Fluid filtration system

Abstract

An improved fluid filtration system is described that uses an improved sensor assembly to avoid biomass buildup problems and reduce liquid holdup volume outside the process vessel, significantly improving filtration performance, robustness, and consistency.

Description

Technical Field

[0001] [Cross - Reference to Related Applications] This application claims the benefit of priority of U.S. Provisional Patent Application No. 62 / 705,876, filed Jul. 20, 2020, the content of which is incorporated herein by reference.

[0002] This disclosure relates to a filtration system. More specifically, the present invention relates to a cross - flow filtration system having an improved level sensor assembly for filtering fluids, particularly biological fluids containing cells.

Background Art

[0003] Accurate detection and control of liquid level is important for several applications, particularly for certain types of filtration systems, for example. Filtration is typically performed to separate, clarify, modify, and / or concentrate fluid solutions, mixtures, or suspensions. In the biotechnology and pharmaceutical industries, filtration is essential for the success of the production, processing, and testing of new drugs, diagnostics, and other biological products. For example, in the manufacturing process of biological agents using cell culture, particularly animal cell culture, filtration is performed for clarification, selective removal, and concentration of specific components from the culture medium, or to modify the medium prior to further processing. Filtration may also be used to increase productivity by maintaining the culture in perfusion at a high cell concentration.

[0004] This application describes an improved fluid filtration system having an improved level sensor, and using this system, the performance, robustness, and consistency of filtration can be significantly enhanced.

Summary of the Invention

[0005] In one general aspect, this application describes a filtration system that (1) an expansion chamber having a first end and an opposite second end, and a length extending between the first end and the second end, (2) comprising a first sensor assembly and a second sensor assembly mounted on the outer surface of the expansion chamber for monitoring the fluid level inside the expansion chamber, (i) The first sensor assembly is located near the first end of the expansion chamber, (ii) The second sensor assembly is located near the second end of the expansion chamber, (iii) Each of the first and second sensor assemblies includes a transmitter and a receiver, the receiver detecting a chamber empty signal when there is no fluid between the respective receiver and transmitter in the expansion chamber, and the receiver detecting a chamber full signal when there is fluid between the respective receiver and transmitter in the expansion chamber, and the trigger point between the chamber empty signal and the chamber full signal is set to control the direction of fluid flow in the expansion chamber so that the fluid fluctuates between the upper and lower limits of the expansion chamber. (A) The trigger point is set to be significantly different from the chamber empty signal, preferably 25-35% lower or higher than the chamber empty signal. (B) The first sensor assembly is longitudinally offset from the upper limit by a distance of 15% to 25% of the length of the expansion chamber, and / or the direction of the offset is away from the first end of the expansion chamber. (C) The direction of fluid flow within the expansion chamber is changed after a certain time delay following the detection of a signal by the first or second sensor assembly that crosses the trigger point.

[0006] This application also describes the uses and methods for using the above-described filtration system.

[0007] Other aspects, features, and advantages of the present invention will become apparent from the following disclosure, including a detailed description of the present invention and its preferred embodiments, and the appended claims. [Brief explanation of the drawing]

[0008] [Figure 1]This figure shows the piping and measurement equipment diagrams (P and ID) for an alternating tangential flow filtration system, including the sensor assembly and gas flow controller system. [Figure 2] This figure shows an expansion chamber equipped with a sensor assembly according to one embodiment of the present invention. [Figure 3A] This figure shows an alternating tangential flow filtration system according to one embodiment of the present invention. [Figure 3B] Another diagram of the expansion chamber of the alternating tangential flow filtration system shown in Figure 3A. [Figure 4A] This is a graphical representation of the operation of an upper level sensor assembly according to one embodiment of the present invention. [Figure 4B] This is a graphical representation of the operation of a lower level sensor assembly according to one embodiment of the present invention. [Figure 5A] This is a graphical representation of sensor values ​​from a conventional alternating tangential flow filtration system, where the unit of the sensor value (Y-axis) is negative centibels (-cB). [Figure 5B] This is a graphical representation of sensor values ​​for an alternating tangential flow filtration system according to one embodiment of the present invention, where the unit of the sensor value (Y axis) is -cB. [Figure 6] Figure 6A is a photograph showing the biomass accumulation in the inflation chamber of a pneumatic alternating cell separator (PACS) on day 8 of mammalian cell culture using a conventional sensor assembly. Figure 6B is a photograph showing the disappearance of biomass accumulation in the inflation sensor using an improved sensor assembly according to one embodiment of the present invention. [Modes for carrying out the invention]

[0009] The following description is provided so that those skilled in the art may create and use various embodiments. Descriptions of specific compositions, techniques, and applications are provided merely as examples. Various modifications to the examples described herein will be immediately apparent to those skilled in the art, and the general principles defined herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Thus, the various embodiments are not limited to the examples described and illustrated herein, but are given a scope consistent with the claims.

[0010] Various publications, articles, and patents are cited or mentioned throughout the background art and specification, and each of these cited documents is incorporated herein by reference in its entirety. The documents, operations, materials, apparatus, articles, etc. included in this application are intended to provide context relating to the invention. No such discussion shall be considered to constitute part of the prior art with respect to the disclosed or claimed invention.

[0011] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art relating to the present invention. Otherwise, certain terms used herein have the meanings set forth herein. All patents, published patent applications, and publications cited herein are incorporated by reference as being described herein in whole.

[0012] It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise.

[0013] Unless otherwise specified, the phrase “at least” preceding a set of elements should be understood to refer to all of those elements. Those skilled in the art will recognize many equivalents to the specific embodiments of the invention described herein, or they may determine this by ordinary experimentation alone. Such equivalents shall be encompassed by the invention.

[0014] Throughout this specification and the subsequent claims, unless the context otherwise requires, the words “equipped with” and variations such as “equipped with,” “with,” etc., are understood to imply the inclusion of the described whole or step, or group of wholes or steps, but not the exclusion of other wholes or steps, or groups of wholes or steps. When used herein, the word “equipped with” may be replaced with “contains,” “includes,” or, sometimes as used herein, the word “has.”

[0015] When used herein, “~consisting of” excludes elements, steps, or raw materials not expressed in the claim elements. When used herein, “~basically consisting of” does not exclude materials or steps that do not substantially affect the basic and novel characteristics of the claim. The words “~equipped with,” “contains,” “includes,” and “have,” as used herein in the context of aspects or embodiments of the Application, may be replaced with the words “~consisting of” or “~basically consisting of” to differentiate the scope of the Disclosure.

[0016] When used herein, the conjunction "and / or" between multiple enumerated elements is understood to encompass both individual options and combined options. For example, when two elements are connected by "and / or," the first option refers to the applicability of the first element without the second element. The second option refers to the applicability of the second element without the first element. The third option refers to the applicability of the first and second elements combined. All of these options are understood to fall under that meaning and therefore satisfy the requirements of the word "and / or" as used herein. The simultaneous applicability of two or more options is also understood to fall under that meaning and therefore satisfy the requirements of the word "and / or."

[0017] Unless otherwise indicated, numerical values such as concentrations and concentration ranges described in this specification should be understood to be modified by the term "about" in all instances. Thus, the numerical values typically include ±10% of the stated value. For example, a concentration of 1 mg / mL includes 0.9 mg / mL to 1.1 mg / mL. Similarly, a concentration range of 1 mg / mL to 10 mg / mL includes 0.9 mg / mL to 11 mg / mL. As used herein, the use of a numerical range includes all individual numerical values within that range, all possible sub-ranges, integers, and fractions of values within that range, unless the context clearly indicates otherwise.

[0018] Filtration systems for biological fluids have been described in the art heretofore. One type of filtration system developed previously is known as an alternating tangential flow (ATF) filtration system. A particular type of ATF filtration system, a pneumatic alternating cell separator (PACS), is described in U.S. Patent No. 8,845,902, the contents of which are hereby incorporated by reference in their entirety.

[0019] An exemplary PACS is shown in FIG. 1, which is the same as FIG. 1 of U.S. Patent No. 8,845,902. The PACS includes a process vessel (1) connected to a filtration module (6), and the filtration module (6) has a filter element (8), an inlet end (7), and an outlet end (9). The outlet end of the filtration module is connected to an expansion chamber (17), and the expansion chamber is connected to a gas flow controller (28). The gas flow controller alternately provides positive and negative pressures (e.g., compressed air and vacuum) into the expansion chamber, causing the fluid contained in the process vessel (1) to alternately be drawn through the filter element (8) into the expansion chamber (17) and discharged from the expansion chamber through the filter element back into the vessel. By doing so, the system creates an alternating tangential flow of fluid, such as a liquid cell culture or a fluid containing lysed cell contents (i.e., cell lysate), through the filter element.

[0020] The expansion chamber (17) is provided with two level sensors (25 and 26) for determining the height of the fluid in the expansion chamber and providing feedback to the gas flow controller (28), and the controller (28) then initiates alternating positive and negative pressure cycles in the expansion chamber. The level sensors can be removably mounted to the expansion chamber. The sensors are designed to direct a signal, such as a microwave signal emitted from the transmitter portion of the sensor, through a window of the expansion chamber. The signal can be reflected from a surface within the expansion chamber on the opposite side of the window and collected by the receiver portion. The signal can also be collected by a receiver portion mounted to a second window opposite the first window through which the signal is transmitted. When liquid is present at or above the height of the transmitter and receiver portions within the expansion chamber, the signal undergoes a change. For example, in the case of a microwave signal, the signal is attenuated when passing through the liquid. Also, the signal can increase when different measurement techniques are used, such as when a reflected signal is measured. The sensor electronic circuit compares the received signal with a predetermined threshold level and provides an output indicating whether liquid is present or not at the height of the sensor.

[0021] Referring to FIG. 2, the level sensor assembly is provided in the expansion chamber 17. The expansion chamber 17 has a first or upper end Up and an opposite second or lower end Lo, and a length extending between the first and second ends. The expansion chamber 17 includes a first or upper sensor assembly 26 and a second or lower sensor assembly 25. Each of the sensor assemblies 25 and 26 independently includes a signal transmitter and a signal receiver, and these two portions are preferably located on opposite sides of each other on the outer surface of the expansion chamber. The upper sensor assembly 26 is preferably provided near the upper end Up of the expansion chamber 17, and the lower sensor assembly 25 is preferably provided near the lower end Lo.

[0022] The first and second sensor assemblies are level sensors used to monitor and control the fluid level in the expansion chamber 17. Each level sensor controls the fluid flow in the expansion chamber 17 by sending a signal, including but not limited to a microwave signal, from its transmitter to its respective receiver. When a portion of the expansion chamber 17 is empty and there is no fluid between the two parts of sensor assembly 25 or 26, each part receives a first signal or a predetermined signal, which will hereafter be referred to as the chamber empty signal. Depending on the sensor used, the chamber empty signal may be any preferred value in light of this disclosure. For example, the chamber empty signal may be approximately 650 minus centibels (-cB) for a sensor that emits a microwave signal. However, when the expansion chamber 17 is filled and there is fluid between the transmitter and receiver of sensor 25 or 26, the receiver is expected to receive a second signal, which will hereafter be referred to as the chamber full signal, and which is attenuated or reduced compared to the chamber empty signal. Depending on the sensor used, the value of the chamber empty signal, and the properties of the fluid (e.g., the composition and density of cells in the fluid), the chamber full signal can be any suitable value different from the chamber empty signal. For example, when microwave measurement techniques are used, the chamber full signal may be approximately 300-cB for a chamber empty signal of 650-cB to a sensor emitting a microwave signal. The difference between the values ​​of the chamber empty signal and the chamber full signal is used to control the fluid flow in the expansion chamber 17, using a trigger point or threshold between the chamber empty signal and the chamber full signal.

[0023] When the trigger point in the upper sensor assembly 26 crosses from the chamber empty signal to the chamber full signal, fluid is drawn out of the expansion chamber 17. When the trigger point in the lower sensor assembly 25 crosses from the chamber full signal to the chamber empty signal, fluid is drawn back into the expansion chamber 17. When liquid is drawn from the storage container, negative pressure is applied until the liquid drawn into the expansion chamber reaches the upper limit height (UL). The upper level sensor compares the received signal to a predetermined trigger point or threshold to detect the presence of liquid at UL. When the threshold is crossed, the upper level sensor triggers a switch on the gas flow controller (28) from the negative pressure cycle to the positive pressure cycle, thereby applying positive pressure. Positive pressure is then applied until liquid is released from the expansion chamber and the liquid level in the chamber drops to the lower limit height (LL). The lower level sensor compares the received signal to a predetermined trigger point or threshold to detect that the liquid has dropped to LL. When the threshold is exceeded, the lower level sensor triggers the gas flow controller (28) to switch from a positive pressure cycle to a negative pressure cycle, applying negative pressure and starting a new cycle. However, it should be noted that if the trigger point crosses again from a chamber full signal to a chamber empty signal at the upper sensor assembly 26 while the fluid is moving downwards, or if the trigger point crosses again from a chamber empty signal to a chamber full signal at the lower sensor assembly 25 while the fluid is moving upwards, nothing happens to the gas flow controller.

[0024] The trigger point is conventionally set to a value slightly lower than the chamber empty signal. The upper level sensor is conventionally mounted near UL on the outer surface of the expansion chamber, and the lower level sensor is conventionally mounted near LL on the outer surface of the expansion chamber. The fluid contained within the expansion chamber typically fluctuates between UL and LL to provide the filtration system with a target fluid displacement volume. Such systems have applications in perfusing cultured animal cells, as well as in a variety of other filtration applications.

[0025] However, in practice, it has been found that cell culture biomass tends to accumulate on the inner surface of the expansion chamber, particularly in or near the upper level sensor (UL). Depending on the type of sensor used (and the sensor's measurement principle), the cell culture biomass can interfere with the sensor signal, impairing the upper level sensor's ability to function properly and thus negatively impacting the overall operation of the filtration system.

[0026] In addition, since the lower level sensor is positioned above the lower end of the expansion chamber, the liquid column stops at this height when the liquid is released from the expansion chamber, resulting in a liquid hold-up volume in the lower part of the expansion chamber (17) and the U-shaped curved section (14) connected to the filtration module (6). Since this liquid is a cell suspension outside the controlled environment of the process vessel, it is preferable to minimize this liquid hold-up volume.

[0027] In this invention, it was found that lowering the trigger point or threshold of the upper level sensor results in more accurate detection of UL, and thus more reliable control of the gas flow controller. Furthermore, in this invention, it was found that biomass accumulates over time near the UL where the upper level sensor is located on the surface of the expansion chamber and gradually deteriorates, but due to the washing effect created by the larger flux of alternating liquid flow at lower positions, biomass is not significantly observed at new positions below that area. In addition, a time delay can be implemented before the gas controller 28 initiates the application of positive or negative pressure to maintain the target cell culture displacement volume and / or minimize the liquid hold-up volume in the lower part of the expansion chamber (17) and the U-shaped curved section (14) connected to the filtration module (6).

[0028] Therefore, in one general aspect, this wishThis invention relates to an improved level sensor assembly for use in a fluid filtration system, wherein the level sensor has a trigger point or threshold set to a value significantly lower than the chamber empty signal. In one embodiment, the sensor is a microwave sensor, and the trigger point is set 25–35%, for example 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35% lower than the chamber empty signal. Other sensors, such as sensors based on light scattering and sensors based on volume measurement, may also be used in the present invention. The trigger points or thresholds of such other sensors may be determined in light of this disclosure using methods known in the art. In one embodiment, the sensor detects a reflected signal, and the trigger point is set 25–35%, for example 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, or 35% higher than the chamber empty signal.

[0029] In one embodiment of the present application, the sensor is a microwave sensor, and there is a difference of 160-cB to 200-cB, more preferably about 175-cB, between the trigger point of sensor assemblies 25 and 26 and the chamber empty value. For example, if the chamber empty value is 650-cB, the trigger point is preferably about 450-cB to 490-cB, for example, 450-cB, 455-cB, 460-cB, 465-cB, 470-cB, 475-cB, 480-cB, 485-cB, or 90-cB, more preferably about 475-cB.

[0030] In one embodiment, the filtration system of the present invention uses sensing means for more accurate detection of UL standards, and thus more reliable control of the gas flow controller.

[0031] In another general embodiment, the present application relates to an improved expansion chamber for a liquid filtration system, the chamber having an upper level sensor located on the outer surface of the expansion chamber, at a position significantly lower than the upper height (UL). Preferably, the expansion chamber 17 has a maximum trigger point or threshold. In one embodiment, a first (upper) sensor assembly 26, more particularly the transmitter and receiver of the first sensor assembly 26, is longitudinally offset by a certain distance from the UL, i.e., the upper sensor is located significantly lower than the UL along the cylindrical axis of the expansion chamber. In a preferred embodiment, the first sensor assembly 26, more particularly the transmitter and receiver of the first sensor assembly 26, is longitudinally offset from the UL by a distance of about 15% to 25% of the length of the expansion chamber 17, for example, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%. The offset distance is preferably such that the location where the biomass is accumulating (e.g., UL) is sufficiently far from the position of the upper sensor assembly 26 to ensure that there is no or minimal interference in the sensor signal caused by the accumulated biomass. The exact offset distance depends on the scale. In one embodiment, the offset distance is about 3.5 to 5.5 inches, e.g., about 3.5, 4, 4.5, 5, or 5.5 inches. In one embodiment, the offset distance is more preferably about 4.5 inches. The direction of the offset is away from the upper end of the expansion chamber 17, and as a result, the first sensor assembly 26 is positioned lower than UL by a distance (e.g., about 4.5 inches) that is 15% to 25% of the length of the expansion chamber 17, when viewed along the longitudinal axis of the expansion chamber.

[0032] In one embodiment, the filtration system of the present invention uses means to sufficiently distance the location of the biomass accumulation from the location of the upper sensor assembly 26 so that there is no or minimal interference in the sensor signal caused by the accumulated biomass.

[0033] In another general embodiment, the present application relates to an improved fluid filtration system comprising a time delay mechanism after either the first or second sensor assembly 26 or 25 is triggered (i.e., the signal sensed by the sensor assembly 26 or 25 exceeds the trigger point) and before the fluid is drawn out of or drawn into the expansion chamber 17. In one embodiment, the time delay is performed after the sensor is triggered by the signal exceeding a trigger point or threshold set to a value significantly lower than the chamber empty signal, thereby maintaining the target cell culture displacement volume. In another embodiment, the time delay is performed after the upper level sensor, located significantly below the upper height (UL) on the outer surface of the expansion chamber, thereby maintaining the target cell culture displacement volume. In a further embodiment, the time delay is performed after the lower sensor is triggered, thereby reducing the volume between the lower sensor and the lower end of the hollow fiber, and thus minimizing the number of cells that remain uncontrolled outside the process vessel at the end of the pressure cycle. Depending on the scale of the system, such as the total cycle time, and other factors such as the type of application and the desired cross-flow flow rate, the time delay may vary. In one embodiment, the time delay is approximately 1000ms to 1300ms, for example, 1000ms, 1100ms, 1200ms, 1300ms, or any value in between, preferably approximately 1200ms.

[0034] In one embodiment, the filtration system of the present invention uses means to reduce the volume between the lower sensor and the lower end of the hollow fiber, thereby minimizing the number of cells that remain uncontrolled outside the process vessel at the end of the pressure cycle.

[0035] Next, the present invention will be described in more detail in the context of exemplary filtration systems, and more particularly, pneumatic alternating cell separation systems having applications for perfusing cultured animal cells. However, it will be understood that the sensor assemblies of the present invention are not limited to such applications and may be similarly used for any alternating tangential flow filtration system, in particular, as described below.

[0036] Referring to Figures 3A and 3B, a filtration system is shown comprising a process vessel 1, an expansion chamber 17, a filtration module 6, and at least one gas flow controller 28.

[0037] Process vessel 1 may be any suitable container for the fluid to be filtered. The term “fluid” will be understood to be used interchangeably with the term “liquid” in this specification when describing the fluid transferred between process vessel 1 and expansion chamber 17. Process vessel 1 may be, for example, a bioreactor, a fermenter, or any other container capable of holding a liquid, including but not limited to tubs, buckets, tanks, bottles, flasks, containers, etc. Process vessel 1 may be made of any suitable material, such as ultra-low density polyethylene (ULDPE), low density polyethylene (LDPE), multilayer materials such as CX5-14 film, polyester, tie barrier tank, ethyl vinyl alcohol (EVOH), and polyester elastomer (PE), or multilayer materials containing PET, PA, EVOH, and ULDPE, metals such as stainless steel, glass, etc.

[0038] In one embodiment, the process vessel 1 is connected to the filtration module 6 by a fluid transfer line or conduit 4, so that fluid is guided from the process vessel 1 to the filtration module 6 via the inlet end 7 of the filtration module 6. In one embodiment, one end of the fluid transfer line 4 is optionally connected to the process vessel 1 by a valve (not shown), and the other end is optionally connected to a port formed at the inlet end 7 of the filtration module 6 by a valve (not shown). In one embodiment, the fluid transfer line 4 comprises piping. Preferably, the piping is kept as short as possible to minimize the liquid hold-up volume.

[0039] Suitable ports include, but are not limited to, any sanitary, leak-proof fittings known in the art, such as compression, standard Ingold, or sanitary fittings. Suitable fittings include, but are not limited to, pipes, tubes, hoses, hollow fitting assemblies, etc. Fittings may vary from system to system based on the configuration and requirements of the vessel and process. In a preferred embodiment, the fluid transfer line 4 is connected to the inlet end 7 of the filtration module 6 via tubular connections such as silicone rubber, C-flex, bioprene, or dry-to-dry sterile connections. The fluid transfer line 4 may also be connected to the process vessel 1 and the filtration module 6 using suitable clamps such as valves and triclamp sanitary fittings. This does not preclude the use of other suitable connections.

[0040] In addition to the inlet end 7, the filtration module 6 has an outlet end or concentrate end 9 and a permeate port or fluid harvest port 10 that allows for the recovery or harvesting of permeate. In one embodiment, the fluid filtration system further comprises at least one permeate pump 12 or filtrate pump connected to the permeate port 10. The concentrate outlet end 9 of the filtration module 6 is connected to the expansion chamber 17, for example, by a fluid transfer line 14 or a dry-state sterile connection. Preferably, the fluid transfer line 14 is in the form of a tube assembly, but other types of connectors are also suitable.

[0041] Suitable materials for the filtration module 6 include, but are not limited to, plastics such as polysulfone, metals, or glass. In a preferred embodiment, suitable materials are those commonly used as disposable materials (i.e., generally for single use) that are suitable for gamma ray sterilization. Those skilled in the art will know what materials are commonly used and suitable for this application. Most preferably, the filtration module 6 is made from a disposable material, and preferred examples, but are not limited to, polysulfone, polyethersulfone, and modified polyethersulfone. The filtration module 6 comprises a filter 8. Suitable filter elements, but are not limited to, hollow fiber filters, mesh filters, screen filters, etc.

[0042] Most preferably, the filter element 8 is a filter consisting of a hollow fiber filter or a screen mesh. Suitable hollow fiber filtration membranes or screen filters are generally available from various manufacturers, for example, GE Healthcare or WaterSep's processable hollow fibers, Spectrum's Krosflo hollow fibers, and Pall's Microza hollow fibers. In one preferred embodiment, the filter 8 is located from the inlet end 7 to the outlet end 9 of the filtration module 6 and extends longitudinally, thereby allowing tangential flow of fluid along the filter 8. If the filter 8 is a hollow fiber filter, the axis of the hollow fiber preferably extends longitudinally from the inlet end 7 to the outlet end 9 of the filtration module 6.

[0043] Furthermore, if the filter 8 is a hollow fiber filter, the inlet and outlet ends of the filter 8 are sealed against the housing wall of the filtration module 6 to prevent mixing of the concentrated liquid side and the permeate (filtered liquid) side of the filter 8. The concentrated liquid side of the filter 8 is the lumen side of the hollow fiber, and the permeate (filtrate) side is the outer shell side of the hollow fiber. Such leak-proof sealing can be formed by several methods known in the art, including O-rings, gaskets, or other means of forming an impermeable barrier between the outer circumference of each end of the filter 8 and the inner wall of the housing.

[0044] The expansion chamber 17 can be any type of container having any shape, such as cylindrical, square, or circular (but not limited to). In one embodiment, the expansion chamber 17 has a cylindrical shape. However, the expansion chamber 17 must be suitable for accommodating both the fluid supplied from the process vessel 1 and the gas supplied from the gas flow controller 28 (for example, through the gas line 22).

[0045] The expansion chamber 17 is preferably made of a transparent material, at least partially (e.g., with a "window") or substantially entirely, to visualize the liquid level within the chamber 17. Suitable materials for the expansion chamber 17 include, but are not limited to, plastics such as polysulfone, polyethersulfone, and modified polyethersulfone. Alternatively, the expansion chamber 17 may be made of a metal such as stainless steel. In a preferred embodiment, a material suitable for gamma ray sterilization is used as a suitable material. Those skilled in the art will know what materials are commonly used and suitable for this application.

[0046] The expansion chamber 17 has a first end 16 and a second end 18 on the opposite side, as well as a length extending between the first end 16 and the second end 18. The expansion chamber 17 is connected on one side to the outlet end 9 of the filtration module 6 and on the other side to the gas flow controller 28. More specifically, the first end 16 of the expansion chamber 17 (also referred to herein as the inlet end) includes a first opening through which fluid flows from the outlet end 9 of the filtration module 6. The second end 18 of the expansion chamber 17 (also referred to herein as the outlet end) includes a second opening and is operably connected to the gas flow controller 28 by a gas line 22.

[0047] In a preferred embodiment, the gas line 22 is a reversible intake / exhaust line. In other embodiments, separate intake and exhaust gas lines are provided (not shown). Preferably, the gas line 22 includes a sterile filter 21 to supply a sterile gas, such as compressed air, to the expansion chamber 17, thereby minimizing the risk of contaminating the liquid phase within the expansion chamber 17. In a preferred embodiment, the sterile filter 21 is an air filter, which preferably includes a heater to prevent blockage of the filter due to wetting by vapors generated within the expansion chamber 17. If the gas line 22 includes a sterile filter 21, the filter is further connected to the expansion chamber 17 by an additional gas line 20.

[0048] During the operation of the filtration system, fluid is alternately and repeatedly drawn from the process vessel 1 through the filter 8 into the expansion chamber 17, received, and discharged from the expansion chamber 17 back to the process vessel 1 through the filter 8. More specifically, the gas flow controller 28 alternately supplies positive and negative pressure to the expansion chamber 17 through the gas line 22 so that the fluid contained in the process vessel 1 is alternately drawn into the expansion chamber 17 through the filter element 8, discharged from the expansion chamber 17 back to the vessel 1 through the filter 8.

[0049] The positive pressure, defined as a pressure higher than the pressure inside the filtration module 6, is preferably obtained by supplying a gas, such as compressed air (from a source), through the gas line 22. Instead of compressed air, other gases or gas mixtures, such as nitrogen, nitrogen / oxygen, or a mixture of nitrogen / oxygen / carbon dioxide, may be used. The negative pressure, defined as a pressure lower than the pressure inside the filtration module 6, is generated within the controller, for example, by creating a vacuum. The negative pressure is preferably obtained by applying an underpressure or vacuum into the expansion chamber 17. The vacuum can be generated by any known system or method for creating an underpressure in the expansion chamber 17, such as a vacuum pump or vacuum injection device. However, in a preferred embodiment, the gas flow controller 28 does not require a separate vacuum supply.

[0050] In this way, an alternating tangential flow of fluid is generated between the process vessel 1 and the expansion chamber 17 through the filter 8. The tangential flow can be harvested into the permeate line 11 through the fluid harvest port 10. In a preferred embodiment, the permeate line 11 includes a permeate pump 12, which regulates the permeate flow, controls the extraction of filtered fluid permeate from the system, and acts as a check valve to regulate the unrestricted flow of permeate from the filtration module 6. The tangential flow (more commonly known as crossflow) is regulated by a PACS controller, i.e., a gas flow controller 28. The pressure in the permeate line can be monitored by a pressure sensor 30, as shown in Figure 1. The alternating flow of concentrated fluid between the expansion chamber 17 and the process vessel 1 passes through the tubular side of the filter 8 in the filtration module 6. When in operation, the expansion chamber 17 has a direct gas-liquid interface formed by the liquid contained in the system, which is in direct contact with the gas phase provided by the gas flow controller 28, and has no separation means.

[0051] In one embodiment, the gas flow controller 28 may include a pressure measuring device 32, such as a pressure sensor, which is responsible for monitoring and / or adjusting the pressure in the gas line 22. In addition, the gas flow controller 28 may include a pressure measuring device 30, which is responsible for measuring the pressure in the permeate line 11. In one embodiment, the gas flow controller 28 is connected to an air or other gas supply that supplies air or gas to the gas flow controller, from which the pressure can optionally be reduced using a pressure reducing valve 46. The gas, which may also be reduced in pressure, is further guided toward the gas line 22 through a pressure controller 44 and control valve 40 to give positive pressure, or alternatively, through a pressure controller 42, vacuum injection device 36 and control valve 41 to give negative pressure to the gas line 22 and expansion chamber 17.

[0052] The first level sensor assembly 26 and the second level sensor assembly 25 monitor the liquid level in the expansion chamber 17 and provide feedback to the gas flow controller 28. The gas flow controller 28 then initiates alternating positive and negative pressure cycles in the expansion chamber 17. Referring to Figure 3B, the first level sensor assembly 26 includes a signal generator or transmitter 54 and a detector or receiver 55, and the second level sensor assembly 25 includes a signal generator or transmitter 56 and a detector or receiver 57. The respective transmitters 54 and 56 are located opposite the respective receivers 55 and 57. Referring to Figures 3A-3B, the first sensor assembly 26 is preferably located near the upper end 18 of the expansion chamber 17, and the second sensor assembly 25 is preferably located near the lower end 16. More specifically, the transmitter 54 and receiver 55 of the first sensor assembly 26 are preferably located on opposite sides of each other near the (upper) second end 18 of the expansion chamber 17, so that the first level sensor assembly 26 monitors the liquid level UL in the expansion chamber 17. The transmitter 56 and receiver 57 of the second level sensor assembly 25 are preferably located on opposite sides of each other near the (lower) first end 16 of the expansion chamber 17, so that the second level sensor assembly 25 monitors the liquid level LL in the expansion chamber 17. The transmitters 54, 56 and receivers 55, 57 are preferably mounted on the outer surface of the expansion chamber 17.

[0053] Level sensors such as light scattering sensors, volumetric measurement sensors, and microwave sensors are known in the art and can be used to measure the height of the liquid in the expansion chamber 17, with various parameters being utilized. In some embodiments, the sensor assemblies 26, 25 are microwave sensors, and as will be described in detail below, when the liquid level reaches UL or LL and exceeds the trigger point, the transmitter 54 or 56 of each assembly 26 or 25 sends a microwave signal to the respective receiver.

[0054] Referring to Figures 4A-4B, in the exemplary PACS, when the expansion chamber 17 is empty, more specifically, when there is no fluid, i.e., cell culture, between the sensors of each sensor assembly 26 or 25, the receiver is expected to read a first signal or chamber empty signal, e.g., approximately 650-cB. However, when the expansion chamber 17 is full and cell culture is present between the sensor assemblies 26, 25, the signal is attenuated, and the expected value changes by more than 50% on a logarithmic scale relative to the chamber empty signal (e.g., approximately 300-cB), which will hereafter be referred to as the chamber full signal. The difference between the values ​​of the receiver is used to control the fluid flow in the expansion chamber 17 by using a trigger point or threshold between the chamber empty signal and the chamber full signal. In a preferred embodiment, there is a difference of 160-cB to 200-cB, more specifically, approximately 175-cB, between the trigger point signals of the sensor assemblies 26, 25 and the chamber empty signal of the microwave sensors. For example, if the chamber empty signal is 650-cB, the trigger point signal is preferably between 450-cB and 490-cB, more preferably around 475-cB.

[0055] Preferably, the first (upper) sensor assembly 26, more specifically the transmitter 54 and receiver 55 of the first sensor assembly 26, are longitudinally offset by a certain distance from the UL. In an exemplary PACS design, the first sensor assembly 26, more specifically the transmitter and receiver 54, 55 of the first sensor assembly 26, are longitudinally offset from the UL by a distance of about 15% to 25% of the length of the expansion chamber 17. The offset is in the negative direction away from the upper end, thereby ensuring that the UL is above the upper level sensor. The predetermined distance is preferably such that the location where the biomass is accumulating (i.e., the UL) is sufficiently far from the location of the transmitter 54 and receiver 55 of the first sensor assembly 26 to ensure that there is no or minimal interference in the sensor signal caused by the accumulated biomass. In one embodiment, the offset distance is preferably between 3.5 and 5.5 inches. In one embodiment, the offset distance is more preferably about 4.5 inches. The offset is in the direction away from the upper end 18 of the expansion chamber 17, and as a result, when viewed along the longitudinal axis of the expansion chamber 17, the first sensor assembly 26 is positioned lower than the UL by a distance between 15% and 25% of the length of the expansion chamber 17 (for example, approximately 4.5 inches).

[0056] In a preferred embodiment, when either the first or second sensor assembly 26, 25 is triggered (i.e., when either sensor assembly 26, 25 exceeds the trigger point signal), there is preferably a time delay before the gas controller 28 initiates the application of positive or negative pressure in order to maintain the target fluid displacement volume. The desired duration of the time delay depends on the scale, application, and desired cross-flow rate. In an exemplary PACS design, the time delay is about 1000–1300 ms, e.g., about 1000, 1100, 1200, or 1300 ms, more preferably about 1200 ms.

[0057] More specifically, during the filtration process, the liquid contained in the process vessel 1 is drawn out of the vessel 1 through the filter 8 and finally enters the expansion chamber 17, and alternately released from the expansion chamber 17 and returned to the vessel 1 through the filter 8. Referring to Figure 4A, when negative pressure is applied to the expansion chamber 17 by the gas flow controller 28, the liquid is drawn out of the process vessel 1 and into the expansion chamber 17 until the first level sensor assembly 26 responds, i.e., the first sensor assembly 26 detects that the cell culture has reached the height of the upper sensor and the trigger point signal of 475-cB has been surpassed (i.e., the detected signal has increased from below to above the set trigger point signal). When the first level sensor assembly 26 detects that the trigger point signal has been reached or surpassed and the height of the cell culture in the expansion chamber 17 has reached UL, after a time delay of approximately 1200 ms, the gas flow controller 28 is triggered to switch to applying positive pressure to the expansion chamber 17. When positive pressure is applied to the expansion chamber 17, liquid is released from the expansion chamber 17 and returned to the process vessel 1 until the second sensor assembly 25 detects that the height of the cell culture in the expansion chamber 17 has reached LL, i.e., the signal from the second sensor assembly 25 has dropped below the trigger point of 475-cB. Subsequently, the gas flow controller 28 is triggered again to switch to applying negative pressure to the expansion chamber 17 and drawing liquid from the process vessel 1 into the expansion chamber 17. The switch to applying negative pressure may occur with or without a time delay (e.g., after a time delay of approximately 1200 ms). As a result, the cell culture travels back and forth through the filter 8 in a controlled manner (cross-flow), allowing the permeate extract to proceed to the permeate line 11.

[0058] In one embodiment, the gas flow controller 28 includes a shut-off valve 38 which is in functional contact with first and second level sensor assemblies 26, 25 and closes when the liquid in the expansion chamber 17 reaches UL. The gas flow controller 28 preferably further includes a switching valve 34 which is in contact with first and second level sensor assemblies 26, 25 and determines whether compressed air (having a pressure higher than the pressure in the compartment containing the filter) is applied to the gas line 22, or whether a vacuum is applied, or whether an underpressure (compared to the pressure in the compartment containing the filter) is applied.

[0059] By adjusting the trigger point signals of sensor assemblies 26, 25 to a value significantly lower than the chamber empty signal, the system according to the present invention provides an improved buffer between the chamber empty sensor value and the chamber full sensor value. For example, in a conventional system, the trigger point of a microwave sensor may have a factory set value of 515-cB. According to one embodiment of the present application, the trigger point of a microwave sensor can instead be set to 475-cB. The optimal set value of the trigger point depends on the diameter of the expansion chamber, i.e., the degree of attenuation of the microwave signal due to the thickness of the liquid column between the transmitter and receiver. In some other embodiments, in smaller PACS systems, a substantial portion of the microwave signal travels around the expansion chamber. Therefore, the change in the cB signal between chamber full and chamber empty is smaller, and thus the optimal trigger point is also different.

[0060] Furthermore, implementing a time delay to initiate positive pressure when the upper sensor assembly 26 is triggered leads to a setting where the sensor assembly is positioned offset relative to the UL. This ensures that the position of the sensor assembly 26 is exposed to high-flux cell culture logistics that minimize biomass accumulation and thus signal interference. Similarly, implementing a time delay to initiate negative pressure when the lower sensor assembly 25 is triggered leads to a setting where the expansion chamber 17 is completely emptied to more than the height of the sensor assembly 25. This minimizes the hold-up volume of the assembly and thus minimizes the exposure of cells to conditions in the filtration system, which are less controlled than the conditions in the process vessel.

[0061] These effects are demonstrated in Figures 5A to 5B. Referring to Figures 5A to 5B, "Filter 1 top full" represents the state of the expansion chamber 17 where the culture is present between the transmitter 54 and receiver 55 of the first sensor assembly 26, and "Filter 1 top empty" represents the state of the expansion chamber 17 where the fluid level of the cell culture has decreased and there is no cell culture present between the transmitter 54 and receiver 55 of the first sensor assembly 26. Figure 5A shows the states of "Filter 1 top full" and "Filter 1 top empty" in a conventional system utilizing the trigger point 515-cB, and Figure 5B shows the states of "Filter 1 top full" and "Filter 1 top empty" in an improvement over the conventional system, utilizing the trigger point 475-cB and time delay according to one embodiment of the present application. As can be seen by comparing Figures 5A and 5B, the system of the present invention enables the first sensor assembly 26 to generate a more stable and uniform signal (for example, by applying a time delay), and also provides an improved buffer between the chamber empty sensor value and the chamber full sensor value (i.e., between "filter 1 top full" and "filter 1 top empty") even over relatively long periods of time. Furthermore, referring to Figures 6A and 6B, it is shown that when the first sensor assembly is located below the UL, there is relatively little biomass accumulation in the area of ​​the first sensor assembly 26.

[0062] Those skilled in the art will recognize that modifications to the above embodiments can be made without departing from the broad scope of the present invention. Therefore, it will be understood that the present invention is not limited to the specific embodiments disclosed, but rather encompasses modifications that fall within the spirit and scope of the invention as defined by the appended claims. It should be noted that the present invention includes the following embodiments. [Aspect 1] A filtration system, (1) An expansion chamber having a first end and a second end on the opposite side, and a length extending between the first end and the second end, (2) A first sensor assembly and a second sensor assembly mounted on the outer surface of the expansion chamber for monitoring the fluid level in the expansion chamber, (i) The first sensor assembly is located near the first end of the expansion chamber, (ii) The second sensor assembly is located near the second end of the expansion chamber, (iii) Each of the first and second sensor assemblies includes a transmitter and a receiver, the receiver detecting a chamber empty signal when there is no fluid between the respective receiver and transmitter in the expansion chamber, the receiver detecting a chamber full signal when there is fluid between the respective receiver and transmitter in the expansion chamber, and the trigger point between the chamber empty signal and the chamber full signal is set to control the flow direction of the fluid in the expansion chamber so that the fluid fluctuates between the upper and lower limits of the expansion chamber. (A) The trigger point is set to differ by 25-35% from the chamber empty signal. (B) The first sensor assembly is longitudinally offset from the upper limit by a distance of 15% to 25% of the length of the expansion chamber, and the direction of the offset is away from the first end of the expansion chamber, and / or (C) A filtration system in which the flow direction of the fluid in the expansion chamber is changed after a time delay following the detection of a signal exceeding the trigger point by the first or second sensor assembly. [Aspect 2] The filtration system according to Embodiment 1, wherein the first sensor assembly is longitudinally offset from the upper end by a distance of 15% to 25% of the length of the expansion chamber toward the upper end, and the flow direction of the fluid in the expansion chamber is changed after the time delay. [Aspect 3] The filtration system according to Embodiment 1, wherein the trigger point differs by 25-30% from the chamber empty signal, and the flow direction of the fluid in the expansion chamber is changed after the time delay. [Aspect 4] The filtration system according to Embodiment 1, wherein the trigger point differs from the chamber empty signal by 25-30%, the first sensor assembly is longitudinally offset from the upper end by a distance that is 15-25% of the length of the expansion chamber toward the upper end, and the flow direction of the fluid in the expansion chamber is changed after the time delay. [Aspect 5] The filtration system according to any one of embodiments 1 to 4, wherein the time delay is 1000ms to 1300ms, for example 1000ms, 1100ms, 1200ms, 1300ms, or any value in between, preferably 1200ms, from the time the first or second sensor assembly detects a signal exceeding the trigger point. [Aspect 6] The filtration system according to any one of embodiments 1 to 5, wherein the first sensor assembly is offset longitudinally from the upper limit by a distance of 3.5 to 5.5 inches, preferably 4.5 inches. [Aspect 7] The filtration system according to any one of embodiments 1 to 6, wherein each of the upper level sensor assembly and the lower level sensor assembly is independently selected from the group consisting of light scattering-based sensors, volume measurement-based sensors, and microwave sensors. [Aspect 8] The filtration system according to embodiment 7, wherein each of the upper level sensor assembly and the lower level sensor assembly is a microwave level sensor. [Aspect 9] The filtration system according to embodiment 8, wherein the trigger point is lower than the chamber empty signal by about 150-cB to 200-cB, for example, 150-cB, 160-cB, 170-cB, 180-cB, 190-cB, 200-cB, or any value in between, preferably 175-cB. [Aspect 10] The filtration system according to embodiment 9, wherein the chamber empty signal is 650-cB and the trigger point is 475-cB. [Aspect 11] A process vessel containing the fluid to be filtered, A filtration module comprising a filter and having an inlet end and an outlet end, wherein the process vessel is in fluid communication with the filtration module, It also includes a gas flow controller, The expansion chamber is in fluid communication with the filtration module and is operationally connected to the gas flow controller, which alternately applies positive and negative gas pressure to the expansion chamber. When the first sensor assembly first detects a signal exceeding the trigger point, the gas flow controller is triggered, after a first time delay, to apply positive gas pressure to the expansion chamber so that fluid is drawn out of the expansion chamber and into the process vessel. A fluid filtration system according to any one of embodiments 1 to 10, wherein when the second sensor assembly first detects a signal exceeding the trigger point, the gas flow controller is triggered, after a second time delay, to apply negative pressure to the expansion chamber so that fluid is drawn out of the process vessel and into the expansion chamber. [Aspect 12] The fluid filtration system according to embodiment 11, wherein the first time delay and the second time delay are the same. [Aspect 13] A fluid filtration system according to embodiment 11, wherein the first time delay and the second time delay are different. [Aspect 14] A fluid filtration system according to any one of embodiments 11 to 13, wherein each of the first time delay and the second time delay is independently 1000ms to 1300ms, for example 1000ms, 1100ms, 1200ms, 1300ms, or any value in between, preferably 1200ms. [Aspect 15] A fluid filtration system according to any one of embodiments 1 to 14, wherein the negative pressure is obtained by creating a vacuum in the expansion chamber, and the positive pressure is obtained by injecting gas into the expansion chamber. [Aspect 16] A fluid filtration system according to any one of embodiments 11 to 15, wherein the filtration module includes a hollow fiber filter. [Aspect 17] A fluid filtration system according to any one of embodiments 11 to 15, wherein the filtration module and / or the expansion chamber are disposable. [Aspect 18] A method for filtering a liquid, comprising filtering the liquid using a fluid filtration system described in any one of embodiments 1 to 17. [Aspect 19] The method according to embodiment 18, comprising: a) obtaining a fluid filtration system according to any one of embodiments 11 to 17; b) drawing liquid from a process vessel and introducing it into the expansion chamber through a filtration module by applying negative pressure to the expansion chamber; c) releasing the liquid from the expansion chamber and returning it to the process vessel through a filter by applying positive pressure to the expansion chamber; and d) removing the filtered liquid from the filtration system. [Aspect 20] The method according to embodiment 18 or 19, wherein the liquid is a liquid cell culture or cell lysate. [Explanation of symbols]

[0063] 1. Process container 4. Fluid transfer lines, conduits 6 Filtration Module 7 Inlet end 8 filters 9 Outlet end, concentrate end 10 Permeate ports, fluid harvesting ports 12 Permeate pump 14 U-shaped curved section 17 Expansion Chamber 22 Gas lines 28 Gas flow controller 16 First end, bottom end 18. Second end, upper end 21 Sterile filter 30 Pressure Sensors 32 Pressure measuring device 30 Pressure measuring device 34. Switching valve 46 Pressure Reducing Valve 42 Pressure Controller 36 Vacuum injection device 41 Control valve 26. First level sensor assembly 25 Second level sensor assembly 54 Signal generator, transmitter 55 Detector, Receiver 56 Signal generator, transmitter 57 Detector, Receiver

Claims

1. (1) An expansion chamber having a first end and a second end on the opposite side, and a length extending between the first end and the second end, (2) To monitor the fluid level in the expansion chamber, a first sensor assembly and a second sensor assembly are mounted on the outer surface of the expansion chamber. Equipped with, (i) The first sensor assembly is located near the first end of the expansion chamber, (ii) The second sensor assembly is located near the second end of the expansion chamber, (iii) A filtration system in which each of the first and second sensor assemblies includes a transmitter and a receiver, the receiver detects a chamber empty signal when there is no fluid between the respective receiver and transmitter in the expansion chamber, the receiver detects a chamber full signal when there is fluid between the respective receiver and transmitter in the expansion chamber, and the trigger point between the chamber empty signal and the chamber full signal is set to control the flow direction of the fluid in the expansion chamber so that the fluid fluctuates between the upper and lower limits of the expansion chamber, (A) The trigger point is set to differ by 25 to 35 percent from the chamber empty signal. (B) The first sensor assembly is longitudinally offset from the upper limit by a distance of 15% to 25% of the length of the expansion chamber, and the direction of the offset is away from the first end of the expansion chamber, and / or (C) A filtration system in which the flow direction of the fluid in the expansion chamber is changed after a time delay following the detection of a signal exceeding the trigger point by the first or second sensor assembly.

2. The filtration system according to claim 1, wherein the first sensor assembly is longitudinally offset from the upper end by a distance of 15% to 25% of the length of the expansion chamber toward the upper end, and the flow direction of the fluid in the expansion chamber is changed after the time delay.

3. The filtration system according to claim 1, wherein the trigger point differs by 25-30% from the chamber empty signal, and the flow direction of the fluid in the expansion chamber is changed after the time delay.

4. The filtration system according to claim 1, wherein the trigger point differs from the chamber empty signal by 25-30%, the first sensor assembly is longitudinally offset from the upper end by a distance of 15-25% of the length of the expansion chamber toward the upper end, and the flow direction of the fluid in the expansion chamber is changed after the time delay.

5. The filtration system according to any one of claims 1 to 4, wherein the time delay is 1000 ms to 1300 ms after the first or second sensor assembly detects a signal exceeding the trigger point.

6. The filtration system according to any one of claims 1 to 5, wherein the first sensor assembly is longitudinally offset from the upper limit by a distance of 8.89 to 13.97 cm (3.5 to 5.5 inches).

7. The filtration system according to any one of claims 1 to 6, wherein each of the upper level sensor assembly and the lower level sensor assembly is independently selected from the group consisting of light scattering-based sensors, volume measurement-based sensors, and microwave sensors.

8. The filtration system according to claim 7, wherein each of the upper level sensor assembly and the lower level sensor assembly is a microwave level sensor.

9. The filtration system according to claim 8, wherein the trigger point is about 150-cB to 200-cB lower than the chamber empty signal.

10. The filtration system according to claim 9, wherein the chamber empty signal is 650-cB and the trigger point is 475-cB.

11. A process vessel containing the fluid to be filtered, A filtration module comprising a filter and having an inlet end and an outlet end, wherein the process vessel is in fluid communication with the filtration module, It also includes a gas flow controller, The expansion chamber is in fluid communication with the filtration module and is operationally connected to the gas flow controller, which alternately applies positive and negative gas pressure to the expansion chamber. When the first sensor assembly first detects a signal exceeding the trigger point, the gas flow controller is triggered, after a first time delay, to apply positive gas pressure to the expansion chamber so that fluid is drawn out of the expansion chamber and into the process vessel. The fluid filtration system according to any one of claims 1 to 10, wherein when the second sensor assembly first detects a signal exceeding the trigger point, the gas flow controller is triggered, after a second time delay, to apply negative pressure to the expansion chamber so that fluid is drawn out of the process vessel and into the expansion chamber.

12. The fluid filtration system according to claim 11, wherein the first time delay and the second time delay are the same.

13. The fluid filtration system according to claim 11, wherein the first time delay and the second time delay are different.

14. A fluid filtration system according to any one of claims 11 to 13, wherein each of the first time delay and the second time delay is independently 1000 ms to 1300 ms.

15. The fluid filtration system according to any one of claims 11 to 14, wherein the negative pressure is obtained by creating a vacuum in the expansion chamber, and the positive pressure is obtained by injecting gas into the expansion chamber.

16. The fluid filtration system according to any one of claims 11 to 15, wherein the filtration module includes a hollow fiber filter.

17. A fluid filtration system according to any one of claims 11 to 15, wherein the filtration module and / or the expansion chamber is disposable.

18. A method for filtering a liquid, comprising filtering the liquid using a fluid filtration system according to any one of claims 1 to 17.

19. The method according to claim 18, comprising: a) obtaining a fluid filtration system according to any one of claims 11 to 17; b) drawing liquid from a process vessel and introducing it into the expansion chamber through a filtration module by applying negative pressure into the expansion chamber; c) releasing the liquid from the expansion chamber and returning it to the process vessel through a filter by applying positive pressure into the expansion chamber; and d) removing the filtered liquid from the filtration system.

20. The method according to claim 18 or 19, wherein the liquid is a liquid cell culture or a cell lysate.

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