column of the hollow fiber column assembly. The tangential flow filtration device with cleaning device according to any one of claims 1-7, wherein the bioreactor is connected with the first interface of the hollow fiber column assembly through a main pipeline; the first diaphragm pump of the tangential flow filtration device and the first air pump assembly constitute an axial driving unit, and the second diaphragm pump of the tangential flow filtration device and the second air pump assembly constitute a radial driving unit; the first air pump assembly, the second air pump assembly and the pressure detection table of the tangential flow filtration device are connected with the control unit; the control unit controls the working state of the axial driving unit and the radial driving unit according to the pressure change in the waste liquid cavity detected by the pressure detection table; when the pressure change value of the liquid in the waste liquid cavity detected by the pressure detection table is higher than a set value, the axial driving unit works normally to drive the liquid in the hollow fiber column assembly to flow back and forth, thereby realizing tangential filtration; when the pressure change value of the liquid in the waste liquid cavity detected by the pressure detection table is lower than the set value, the radial driving unit starts to work to drive the liquid in the waste liquid cavity to perform reverse flushing on the hollow fiber column of the hollow fiber column assembly. The tangential flow filtration device with cleaning device according to any one of claims 1-7, wherein the bioreactor is connected with the first interface of the hollow fiber column assembly through a main pipeline; the first diaphragm pump of the tangential flow filtration device and the first air pump assembly constitute an axial driving unit, and the second diaphragm pump of the tangential flow filtration device and the second air pump assembly constitute a radial driving unit; the first air pump assembly, the second air pump assembly and the pressure detection table of the tangential flow filtration device are connected with the control unit; the control unit controls the working state of the axial driving unit and the radial driving unit according to the pressure change in the waste liquid cavity detected by the pressure detection table; when the pressure change value of the liquid in the waste liquid cavity detected by the pressure detection table is higher than a set value, the axial driving unit works normally to drive the liquid in the hollow fiber column assembly to flow back and forth, thereby realizing tangential filtration; when the pressure change value of the liquid in the waste liquid cavity detected by the pressure detection table is lower than the set value, the radial driving unit starts to work to drive the liquid in the waste liquid cavity to perform reverse flushing on the hollow fiber column of the hollow fiber column assembly. ​ 9. A perfusion culture method, characterized by, ​ ​ ​ ​ ​ ​ ​ ​ 10. The perfusion culture process of claim 9, wherein, ​ ​ Step S22, through the second air pump assembly to the rigid spherical shell in the pumping operation, the second diaphragm pump elastic ballon expansion, so that the liquid in the hollow fiber column assembly via the second liquid outlet again into the tangential flow in the second diaphragm pump elastic ballon; Step S23, the operation of step S21-step S22 constantly circulating.

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