Filtration system and method

Abstract

The fluid filtration system includes a fluid reservoir, such as a bioreactor, a filter housing including a filter element disposed therein, a pump coupled between the fluid reservoir and the filter housing, and a flow diverter disposed between the pump and the filter housing. The pump is configured to move fluid from the fluid reservoir through the filter element, and the flow diverter is configured to selectively direct fluid received from the pump to a first or second end of the filter housing. In a first mode of operation, the flow diverter directs flow through the filter housing in a first direction, while in a second mode of operation, the flow diverter directs flow through the filter housing in a second direction opposite the first direction.

Description

[Technical Field]

[0001] [Cross-reference of related applications] This is a non-provisional application of pending provisional patent application No. 63 / 176,134, filed on 16 April 2021, which is incorporated herein by reference in its entirety.

[0002] Embodiments of the present disclosure relate, in general, to filtration systems, and more specifically to filtration systems including a single pump for selectively providing two opposite flows through a filter member. [Background technology]

[0003] Filtration is typically performed to separate, clarify, modify, and / or concentrate fluid solutions, mixtures, or suspensions. In the biotechnology, pharmaceutical, and medical industries, filtration is crucial for the success of the manufacture, processing, and analysis of drugs, diagnostic agents, and chemicals, as well as many other products. For example, filtration can be used to sterilize fluids and to clarify complex suspensions into filtered "clear" and unfiltered fractions. Similarly, components in a suspension can be concentrated by removing or "filtering out" the suspension medium. Furthermore, with the appropriate selection of filter material, filter pore size, and / or other filter variable elements, many other specialized applications have been developed. These applications may involve the selective isolation of components from a variety of sources, including cultures of microorganisms, blood, and other fluids, which may be solutions, mixtures, or suspensions.

[0004] Biopharmaceutical manufacturing processes have advanced through considerable process enhancements. Cell cultures of eukaryotic and microbial cells for the production of recombinant proteins, virus-like particles (VLPs), genetic biparticles, and vaccines now include cell culture technologies capable of achieving over 100 e6 cells / ml. This is achieved using cell retention devices that remove metabolic waste products and refresh the culture with additional nutrients. One common means for cell retention is to perfuse the culture in a bioreactor using hollow fiber filtration with alternating tangential flow (ATF).

[0005] Commercial and development-scale processes use devices that control pumps to run ATF through hollow fiber filters. Typically, these systems are configured so that the pump moves the fluid in one direction through the filter. This can result in cultures being left outside the bioreactor for undesirably long periods of time, and can also lead to premature fouling of the hollow fiber filter.

[0006] Therefore, it is desirable to provide an improved pump configuration that increases the utilization of the entire filter length of hollow fiber filters used in conjunction with containers such as bioreactor vessels. It is also desirable to provide a pump configuration that improves the overall efficiency of the pump system. [Overview of the project]

[0007] A fluid filtration system may include a fluid storage container, a filter housing containing filter elements arranged inside, a pump connected between the fluid storage container and the filter housing having first and second ends, and a flow divider located between the pump and the filter housing. The pump is configured to move fluid from the fluid storage container through the filter elements. The flow divider is configured to selectively direct the fluid received from the pump to the first or second end of the filter housing.

[0008] The system further includes a first filtration line connected between the first end of the filter housing and the first outlet of the diversion section; a first return line positioned between the fluid storage container and the first filtration line; and a first isolation valve positioned in the first return line for selectively allowing fluid flow between the filter housing and the fluid storage container via the first return line. The system further includes a second filtration line connected between the second end of the filter housing and the second outlet port of the three-way valve; a second return line positioned between the fluid storage container and the second filtration line; and a second isolation valve positioned in the second return line for selectively allowing fluid flow between the filter housing and the fluid storage container via the second return line.

[0009] The system may further include a flow sensor for determining the actual flow rate from the discharge portion of the pump. The system may further include the pump, the flow sensor, the first and second isolation valves, and a controller connected to the flow divider for selectively controlling the fluid flow path through the system. The system may further include a memory associated with the controller, which stores a plurality of preset positions for the first and second isolation valves and the flow divider. The controller may adjust the speed of the pump based on the sensed flow rate information received from the flow sensor.

[0010] In some embodiments, the pump is a low-shear pump. In some embodiments, the filter element is a hollow fiber filter. In some embodiments, the fluid storage container is a bioreactor. In some embodiments, the fluid contains a cell culture. The cell culture may be a fed-batch cell culture or a concentrated fed-batch cell culture, and the disclosed systems and methods may be used to produce any of a variety of desired cell products, including but not limited to endogenous and recombinant products containing proteins, peptides, nucleic acids, viruses, amino acids, antibiotics, specialty chemicals, and other valuable molecules. Desired proteins may include, but are not limited to, monoclonal antibodies, enzymes, and other recombinant antibodies, enzymes, peptides, and viruses.

[0011] In some embodiments, the diversion section includes a three-way valve. In other embodiments, the diversion section includes first and second diversion section isolation valves, the first diversion section isolation valve being located between the pump discharge line and the first filtration line, and the second diversion section isolation valve being located between the pump discharge line and the second filtration line.

[0012] A method for operating a fluid filtration system that provides bidirectional flow through a filter housing is disclosed. The method may include, in a first mode of operation, the steps of transferring the fluid from a fluid storage container to the first end of the filter housing by configuring a diversion section to direct the flow of fluid from a pump through a first filtration line connected to the first end of the filter housing; and in a second mode of operation, the steps of transferring the fluid from the fluid storage container to the second end of the filter housing by configuring the diversion section to direct the flow of fluid from the pump through a second filtration line connected to the second end of the filter housing. In the first mode of operation, the fluid moves from the first end of the filter housing to the second end of the filter housing, and in the second mode of operation, the fluid moves from the second end of the filter housing to the first end of the filter housing.

[0013] The method may further include, in the first mode of operation, the step of directing the flow of the fluid from the second end of the filter housing to the fluid storage container via a first return line; and in the second mode of operation, the step of directing the flow of the fluid from the first end of the filter housing to the fluid storage container via a second return line.

[0014] In the first mode of operation, the step of directing the flow of the fluid from the second end of the filter housing to the fluid storage container may include the steps of opening an isolation valve located in the first return line and closing an isolation valve located in the second return line. In the second mode of operation, the step of directing the flow of the fluid from the first end of the filter housing to the fluid storage container may include the steps of opening an isolation valve located in the second return line and closing an isolation valve located in the first return line. The method may further include the step of adjusting the speed of the pump based on the output of a flow sensor located downstream of the pump.

[0015] In some embodiments, the pump is a low-shear pump. In some embodiments, the filter element is a hollow fiber filter. In some embodiments, the fluid storage container is a bioreactor. In some embodiments, the fluid contains a cell culture.

[0016] In some embodiments, the diversion section includes a three-way valve. In other embodiments, the diversion section includes first and second diversion section isolation valves, the first diversion section isolation valve being located between the pump and the first filtration line, and the second diversion section isolation valve being located between the pump and the second filtration line.

[0017] A valve for redirecting the flow received from the pump is disclosed. The valve has a base; First and second side supports connected to the base; The first and second stationary plates fixed and connected to the first and second side supports; The first and second movable plates movably connected to the first and second side supports; Actuating members connected to the first and second movable plates for selectively moving the first and second movable plates toward and away from the first and second stationary plates. The first movable plate is disposed between the first and second stationary plates, and the second movable plate is disposed between the second stationary plate and the base. First and second flexible tubes can be positioned between the base and the second movable plate, and third and fourth flexible tubes can be positioned between the first movable plate and the first stationary plate.

[0018] In the first position of the valve, in order to allow fluid to flow through the first and second flexible tubes, the second movable plate is displaced from the base by a distance equal to or greater than the outer diameter of the first and second flexible tubes. In the first position, in order to prevent fluid from flowing through the third and fourth flexible tubes, the first movable plate is displaced from the first stationary plate by an amount sufficient to compress the third and fourth flexible tubes.

[0019] In the second position of the valve, in order to prevent fluid from flowing through the first and second flexible tubes, the second movable plate is displaced from the base by an amount sufficient to compress the first and second flexible tubes. In the second position, in order to allow fluid to flow through the third and fourth flexible tubes, the first movable plate is displaced from the first stationary plate by a distance equal to or greater than the outer diameter of the third and fourth flexible tubes.

[0020] In some embodiments, the actuating member is connected to an actuator, and the actuator is controllable by a controller connected thereto.

Brief Description of the Drawings

[0021] The accompanying drawings illustrate preferred embodiments of the disclosed method devised for practical applications of its principles.

[0022] [Figure 1] Schematic diagram of an exemplary pump and filter system according to the present disclosure operating in a first flow mode.

[0023] [Figure 2] Schematic diagram of the exemplary pump and filter system of FIG. 1 operating in a second flow mode.

[0024] [Figure 3] Schematic diagram of another exemplary pump and filter system according to the present disclosure.

[0025] [Figure 4A] Schematic diagram of another exemplary pump and filter system according to the present disclosure. [Figure 4B] Schematic diagram of another exemplary pump and filter system according to the present disclosure.

[0026] [Figure 5] Schematic diagram of an exemplary valve according to the present disclosure.

[0027] [Figure 6A] Schematic diagram of another exemplary pump and filter system according to the present disclosure. [Figure 6B] Schematic diagram of another exemplary pump and filter system according to the present disclosure.

[0028] [Figure 7A] Schematic diagram of another exemplary pump and filter system according to the present disclosure. [Figure 7B] This is a schematic diagram of another exemplary pump and filter system as described herein.

[0029] [Figure 8A] This is a schematic diagram of yet another exemplary pump and filter system as described herein. [Figure 8B] This is a schematic diagram of yet another exemplary pump and filter system as described herein.

[0030] [Figure 9A] This is a schematic diagram of another exemplary pump and filter system as described herein. [Figure 9B] This is a schematic diagram of another exemplary pump and filter system as described herein.

[0031] [Figure 10] These are illustrative graphs of flow curves in operation, obtained using one or more of the pump and filter systems shown in Figures 1 to 9B. [Figure 11] These are illustrative graphs of flow curves in operation, obtained using one or more of the pump and filter systems shown in Figures 1 to 9B. [Figure 12] These are illustrative graphs of flow curves in operation, obtained using one or more of the pump and filter systems shown in Figures 1 to 9B.

[0032] [Figure 13] This is a side view of an exemplary filter for use with the systems shown in Figures 1 to 9B.

[0033] [Figure 14] These are perspective views of exemplary filter housings and filter elements for use with the systems shown in Figures 1 to 9B.

[0034] [Figure 15] This is a schematic diagram of the control system to be used in conjunction with the systems shown in Figures 1 to 7B.

[0035] [Figure 16] This flowchart illustrates an exemplary process flow as described herein. [Modes for carrying out the invention]

[0036] A system comprising a bioreactor, a pump, and a filter is disclosed. The pump moves fluid in alternating directions through the filter via associated piping and a flow divider, not limited to a three-way valve, rotary valve, pinch valve, or shuttle valve. The system may be employed to provide rapid, low-shear alternating tangential flow (ATF) of fluid through a filter, which in some embodiments is a hollow fiber filter. Such systems have applications in perfusing cultured animal cells and a variety of other filtration applications.

[0037] As will be discussed in more detail later, the disclosed assembly can reduce the time the cell culture is outside the bioreactor, and can also provide more uniform filter use and reduced fouling compared to current systems. In some embodiments, the pump operation control can be based on an algorithm that can periodically apply operational subroutines to facilitate filter cleanup / backflushing. These and other advantages will be discussed below.

[0038] Figures 1 and 2 show an exemplary system 1 which may include a pump 4 and a fluid storage container 2 (hereinafter referred to as the “container”) connected to a filter housing 6. The pump 4 is positioned to draw fluid from the container 2 via a suction line 8 located at or near the bottom of the container 2. The pump 4 is connected to a discharge line 10, which is further connected to an inlet port 12 of a diversion section, which in the illustrated embodiment is a three-way valve 14. The first outlet port 16 of the three-way valve 14 is connected to a first filtration line 18, which is further connected to a first end 20 of the filter housing 6. The second outlet port 22 of the three-way valve 14 is connected to a second filtration line 24, which is further connected to a second end 26 of the filter housing 6. A first return line 28 is connected between the second filtration line 24 and the container 2. A first isolation valve 30 is located in the first return line 28 to selectively allow flow between the container 2 and the second end 26 of the filter housing 6. A second return line 32 is connected between the first filtration line 18 and the container 2. A second isolation valve 34 is located in the second return line 32 to selectively allow flow between the container 2 and the first end 20 of the filter housing 6. In some embodiments, a flow switch 36 may be located in the discharge line 10 between the pump 4 and the three-way valve 14.

[0039] In some embodiments, it will be understood that it is desirable to minimize the length of the discharge and return lines between the container 2 and the filter housing 6 in order to minimize the exposure of the cell culture outside the container.

[0040] The filter housing 6 encloses a filter element (not shown), which in one non-limiting illustrative embodiment is a hollow fiber filter, but this is not important, and any of various other filter elements can be used. The filter housing 6 may be made from plastic, metal such as stainless steel, glass, etc. Suitable filter elements include hollow fiber filters, screen filters, etc. In one non-limiting illustrative embodiment, the filter element is a hollow fiber filter (see, for example, Figure 13). In some implementations, the hollow fiber filter has a pore size of about 0.1 to 5.0 microns, e.g., 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9 microns, or 1, 2, 3, or 4 microns, or about 500 to 1000 kD, e.g., 550, 600, 650, 700, 750, 800, 850, 900, or 950 kD.

[0041] To minimize the adverse effects of pumping on cells in the pumped fluid, a dedicated pump type is desirable. In the illustrated embodiment, pump 4 is a diaphragm pump, but it will be understood that this disclosure is not limited thereto. Therefore, pump 4 can be any suitable low-shear pump type, examples of which include Levitronix pumps (www.levitronix.com) and Quattroflow pumps from Holland Applied Technologies (www.hollandapt.com). Peristaltic pumps can be used for non-cell culture applications. Furthermore, permeate and retention fluid pumps may be peristaltic pumps.

[0042] Container 2 can be any suitable container for containing the fluid to be filtered. For example, the fluid container can be a bioreactor, a fermenter, or any other container, non-exclusively including tubs, barrels, tanks, bottles, flasks, containers, etc., that can contain liquid. The container can be made of any suitable material, such as plastic, metal such as stainless steel, or glass.

[0043] Generally, the pump 4, the three-way valve 14, and the first and second isolation valves 30 and 32 function to selectively provide flow from the container 2 through the filter housing 6 (and the filter elements inside it) in one or two different directions.

[0044] In the first mode of operation shown in Figure 1, System 1 is configured to direct the flow from the container 2 to the first end 20 of the filter housing 6 via the first filtration line 18. Therefore, the three-way valve 14 is operated to direct the flow from the pump 4 to the first filtration line 18. The second isolation valve 34 is operated to the "closed" position, thereby preventing flow between the first filtration line 18 and the second return line 32. Thus, the fluid flows from the container 2, through the pump 4, through the three-way valve 14, through the first filtration line 18, and there into the first end 20 of the filter housing 6. The fluid moves through the filter housing 6 in the direction of arrow "A" and exits from the second end 26 of the filter housing. The fluid is filtered within the filter housing 6, and a portion of the fluid (e.g., permeate) may exit the filter housing 6 via a permeate discharge line 38 using a separate pump (not shown). The remaining portion of the fluid is returned to the container 2 via the second filtration line 24, the first isolation valve 30 (which operates to take the "open" position), and the first return line 28.

[0045] In the second mode of operation shown in Figure 2, System 1 is configured to direct the flow from the container 2 to the second end 26 of the filter housing 6 via the second filtration line 24. Therefore, the three-way valve 14 is operated to direct the flow from the pump 4 to the second filtration line 24. The first isolation valve 30 is positioned in the "closed" position, thus preventing flow between the second filtration line 24 and the first return line 28. Thus, the fluid flows from the container 2, through the pump 4, through the three-way valve 14, through the second filtration line 24, and there into the second end 26 of the filter housing 6. The fluid moves through the filter housing 6 in the direction of arrow "B" and exits from the first end 20 of the filter housing. The fluid is filtered within the filter housing 6, and a portion of the fluid (e.g., permeate) may exit the filter housing 6 via a permeate discharge line 38 using a separate pump (not shown). The remaining portion of the fluid is returned to the container 2 via the first filtration line 18, the second isolation valve 34 (which operates to take the "open" position), and the second return line 32.

[0046] The disclosed system 1 allows a single pump 4 to be used to continuously pump cell cultures from a container 2 (bioreactor) based on a user-defined flow rate. The cell cultures flow through the filter housing 6 and filter elements in one direction (either "A" in the first mode or "B" in the second mode), or selectively in two opposite directions ("A" in the first mode and "B" in the second mode) based on the selected operating mode.

[0047] In alternating tangential flow mode, the flow of the cell culture is directed again by the three-way valve 14 along with the simultaneous opening and closing of the first and second isolation valves 30 and 34. Furthermore, when system 1 is configured to accommodate alternating tangential flow, pump 4 does not need to drain the entire volume of cell culture from container 2. Rather, multiple pump cycles may be required to move the entire volume of cell culture through the filter housing 6. The time-based pumping mandated by the flow of the proposed technology ensures complete replacement of the cell culture in a single recirculation loop cycle.

[0048] The time for unidirectional flow is the time it takes for a single microparticle (cell) to travel from container 2 (e.g., bioreactor) through the entire loop of the pipe (tube), through filter 6, and back to the container. This time depends on the flow rate set by pump 4. An algorithm performed by controller 44 (see Figure 10) calculates the time required for the cell to complete the loop. The same time is then applied to the flow of cells in the opposite direction. If pump 4 is set to operate at a low flow rate, it will take a relatively long time for the cell to complete the loop in one direction, while by setting the pump to operate at a higher flow rate, the time required for the cell to complete the loop in one direction will be shorter. The disclosed alternating flow configuration (i.e., flow through the loop in a first direction followed by flow through the loop in a second, opposite direction) may be effective in preventing premature filter blockage. The flow through the permeate discharge line 38 can be controlled by adjusting the speed of an associated permeate pump (not shown), which may be based on the flow rate of a retaining fluid pump (not shown). To further aid in filter purification and extend its lifespan, the flow rates of the retaining fluid and permeate pumps can be periodically increased over short periods.

[0049] Figure 3 shows an alternative embodiment of the disclosed system 1, wherein the flow diversion section includes first and second flow diversion isolation valves 15A, 15B. As can be seen, the system 1 of Figure 3 is substantially the same as the system described in relation to Figures 1 and 2, and includes the vessel 2, pump 4, and filter housing 6 together with pump suction and discharge lines 8, 10, first and second filtration lines 18, 24, first and second return lines 28, 32, and first and second isolation valves 30 and 34, all of which function in the same manner as described in relation to Figures 1 and 2. The first flow diversion isolation valve 15A is located between the pump discharge line 10 and the first filtration line 18. The second flow diversion isolation valve 15B is located between the pump discharge line 10 and the second filtration line 24. As can be understood, the operation of the first and second flow diversion isolation valves 15A, B together can function to redirect the flow in the same manner as described for the three-way valve 14 of the previous embodiment.

[0050] Therefore, in order to provide flow through the filter housing 6 (and filter) in the direction of arrow "A" (i.e., the first mode of operation in which system 1 is configured to direct flow from container 2 through the first filtration line 18 to the first end 20 of the filter housing 6), the first diversion isolation valve 15a is configured in the open position, while the second diversion isolation valve 15b is configured in the closed position. With this configuration, the flow from pump 4 is directed to the first filtration line 18. The second isolation valve 34 is set to the "closed" position and is operated in such a way to prevent flow between the first filtration line 18 and the second return line 32. Thus, the fluid flows from container 2, through pump 4, through the first diversion isolation valve 15a, through the first filtration line 18, and there into the first end 20 of the filter housing 6. The fluid moves through the filter housing 6 in the direction of arrow "A" and exits from the second end 26 of the filter housing. The fluid is filtered within the filter housing 6, and a portion of the fluid (e.g., permeate) may be discharged from the filter housing 6 via a permeate discharge line 38 using a separate pump (not shown). The remaining portion of the fluid is returned to the container 2 via a second filtration line 24, a first isolation valve 30 (which operates to take the "open" position), and a first return line 28.

[0051] In order to provide flow through the filter housing 6 (and filter) in the direction of arrow "B" (i.e., in the second mode of operation, where system 1 is configured to direct flow from container 2 through the second filtration line 24 to the second end 26 of the filter housing 6), the first diversion isolation valve 15A is configured in the closed position, while the second diversion isolation valve 15b is configured in the open position. With this configuration, the flow from pump 4 is directed to the second filtration line 24. The first isolation valve 30 is set to the "closed" position and is operated in such a way to prevent flow between the second filtration line 24 and the first return line 28. Thus, the fluid flows from container 2, through pump 4, through the second diversion isolation valve 15b, through the second filtration line 24, and there into the second end 26 of the filter housing 6. The fluid moves through the filter housing 6 in the direction of arrow "B" and exits from the first end 20 of the filter housing. The fluid is filtered within the filter housing 6, and a portion of the fluid (e.g., permeate) may be discharged from the filter housing 6 via a permeate discharge line 38 using a separate pump (not shown). The remaining portion of the fluid is returned to the container 2 via the first filtration line 18, a second isolation valve 34 (which operates to take the "open" position), and a second return line 32.

[0052] In the embodiment shown in Figure 3, a single pump 4 can be used to continuously pump cell cultures from container 2 (bioreactor) based on a user-defined flow rate. The cell cultures flow through the filter housing 6 and filter elements in one direction (either "A" in the first mode or "B" in the second mode), or selectively in two opposite directions ("A" in the first mode and "B" in the second mode) based on the selected operating mode.

[0053] Figures 4A and 4B show alternative embodiments of the disclosed system 1 in which the flow diversion section includes a pinch valve 17 (Figure 5). As can be seen, system 1 in Figures 4A and 4B is substantially the same as the system described in relation to Figures 1 and 2, and includes a vessel 2, a pump 4, and a filter housing 6, together with pump suction and discharge lines 8, 10, first and second filtration lines 18, 24, and a first return line 28. System 1 in Figures 4A and 4B, in particular, does not include a second return line and also does not include first and second isolation valves 30 and 34. The pinch valve 17 is positioned between the pump discharge line 10 and the first and second filtration lines 18, 28. As positioned, the operation of the pinch valve 17 functions to redirect the flow in the same manner as described for the three-way valve 14 in Figure 1.

[0054] To provide flow through the filter housing 6 (and filter) in the direction of arrow "A" (i.e., the first mode of operation shown in Figure 4A, in which system 1 is configured to direct flow from container 2 through the first filtration line 18 to the first end 20 of the filter housing 6), the pinch valve 17 is configured to direct flow from the pump discharge 10 to the first filtration line 18 and to block flow from the pump discharge to the second filtration line 24. In this configuration, the pinch valve 17 is also configured to direct flow from the second filtration line 24 to the first return line 28. With this configuration, the fluid flows from container 2, through pump 4, through pinch valve 17, and then through the first filtration line 18, where it enters the first end 20 of the filter housing 6. The fluid moves through the filter housing 6 in the direction of arrow "A" and exits from the second end 26 of the filter housing. The fluid is filtered within the filter housing 6, and a portion of the fluid (e.g., permeate) may be discharged from the filter housing 6 via a permeate discharge line 38 using a separate pump (not shown). The remaining portion of the fluid is returned to the container 2 via a second filtration line 24, a pinch valve 17, and a first return line 28.

[0055] To provide flow through the filter housing 6 (and filter) in the direction of arrow "B" (i.e., the second mode of operation shown in Figure 4B, in which system 1 is configured to direct flow from container 2 through a second filtration line 24 to the second end 26 of the filter housing 6), the pinch valve 17 is configured to direct flow from the pump discharge 10 to the second filtration line 24 and to block flow from the pump discharge 10 to the first filtration line 18. In this configuration, the pinch valve 17 is also configured to direct flow from the first filtration line 18 to the first return line 28. With this configuration, the fluid flows from container 2, through pump 4, through pinch valve 17, and then through the second filtration line 24, where it enters the second end 26 of the filter housing 6. The fluid moves through the filter housing 6 in the direction of arrow "B" and exits from the first end 20 of the filter housing. The fluid is filtered within the filter housing 6, and a portion of the fluid (e.g., permeate) may be discharged from the filter housing 6 via a permeate discharge line 38 using a separate pump (not shown). The remaining portion of the fluid is returned to the container 2 via a first filtration line 18, a pinch valve 17, and a first return line 28.

[0056] In the embodiments shown in Figures 4A and 4B, a single pump 4 can be used to continuously pump cell cultures from container 2 (bioreactor) based on a user-defined flow rate. The cell cultures flow through the filter housing 6 and filter elements in one direction ("A" of the first mode or "B" of the second mode), or selectively in two opposite directions ("A" of the first mode and "B" of the second mode) based on the selected operating mode.

[0057] Figure 5 shows an exemplary pinch valve 17 for use in the exemplary systems of Figures 4A and 4B. The pinch valve 17 includes a base 50, first and second side supports 52, 54, first and second stationary plates 56, 58, and first and second movable plates 60, 62. The base 50 may have an opening (not shown) for receiving an actuating member 64 of an actuator 66 through it. The actuating member 64 may be connected to the first and second movable plates 60, 62 to adjust the position of the first and second movable plates with respect to the base 50 and the first and second stationary plates 56, 58. As will be described in more detail, when multiple flexible tubes are arranged between the first and second movable plates 60, 62 and the first and second stationary plates 56, 58, the flow of fluid through the flexible tubes can be selectively controlled by compressing or pinching selected flexible tubes so that fluid cannot flow through them. By allowing fluid to flow through the remaining uncompressed tubes, it becomes possible to control the flow between selected components of System 1.

[0058] The first and second stationary plates 56, 58 can be fixed to the base 50 via the first and second side supports 52, 54 so that they do not move during the operation of the pinch valve 17. The first and second movable plates 60, 62 are slidable along the first and second side supports 52 so that they can reciprocate during the operation of the pinch valve 17. An actuator 64 is connected to the first and second movable plates 60, 62 so that the actuator 66 can selectively reciprocate the first and second movable plates between first and second positions. In the first position (shown in Figure 5), the actuator moves in the direction of arrow "C" such that the first movable plate 60 moves toward the first stationary plate 56 and the second movable plate 62 moves toward the second stationary plate 58. In the second position (not shown), the operating member moves in the direction of arrow "D" such that the first movable plate 60 moves toward the second stationary plate 58 and the second movable plate 62 moves toward the base 50.

[0059] Multiple flexible tubes may be arranged between the first and second stationary plates 56, 58 and the first and second movable plates 60, 62. In the illustrated embodiment, the first and second flexible tubes 68, 70 are arranged between the base 50 and the second movable plate 62, while the third and fourth flexible tubes 72, 74 are arranged between the first movable plate 60 and the first stationary plate 56. The flexible tubes may be made from any material suitable for bioprocess applications, such as fluoropolymers.

[0060] As can be seen, when the pinch valve 17 moves to the first position shown in Figure 5 (i.e., when the actuating member 64 and the first and second movable plates 60, 62 move in the direction of arrow "C"), the second movable plate 62 moves a sufficient distance (for example, an amount equal to or greater than the outer diameter of the first and second flexible pipes 68, 70) away from the base 50 so that the first and second flexible pipes 68, 70 are not substantially compressed and thus allow fluid to flow through the first and second flexible pipes. In contrast, in the first position, the first movable plate 60 moves toward the first stationary plate by a sufficient amount to compress the third and fourth flexible pipes 72, 74 and prevent fluid from flowing through the third and fourth flexible pipes.

[0061] When the pinch valve 17 moves to the second position (i.e., when the operating member 64 and the first and second movable plates 60, 62 move in the direction of arrow "D"), the second movable plate 62 moves toward the base 50 by an amount sufficient to compress the first and second flexible tubes 68, 70 and prevent fluid from flowing through the first and second flexible tubes. In contrast, in the second position, the first movable plate 60 moves toward the first stationary plate 56 by a distance sufficient to allow the third and fourth flexible tubes to flow through the third and fourth flexible tubes, for example, by an amount equal to or greater than the outer diameter of the third and fourth flexible tubes 72, 74, so that the third and fourth flexible tubes are not substantially compressed and thus allow fluid to flow through the third and fourth flexible tubes.

[0062] When the pinch valve 17 is incorporated into the system 1 shown in Figures 4A and 4B, the first flexible pipe 68 may be connected between the second filtration line 24 and the first return line 28, the second flexible pipe 70 may be connected between the pump discharge section 10 and the first filtration line 18, the third flexible pipe 72 may be connected between 10 and 24, and the fourth flexible pipe 74 may be connected between the first filtration lines 18 and 28. In this arrangement, at the first position of the pinch valve 17 (i.e., the position shown in Figure 5), the first and second flexible pipes 68 and 70 are not compressed, allowing flow between the second filtration line 24 and the first return line 28, and between the pump discharge section 10 and the first filtration line 18. The third and fourth flexible tubes 72 and 74 are compressed, preventing flow between the pump discharge section 10 and the second filtration line 24, and between the first filtration line 18 and the first return line 28. Thus, at the first position of the pinch valve 17, the flow from the bioreactor 2 enters the first end 20 of the filter 6 and returns to the bioreactor via the first return line 28.

[0063] To reverse the flow through filter 6, the pinch valve 17 moves to a second position so that the first and second flexible tubes 68 and 70 are compressed to prevent flow between the second filtration line 24 and the first return line 28, and between the pump discharge section 10 and the first filtration line 18, while the third and fourth flexible tubes 72 and 74 are not compressed, allowing flow between the first filtration line 18 and the first return line 28, and between the pump discharge section 10 and the second filtration line 24. Thus, with the pinch valve 17 in the second position, the flow from bioreactor 2 enters the first end 20 of filter 6 and returns to the bioreactor via the first return line 28.

[0064] The advantage of using the pinch valve 17 in System 1 in Figures 4A and 4B is that contact of the liquid with the internal valve components is eliminated and immediate flow redirection (limited only by the time it takes to move the actuator 64 between the first and second positions) is provided.

[0065] Figures 6A and 6B show alternative embodiments of the disclosed system 1 in which the flow diversion section is a rotary valve 21. As can be seen, system 1 in Figures 6A and 6B is substantially the same as the system described in relation to Figures 1 and 2, and includes a vessel 2, a pump 4, and a filter housing 6, together with pump suction and discharge lines 8, 10, first and second filtration lines 18, 24, and a first return line 28. System 1 in Figures 6A and 6B, in particular, does not include a second return line and also does not include first and second isolation valves 30 and 34. The rotary valve 21 is positioned between the pump discharge line 10 and the first and second filtration lines 18, 28. As positioned, the operation of the rotary valve 21 functions to redirect the flow in the same manner as described for the three-way valve 14 in Figure 1 and the pinch valve 17 in Figures 4A and 4B.

[0066] To provide flow through the filter housing 6 (and filter) in the direction of arrow "A" (i.e., the first mode of operation shown in Figure 6A, in which system 1 is configured to direct flow from container 2 through the first filtration line 18 to the first end 20 of the filter housing 6), the rotary valve 21 is configured to direct flow from the pump discharge 10 to the first filtration line 18 and to block flow from the pump discharge to the second filtration line 24. In this configuration, the rotary valve 21 is also configured to direct flow from the second filtration line 24 to the first return line 28. With this configuration, the fluid flows from container 2, through pump 4, through rotary valve 21, and then through the first filtration line 18, where it enters the first end 20 of the filter housing 6. The fluid moves through the filter housing 6 in the direction of arrow "A" and exits from the second end 26 of the filter housing. The fluid is filtered within the filter housing 6, and a portion of the fluid (e.g., permeate) may be discharged from the filter housing 6 via a permeate discharge line 38 using a separate pump (not shown). The remaining portion of the fluid is returned to the container 2 via a second filtration line 24, a rotary valve 21, and a first return line 28.

[0067] To provide flow through the filter housing 6 (and filter) in the direction of arrow "B" (i.e., the second mode of operation shown in Figure 6B, in which system 1 is configured to direct flow from container 2 through a second filtration line 24 to the second end 26 of the filter housing 6), the rotary valve 21 is configured to direct flow from the pump discharge 10 to the second filtration line 18 and to block flow from the pump discharge 10 to the first filtration line 18. In this configuration, the rotary valve 21 is also configured to direct flow from the first filtration line 18 to the first return line 28. With this configuration, the fluid flows from container 2, through pump 4, through rotary valve 21, and then through the second filtration line 24, where it enters the second end 26 of the filter housing 6. The fluid moves through the filter housing 6 in the direction of arrow "B" and exits from the first end 20 of the filter housing. The fluid is filtered within the filter housing 6, and a portion of the fluid (e.g., permeate) may be discharged from the filter housing 6 via a permeate discharge line 38 using a separate pump (not shown). The remaining portion of the fluid is returned to the container 2 via a first filtration line 18, a rotary valve 21, and a first return line 28.

[0068] In the embodiments shown in Figures 6A and 6B, a single pump 4 can be used to continuously pump cell cultures from container 2 (bioreactor) based on a user-defined flow rate. The cell cultures flow through the filter housing 6 and filter elements in one direction (either "A" in the first mode or "B" in the second mode), or selectively in two opposite directions ("A" in the first mode and "B" in the second mode) based on the selected operating mode. Furthermore, the embodiments shown in Figures 6A and 6B allow for complete volume exchange in each cycle of the rotary valve 21.

[0069] Figures 7A and 7B show an alternative embodiment of the disclosed system 1 in which the three-way valve 14 is replaced by a shuttle valve 23. As can be seen, system 1 in Figures 7A and 7B is substantially the same as the system described in relation to Figures 1 and 2, and includes a vessel 2, a pump 4, and a filter housing 6, together with pump suction and discharge lines 8, 10, first and second filtration lines 18, 24, and a first return line 28. System 1 in Figures 7A and 7B, in particular, does not include a second return line and also does not include first and second isolation valves 30 and 34. The shuttle valve 23 is positioned between the pump discharge line 10 and the first and second filtration lines 18, 28. As positioned, the operation of the shuttle valve 23 functions to redirect the flow in the same manner as described for the three-way valve 14 in Figure 1, the pinch valve 17 in Figures 4A and 4B, and the rotary valve 21 in Figures 6A and 6B.

[0070] To provide flow through the filter housing 6 (and filter) in the direction of arrow "A" (i.e., the first mode of operation shown in Figure 7A, in which system 1 is configured to direct flow from container 2 through the first filtration line 18 to the first end 20 of the filter housing 6), the shuttle valve 23 is configured to direct flow from the pump discharge 10 to the first filtration line 18 and to block flow from the pump discharge to the second filtration line 24. In this configuration, the shuttle valve 23 is also configured to direct flow from the second filtration line 24 to the first return line 28. With this configuration, the fluid flows from container 2, through pump 4, through shuttle valve 23, and then through the first filtration line 18, where it enters the first end 20 of the filter housing 6. The fluid moves through the filter housing 6 in the direction of arrow "A" and exits from the second end 26 of the filter housing. The fluid is filtered within the filter housing 6, and a portion of the fluid (e.g., permeate) may be discharged from the filter housing 6 via a permeate discharge line 38 using a separate pump (not shown). The remaining portion of the fluid is returned to the container 2 via a second filtration line 24, a shuttle valve 23, and a first return line 28.

[0071] To provide flow through the filter housing 6 (and filter) in the direction of arrow "B" (i.e., the second mode of operation shown in Figure 7B, in which system 1 is configured to direct flow from container 2 through a second filtration line 24 to the second end 26 of the filter housing 6), the shuttle valve 23 is configured to direct flow from the pump discharge 10 to the second filtration line 24 and to block flow from the pump discharge 10 to the first filtration line 18. In this configuration, the shuttle valve 23 is also configured to direct flow from the first filtration line 18 to the first return line 28. With this configuration, the fluid flows from container 2, through pump 4, through shuttle valve 23, and then through the second filtration line 24, where it enters the second end 26 of the filter housing 6. The fluid moves through the filter housing 6 in the direction of arrow "B" and exits from the first end 20 of the filter housing. The fluid is filtered within the filter housing 6, and a portion of the fluid (e.g., permeate) may be discharged from the filter housing 6 via a permeate discharge line 38 using a separate pump (not shown). The remaining portion of the fluid is returned to the container 2 via a first filtration line 18, a shuttle valve 23, and a first return line 28.

[0072] In the embodiments shown in Figures 7A and 7B, a single pump 4 can be used to continuously pump cell cultures from container 2 (bioreactor) based on a user-defined flow rate. The cell cultures flow through the filter housing 6 and filter elements in one direction (either "A" in the first mode or "B" in the second mode), or selectively in two opposite directions ("A" in the first mode and "B" in the second mode) based on the selected operating mode. The embodiments in Figures 7A and 7B also provide immediate flow redirection (limited only by the time required to move the shuttle of the shuttle valve 23 between positions).

[0073] Figures 8A and 8B show an alternative embodiment of the disclosed system 100 in which first and second pumps 140A and 140B are employed to selectively direct flow from the container 2 to the first and second ends 20 and 26 of the filter housing 6. A shuttle valve 123 is positioned between the first and second pumps 140A and 140B and between the first and second ends 20 and 26 of the filter housing 6. The shuttle valve 123 is configured to selectively allow and prevent flow from the discharges of the first and second pumps 140A and 140B to the filter housing 6. As can be seen, the system 100 in Figures 8A and 8B is similar to the system described in relation to Figures 1 to 7B and includes the container 2, the filter housing 6, the shuttle valve 123 and first and second filtration lines 18 and 24 and a permeate line 38 positioned between the filter housing 6. However, the system 100 in Figures 8A and 8B includes first and second pumps 140A and 140B, each having discharge lines 110A and 110B connected to the shuttle valve 123, and a common return line 128 connected between the shuttle valve 123 and the container 2. As arranged, the operation of the shuttle valve 123 functions to selectively allow the flow from the first or second pumps 140A and 140B to be directed to the first or second ends 20 and 26 of the filter housing 6.

[0074] To provide flow through the filter housing 6 (and filter) in the direction of arrow "A" (i.e., the first mode of operation shown in Figure 8A, in which the system 100 is configured to direct flow from the container 2 through the second filtration line 24 to the second end 26 of the filter housing 6), the shuttle valve 123 is positioned to direct flow from the discharge 110A of the first pump 140A to the second filtration line 24, and to block flow from the discharge 110B of the second pump 140B to the first filtration line 18. In this configuration, the shuttle valve 123 is positioned to direct flow from the first filtration line 18 to the return line 128. With this configuration, the fluid flows from the container 2, through the first pump 104A, through the shuttle valve 123, and then through the second filtration line 24, where it enters the second end 26 of the filter housing 6. The fluid moves through the filter housing 6 in the direction of arrow "A" and exits from the first end 20 of the filter housing. The fluid is filtered within the filter housing 6, and a portion of the fluid (e.g., permeate) may be discharged from the filter housing 6 via a permeate discharge line 38 using a separate pump (not shown). The remaining portion of the fluid is returned to the container 2 via the first filtration line 18, shuttle valve 123, and return line 128.

[0075] To provide flow through the filter housing 6 (and filter) in the direction of arrow "B" (i.e., the second mode of operation shown in Figure 8B, in which the system 100 is configured to direct flow from the container 2 through the first filtration line 18 to the first end 20 of the filter housing 6), the shuttle valve 123 is positioned to direct flow from the discharge 110B of the second pump 140B to the first filtration line 18, and to block flow from the discharge 110A of the first pump 140A to the second filtration line 24. In this configuration, the shuttle valve 123 is also positioned to direct flow from the second filtration line 24 to the return line 128. With this configuration, the fluid flows from the container 2, through the second pump 140B, through the shuttle valve 123, and then through the first filtration line 18, where it enters the first end 20 of the filter housing 6. The fluid moves through the filter housing 6 in the direction of arrow "B" and exits from the second end 26 of the filter housing. The fluid is filtered within the filter housing 6, and a portion of the fluid (e.g., permeate) may be discharged from the filter housing 6 via a permeate discharge line 38 using a separate pump (not shown). The remaining portion of the fluid is returned to the container 2 via a second filtration line 24, a shuttle valve 123, and a return line 128.

[0076] In the embodiments shown in Figures 8A and 8B, the first and second pumps 140A and 140B can be used to continuously pump cell cultures from the container 2 (bioreactor) based on a user-defined flow rate. The cell cultures flow through the filter housing 6 and filter elements in one direction ("A" of the first mode or "B" of the second mode), or selectively in two opposite directions ("A" of the first mode and "B" of the second mode) based on the selected operating mode. The embodiments shown in Figures 8A and 8B also provide immediate flow redirection (limited only by the time required to move the shuttle of the shuttle valve 123 between the above positions).

[0077] In the embodiments shown in Figures 8A and 8B, the operation of the first and second pumps 140A and 140B is continuous, synchronized according to a fixed time schedule, and / or can be manually switched by the user. In the first mode of operation, the first and second pumps 140A and 140B are identical, and the setpoint of the flow in both pumps is the same. The first and second pumps 140A and 140B are arranged to produce flow in the same direction (i.e., drawing from the container 2 and discharging toward the filter housing 6). The first pump 140A is activated and the shuttle valve 123 is circulating so that the flow from the container 2 is directed through the first pump 140A, through the shuttle valve 123, through the second filtration line 24, through the filter housing 6, through the first filtration line 18, and then back to the container 2 through the shuttle valve 123 (i.e., flow path "A" shown in Figure 8A). During this period of operation, the second pump 140B is off. After a predetermined period, the first pump 140A is deactivated and the second pump 140B is activated, and the shuttle valve 123 circulates to receive flow from the second pump 140B, through the shuttle valve 123, through the first filtration line 18, through the filter housing 6, through the second filtration line 24, and then back to the container 2 through the shuttle valve 123 (i.e., flow path "B" shown in Figure 8B). After a predetermined period, the operation can be switched back to the first pump 140A. In this manner, with the associated circulation of the shuttle valve 123, the flow can be circulated between the first and second pumps 140A and 140B multiple times as desired.

[0078] In a second mode of operation, the first and second pumps 140A, 140B operate simultaneously and continuously, and the flow through the filter housing 6 can be controlled simply by selectively circulating the shuttle valve 123 to receive discharge from the first or second pump and direct the flow to the filter housing 6 in either direction "A" or "B" as shown in Figures 8A and 8B. To take this second mode of operation into account, each pump 140A, 140B may be provided with first and second recirculation lines 142A, 142B between the shuttle valve 123 and the suction sections of each pump and / or container, so that discharge flow from pumps not actively pumping liquid through the filter housing 6 is recirculated back to the container 2 or the pump suction section. As can be seen, the shuttle valve 123 may include passages for selectively directing the flow to the first or second recirculation lines 142A, 142B.

[0079] Figures 9A and 9B show alternative embodiments of the disclosed System 1 in which a permeate pump 138 is mounted on a permeate line 38. As can be seen, System 1 in Figures 9A and 9B is substantially the same as the system described in relation to Figures 1 and 2, and includes a vessel 2, a pump 4, and a filter housing 6, together with pump suction and discharge lines 8, 10, a valve 14, first and second filtration lines 18, 24, and first and second return lines 28, 32. The operation of System 1 in Figures 9A and 9B is substantially the same as described in relation to Figures 1 and 2, and includes circulating the three-way valve 14 to achieve selective flow from the vessel 2 through the filter housing 6 in first and second directions (indicated by arrows "A" and "B").

[0080] As mentioned above, the advantage of using ATF technology is the bidirectional flow of cell cultures through the hollow fiber filter (located within the filter housing 6). The bidirectional flow of cell cultures provides a pushing action along the inner diameter of the filter's hollow fibers, which extends the filter's lifespan by reducing filter fouling. Extending filter lifespan is important because filter replacement in a continuous cell culture process poses a risk of system contamination and loss of cell culture products.

[0081] Therefore, the systems disclosed in Figures 9A and 9B can reduce or minimize filter fouling by employing a permeate pump 138 to reverse the flow so that the permeate can be directed back to the filter housing 6 in order to achieve the filter purification function. In some embodiments, the permeate pump 138 is a peristaltic pump, but it will be understood that the permeate pump 138 can be any type of suitable bidirectional pump. The permeate pump 138 can be controlled by an ATF( / TFF) controller algorithm embodied in the controller 44 (see Figure 15). The user can employ the filter purification function by activating hollow fiber filter purification cycle features. In some embodiments, the purification cycle may include (a) backflow at different flow rates, and / or (b) pulsating flow by increasing and decreasing the flow rate in forward and backward modes.

[0082] As can be understood, the permeate pump 138 normally operates in a steady pumping mode during the operation of System 1. This steady pumping mode removes permeate from the filter housing 6 and directs the permeate to a separate retention tank. When the purification cycle is activated, the permeate pump 138 may switch from this steady pumping mode to a filter purification mode for a predetermined period of time.

[0083] The filter purification mode can be set by the user based on trials with results formulated through validation. The purification stages may differ between applications and may be initiated periodically at the start of operation. Two purification modes are intended. In the first purification mode, the permeate pump 138 is turned off. If the permeate pump 138 is of a type that prevents flow through the permeate line 38 when the pump is off and subjected to suction pressure, no additional valve is required. However, if the permeate pump 138 is of a type that does not prevent flow through the permeate line 38 when the pump is off and subjected to suction pressure, a separate valve (not shown) may be provided to prevent permeate flow when the permeate pump 138 is turned off. In the second purification mode, the permeate pump 138 is turned on in the reverse flow direction so that the permeate flow is directed back toward the filter housing 6. In both modes, the retaining fluid pump can be actively pumped. Thus, the retaining fluid flow rate continues during the purification cycle, but in some embodiments, the speed may increase or decrease. A specific profile of the purification cycle, including the flow rate of the retaining fluid pump and the time spent with stopped or reversed permeate flow, can be established and repeated throughout the entire operation.

[0084] After a predetermined period has elapsed, the controller 44 can switch the permeate pump 138 back to a stable pumping mode. Alternatively, the permeate pump 138 may automatically switch to filter purification mode when the pressure sensed by the pressure sensor 139 (located in the permeate line 38 between the permeate pump 138 and the filter housing 6) exceeds a predetermined value. For example, if the pressure sensed by the pressure sensor 139 is reduced to a value close to the vacuum level, the permeate pump 138 may automatically transition to purification mode. The permeate pump 138 may remain in purification mode for a predetermined period of time, or until the pressure sensed by the pressure sensor 139 rises above a predetermined value.

[0085] As mentioned above, when the permeate pump 138 is operating in purification mode, it can reverse the flow so that the permeate moves back through the permeate line 38 to the filter housing 6. Such backflow can occur at a constant flow rate that is the same as, greater than, or less than, the normal flow rate at which the permeate pump 138 removes permeate from the filter housing 6 under normal operating conditions. Alternatively, when the permeate pump 138 is operating in purification mode, it can "pulsate" back and forth by increasing and / or decreasing the flow into and out of the filter housing.

[0086] The user interface allows the user to set the duration of stopped or reversed flow, for example, in units of mL / min. Furthermore, the user can set the frequency of stopped or reversed flow. Such parameters may be specific to the cell culture, the size of container 2, the size of the filter element, and the flow rate through the filter element. In some embodiments, the setting of stopped or reversed permeate flow and the modification of retained fluid flow rate parameters may be determined through testing and validation.

[0087] While the embodiments in Figures 9A and 9B are described in relation to the pump, valve, and pipe / tube arrangements in Figures 1 and 2, it will be understood that the use of the permeate pump 138 in the "purification mode" described above can be employed in any of the system embodiments in Figures 1 to 8B.

[0088] Figures 10 to 12 show illustrative flow graphs for the aforementioned systems 1 and 100. As can be seen in Figure 10, “Flow Direction A” represents the flow through the filter housing 6 in a first direction (e.g., in the direction of arrow “A” in Figures 1 to 9B), while “Flow Direction B” represents the flow through the filter housing 6 in a second direction (e.g., in the direction of arrow “B” in Figures 1 to 9B). “Change of Direction” indicates the switching between the flow in directions “A” and “B”. As can be understood, this change of direction occurs on a nearly vertical line indicating the speed at which the change of flow can be implemented in the disclosed system using the described pump / valve configuration. Figures 11 and 12 are illustrative plots of the change of flow direction at different system flow rates (1000 ml / min in Figure 11 and 1500 ml / min in Figure 12).

[0089] In some embodiments, for example, to ensure complete replacement of the cell culture, the cycle time may be automatically determined by a PLC algorithm based on the inner diameter of the system's tubing, the length of the system's tubing, and the pump flow rate. The cycle time may consist of bidirectional flow from the first and second ends 20, 26 of the filter housing 6. In non-limiting exemplary embodiments, the cycle time may be less than 10 seconds or longer than 30 seconds.

[0090] Figure 13 shows an exemplary filter housing 6 including a hollow fiber filter. The first and second ends 20, 26 of the filter housing 6 are shown as standard elbow-shaped connectors. In the illustrated embodiment, the first and second ends 20, 26 of the filter housing function identically to allow fluid to pass equally through the filter housing in either direction. Fluid directions "A" and "B" are indicated, relating to the first and second modes of operation described in relation to Figures 1 to 7B.

[0091] Figure 14 shows an alternative arrangement of the filter housing 6 for use in System 1 of Figures 1 to 7B. The filter housing 6 of this embodiment includes first and second ends 20, 26, similar to the filter housing described in relation to Figures 1 to 7B. The filter element 40 is located within the housing 6 and includes a flat filter material sheet formed into a tubular shape. A helical member 42 is located within the tube 40 and guides the fluid through the housing 6, improving the fluid's contact with the filtration material. The helical member 42 also draws the fluid into a turbulent regime, thereby increasing the Reynolds number.

[0092] The permeate discharge line 38 is located along the body of the housing 6 and may be connected to a separate pump (not shown). Multiple filter housings 6 may be connected together using a single retaining fluid and a single permeate pump. The permeate discharge section 38 may be located on the side or in the center of the housing 6. Placing the permeate discharge section 38 in the center provides the benefit of symmetry, which may be important when the fluid flows in either direction "A" or "B".

[0093] The pump flow setting, flow redirection via the three-way valve, and opening and closing of the first and second isolation valves 30, 34 can be controlled using feedback from a flow sensor 36 located in the pump discharge line 10. The flow sensor 36 can monitor the actual discharge flow from the pump 4 so that the pump speed can be adjusted to a desired value via the controller. Referring to Figure 15, embodiments of the electronic / computerized control operation of System 1 disclosed in Figures 1 and 2 are described in more detail. It will be understood that this operational arrangement employing the controller 44 described below can be implemented in any of the embodiments of System 1 herein (e.g., Figures 4A, 4B; 6A, 6B; 7A, 7B; 8A, 8B; 9A, 9B).

[0094] To enable System 1 to operate the pump 4 and valves 14, 30, 31 in various sequences and modes, the operation of the pump 4, the three-way valve 14, and the first and second isolation valves 30, 34 may be controlled by a controller 44. The controller may include a processor or microprocessor configured to run an operating system, an application-specific integrated circuit (ASIC), a field-programmable gate array (FPGA), or a combination thereof. The controller may include, but is not limited to, electronic, optical, magnetic, or any other storage or transmission device capable of providing a processor, ASIC, FPGA, etc., with programmable instructions. The memory may include a memory chip, an electronically erasable programmable read-only memory (EEPROM), an erasable programmable read-only memory (EPROM), flash memory, or any other suitable memory from which the controller can read instructions. Instructions may include code from any suitable programming language.

[0095] In some embodiments, the processor of the controller 44 may execute instructions (e.g., subroutines) to actuate the three-way valve and the first and second isolation valves 30, 31 to reconfigure the system between the first and second operating modes. As understood, the controller 44 may also control the speed of the pump 4 to regulate the flow through the system 1. In some embodiments, the controller 44 adjusts the pump speed based on the flow sensed by the flow sensor 34. Various setpoints and operating positions may be stored in the controller memory 46 and executed by the processing unit of the controller 44 in response to user commands or automatically.

[0096] As described above, the controller 44 may include a processor and associated memory 46 for storing information about the pump 4, the three-way valve 14, the first and second isolation valves 30, 34, the filter elements, and / or other aspects of the system. The memory may include instructions executable by the processor for controlling the operation of the pump 4 and the first and second isolation valves 30, 34, thereby controlling the fluid flow between the vessel 2 and the filter housing 6 and the filter elements in any of a variety of desired modes. The controller 44 also includes a user interface for enabling a user to input information into the controller and / or operate the system 1 in a desired mode.

[0097] As can be understood, the disclosed system 1 can be used for both tangential flow filtration (TFF) and alternating tangential flow (ATF). In the case of TFF, the three-way valve 14 is maintained to direct the flow in one direction through the filter housing 6. In the case of ATF, the three-way valve 14 is periodically repositioned to alternate the flow through the filter housing (i.e., alternate between the flow direction of arrow "A" and the flow direction of arrow "B") (see Figures 1 to 9B). As can be understood, the disclosed system 1 can be adapted to the operation of TFF and ATF in a single system. This is an advantage over conventional arrangements that employ separate systems for TFF and ATF.

[0098] In various embodiments, a user interface is provided, allowing a user of the disclosed system to input and / or monitor various aspects of the operation of the system and associated pumps and valves. For example, the user interface may be programmed to display one or more graph outputs of data received and analyzed by the controller 44. The user interface may also display other data stored in the controller 44's memory, including the filter type and size, flow direction mode, permeate pump mode (normal, purification), TFF mode, ATF mode, system flow, system pressure, and system status (running, off). Furthermore, additional parameters that may be displayed to the user in the user interface include flow rates and cycle times for one or more process stages.

[0099] Furthermore, the user interface of certain exemplary embodiments allows the user to control the start or stop of a control process performed by the controller 44. In some embodiments, the start and stop functions may be controlled, for example, via buttons provided on a touchscreen display. The user interface also allows for the input (entry) of specified control parameters.

[0100] As those skilled in the art will understand, according to the disclosed System 1, only electricity is required to activate the system, and no air / vacuum equipment is needed. Furthermore, the disclosed System 1 enables ATF and TFF operation in a single system. In ATF mode, unidirectional pumping is provided to a single supply pump 4. Compared to conventional systems that require six cycles to obtain less than 100% exchange, System 1 enables 100% retained volume exchange in two cycles. Furthermore, a reduction in the cost of ATF filters is achieved by eliminating the air / liquid hemisphere. Moreover, the flow setpoint can be reached in 60 seconds. System 1 also enables synchronized flow between Levitronix (retained fluid) and diaphragm (permeate) pumps. System 1 also operates without flow sensor feedback.

[0101] An exemplary method for operating one or more of the systems shown in Figures 1A to 9B is described here in reference to Figure 16. In step 1000, the fluid is transferred from the fluid storage container to the first end of the filter housing by configuring a flow divider to direct the fluid flow from the pump through a first filtration line connected to the first end of the filter housing so that the fluid moves from the first end of the filter housing to the second end of the filter housing. In step 1100, as the fluid moves through the filter housing, the permeate portion of the fluid is discharged through a permeate line connected to the filter housing. In step 1200, the retained portion of the fluid is discharged from the second end of the filter housing and returned to the fluid storage container via a first return line. In step 1300, the fluid is transferred from the fluid storage container to the second end of the filter housing by configuring a flow divider to direct the fluid flow from the pump through a second filtration line connected to the second end of the filter housing so that the fluid moves from the second end of the filter housing to the first end of the filter housing. In step 1400, as the fluid moves through the filter housing, the permeate portion of the fluid is discharged through a permeate line connected to the filter housing. In step 1500, the retained portion of the fluid is discharged from the second end of the filter housing and returned to the fluid storage container either via the first return line or the second return line. The process is then repeated by returning to step 1000.

[0102] In some embodiments, the filter element is a hollow fiber filter. In some embodiments, the fluid storage container is a bioreactor. In some embodiments, the fluid contains a cell culture. In some embodiments, the flow divider is selected from a list consisting of a three-way valve, a pinch valve, a rotary valve, and a shuttle valve. In other embodiments, the flow divider includes first and second flow divider isolation valves.

[0103] As can be understood, the disclosed system and method offer various advantages over conventional systems. For example, the disclosed system and method use only electricity to operate the ATF valve system (compared to conventional ATF controllers that utilize pneumatics and vacuum to activate the diaphragm pump and obtain system flow). The disclosed system and method enable ATF and TFF operation in a single system. Currently, each of the conventional methods requires separate equipment.

[0104] The power-driven and controlled pumps of the disclosed embodiments are simpler in operation than conventional systems, which are complex in operation due to the compressibility of the air used to operate the diaphragm pump employed as part of their systems. The disclosed ATF filter assembly of the disclosed embodiments eliminates the air / liquid hemispherical subassembly of conventional diaphragm pump-based systems. Such conventional ATF filter assemblies require the air / liquid subassembly, which increases the overall cost of the filter in terms of materials and labor. Furthermore, in such conventional systems, feedback of the liquid flow requires adjustment of the delivery of air and vacuum to the diaphragm pump, and this indirect control of the liquid flow by adjusting the air pressure and vacuum requires additional time to achieve the desired flow rate.

[0105] The pump used in the disclosed system provides unidirectional flow, compared to conventional ATF retention fluid pumps that must pump in two directions. Furthermore, the change in bidirectional flow through the filter is instantaneous and does not involve sudden acceleration or hesitation compared to conventional systems. Therefore, the flow setpoint can be reached in a few seconds, which is an advantage over slower conventional systems.

[0106] Furthermore, fluctuations in the flow rate ratio between the retaining fluid and permeate flows can cause premature filter fouling in conventional systems. The disclosed systems and methods enable the synchronization of the retaining fluid and permeate flows and provide a method for filter purification using a permeate pump in forward / reverse mode, pulsating mode, etc. In some embodiments, the permeate pump flow is adjusted by changing the retaining fluid pump flow, and thus the functional life of the filter is extended. As is understood, in some embodiments, the user sets the permeate flow at the same time that the retaining fluid flow is activated. The permeate flow rate ratio is determined based on the volume of container 2 and the perfusion flow rate (VVD). Also as is understood, a high permeate flow rate ratio requires increased addition of medium to the container, which may be advantageous for cells but may be more harsh on the filter elements.

[0107] In contrast, conventional systems require the retention fluid pump and the permeate fluid pump to operate independently. In some embodiments, the retention fluid pump operates using feedback from an ultrasonic flow sensor in closed-loop operation. The flow is instantaneously adjusted to a set point. In other embodiments, the system can function without flow sensor feedback using natural flow control of the pump (i.e., simply monitoring / controlling the pump's RPM, meaning the flow from the pump speed).

[0108] The disclosed systems and methods provide improved hold-up volume exchange in fewer cycles. In some embodiments, the disclosed systems and methods facilitate 100% hold-up volume exchange in up to two cycles, compared to conventional diaphragm pump systems that require six or more cycles to achieve less than 100% hold-up volume exchange.

[0109] The disclosed systems and methods have applications in perfusion of cultured animal cells and various other filtration applications. Cultured animal cells can mean mammalian cells suspended in a liquid medium. Cultured animal cells have a cell density greater than about 0.1×10 6 cells / mL (e.g., greater than about 1×10 6 cells / mL, greater than about 5×10 6 cells / mL, greater than about 10×10 6 cells / mL, greater than about 15×10 6 cells / mL, greater than about 20×10 6 cells / mL, greater than about 25×10 6 cells / mL, greater than about 30×10 6 cells / mL, greater than about 35×10 6 cells / mL, greater than about 40×10 6 cells / mL, greater than about 45×10 6 cells / mL, greater than about 50×10 6 cells / mL, greater than about 55×10 6 cells / mL, greater than about 60×10 6 cells / mL, greater than about 65×10 6 cells / mL, greater than about 70×10 6 cells / mL, greater than about 75×10 6 cells / mL, greater than about 80×10 6 cells / mL, greater than about 85×10 6 cells / mL, greater than about 90×10 6 cells / mL, greater than about 95×10 6 cells / mL, or greater than about 100×10 6 cells / mL).

[0110] Although the invention has been disclosed with reference to particular embodiments, numerous modifications, alterations, and changes are possible to the described embodiments without departing from the spirit and scope of the invention as defined in the claims. Accordingly, the invention is not intended to be limited to the described embodiments, but rather is intended to have the full scope defined by the following claims' language and their equivalents.

Claims

1. Fluid storage container; A filter housing including a filter element disposed inside, the filter housing having a first end and a second end; A pump connected between the fluid storage container and the filter housing; and A valve positioned between the pump and the filter housing. Equipped with, The pump is configured to provide a unidirectional flow, and the fluid from the fluid storage container is transported through the filter element in a first direction and a second direction, based on the position of the valve. The valve is operable in a first operating mode to direct the fluid from the fluid storage container to the first end of the filter housing so that the fluid moves through the filter housing in a first direction, the fluid is filtered inside the filter housing, the permeate portion of the fluid is discharged from the filter housing via a permeate discharge line, and the remainder of the fluid is returned to the fluid storage container via the second end of the filter housing. The valve is operable in a second operating mode to direct the fluid from the fluid storage container to the second end of the filter housing such that the fluid moves through the filter housing in a second direction opposite to the first direction, the fluid is filtered inside the filter housing, the permeate portion of the fluid is discharged from the filter housing through the permeate discharge line, and the remainder of the fluid is returned to the fluid storage container through the first end of the filter housing. Fluid filtration system.

2. When the fluid from the fluid storage container passes through the filter element in the first direction, the retaining liquid is output from the second end of the filter housing. The fluid filtration system according to claim 1, wherein when the fluid from the fluid storage container passes through the filter element in the second direction, the retained liquid is output from the first end of the filter housing.

3. A first filtration line connected between the first end of the filter housing and the first outlet of the valve; A second return line positioned between the fluid storage container and the first filtration line; and A second isolation valve located within the second return line is provided to selectively allow the flow of fluid between the filter housing and the fluid storage container via the second return line. The fluid filtration system according to claim 1, further comprising the following:

4. A second filtration line connected between the second end of the filter housing and the second outlet port of the valve; A first return line positioned between the fluid storage container and the second filtration line; and A first isolation valve located within the first return line is provided to selectively allow the flow of fluid between the filter housing and the fluid storage container through the first return line. The fluid filtration system according to claim 3, further comprising the following:

5. The fluid filtration system according to claim 4, further comprising a flow sensor for determining the actual flow rate from the discharge portion of the pump.

6. The fluid filtration system according to claim 5, further comprising the pump, the flow sensor, the first isolation valve and the second isolation valve, and a controller connected to the valve for selectively controlling the fluid flow path through the fluid filtration system.

7. The fluid filtration system according to claim 6, further comprising a memory associated with the controller, the memory storing the first isolation valve, the second isolation valve, and a plurality of preset positions of the valves.

8. The fluid filtration system according to claim 7, wherein the controller adjusts the speed of the pump based on the sensed flow rate information received from the flow sensor.

9. The fluid filtration system according to claim 1, wherein the pump is a low-shear pump and the filter element is a hollow fiber filter.

10. The filter housing is further equipped with a permeate pump connected to the filter housing for removing permeate from the filter housing, wherein the permeate pump is connected to the controller, and the controller is programmed to adjust the operation of the permeate pump to perform at least one of the following: (a) synchronizing the flow rate of the permeate pump with the pump; (b) performing a backflow operation to inject the permeate back into the filter housing to purify the filter elements; and (c) performing a pulse flow operation to purify the filter elements. The fluid filtration system according to claim 6.

11. The fluid filtration system according to claim 1, wherein the fluid storage container is a bioreactor.

12. The fluid filtration system according to claim 1, wherein the fluid includes a cell culture.

13. The fluid filtration system according to claim 1, wherein the valve is selected from a list consisting of a three-way valve, a pinch valve, a rotary valve, and a shuttle valve.

14. The fluid filtration system according to claim 1, wherein the valve includes a first flow diverter isolation valve and a second flow diverter isolation valve, the first flow diverter isolation valve being positioned between the discharge line of the pump and the first filtration line, and the second flow diverter isolation valve being positioned between the discharge line of the pump and the second filtration line.

15. The aforementioned pinch valve, base; A first side support and a second side support connected to the base; A first stationary plate and a second stationary plate fixedly connected to the first side support and the second side support; A first movable plate and a second movable plate movably connected to the first side support and the second side support; Actuators connected to the first and second movable plates for selectively moving the first and second movable plates toward and away from the first and second stationary plates. Includes, The first movable plate is positioned between the first stationary plate and the second stationary plate, and the second movable plate is positioned between the second stationary plate and the base; The fluid filtration system according to claim 13, wherein a first flexible tube and a second flexible tube can be positioned between the base and the second movable plate, and a third flexible tube and a fourth flexible tube can be positioned between the first movable plate and the first stationary plate.

16. The fluid filtration system according to claim 15, wherein, at the first position of the pinch valve, the second movable plate is positioned offset from the base by a distance equal to or greater than the outer diameter of the first and second flexible pipes, in order to allow the fluid to flow through the first and second flexible pipes.

17. The fluid filtration system according to claim 16, wherein, at the first position of the pinch valve, the first movable plate is positioned offset from the first stationary plate by an amount sufficient to compress the third and fourth flexible tubes in order to prevent the fluid from flowing through the third and fourth flexible tubes.

18. The fluid filtration system according to claim 15, wherein, at the second position of the pinch valve, the second movable plate is positioned offset from the base by an amount sufficient to compress the first flexible tube and the second flexible tube in order to prevent the fluid from flowing through the first flexible tube and the second flexible tube.

19. The fluid filtration system according to claim 18, wherein, at the second position of the pinch valve, the first movable plate is positioned offset from the first stationary plate by a distance equal to or greater than the outer diameter of the third and fourth flexible pipes, in order to allow the fluid to flow through the third and fourth flexible pipes.

20. The fluid filtration system according to claim 15, wherein the operating member is connected to an actuator, and the actuator is controllable by a controller connected to the actuator.

21. A method for operating a fluid filtration system that selectively and alternately provides two-directional flow through a filter housing, wherein the method is: In the first operating mode, a step is to transfer the fluid from the fluid storage container to the first end of the filter housing by configuring a valve to direct the fluid flow from the pump to a first filtration line connected to the first end of the filter housing; and In the second operating mode, the valve is configured to direct the flow of the fluid from the pump to a second filtration line connected to the second end of the filter housing, thereby transferring the fluid from the fluid storage container to the second end of the filter housing. Equipped with, In the first operating mode, the fluid is filtered inside the filter housing by moving from the first end of the filter housing to the second end of the filter housing, a portion of the fluid is discharged from the filter housing through the permeate discharge line, and the remainder of the fluid is returned to the fluid storage container through the second end of the filter housing. In the second operating mode, the fluid is filtered inside the filter housing by moving from the second end of the filter housing to the first end of the filter housing, a portion of the fluid is discharged from the filter housing through the permeate discharge line, and the remainder of the fluid is returned to the fluid storage container through the first end of the filter housing. method.

22. In the first operating mode, the step of directing the flow of the fluid from the second end of the filter housing through the first return line to the fluid storage container; and In the second operating mode, the step of directing the flow of the fluid from the first end of the filter housing through the second return line to the fluid storage container. The method according to claim 21, further comprising:

23. The method according to claim 22, wherein in the first operating mode, the step of directing the flow of the fluid from the second end of the filter housing to the fluid storage container includes the steps of opening a first isolation valve located in the first return line and closing a second isolation valve located in the second return line.

24. The method according to claim 22, wherein in the second operating mode, the step of directing the flow of the fluid from the first end of the filter housing to the fluid storage container includes the steps of opening a second isolation valve located in the second return line and closing a first isolation valve located in the first return line.

25. The method according to claim 21, further comprising the step of adjusting the speed of the pump based on the output of a flow sensor located downstream of the pump.

26. The method according to claim 21, wherein the pump is a low-shear pump and the filter element disposed inside the filter housing is a hollow fiber filter.

27. The method according to claim 21, further comprising the step of removing permeate from the filter housing, wherein the step of removing permeate from the filter housing further comprises at least one of the following: (a) synchronizing the flow rate of permeate with the flow rate of the pump; (b) periodically performing a backflow operation to inject the permeate back into the filter housing to purify the filter elements disposed inside the filter housing; and (c) performing a pulse flow operation of the flow of permeate to purify the filter elements.

28. The method according to claim 21, wherein the fluid storage container is a bioreactor.

29. The method according to claim 21, wherein the fluid includes a cell culture.

30. The method according to claim 21, wherein the valve is selected from a list consisting of a three-way valve, a pinch valve, a rotary valve, and a shuttle valve.

31. The method according to claim 21, wherein the valve includes a first flow-diverting isolation valve and a second flow-diverting isolation valve, the first flow-diverting isolation valve being positioned between the pump and the first filtration line, and the second flow-diverting isolation valve being positioned between the pump and the second filtration line.

32. The aforementioned pinch valve, base; A first side support and a second side support connected to the base; A first stationary plate and a second stationary plate fixedly connected to the first side support and the second side support; A first movable plate and a second movable plate movably connected to the first side support and the second side support; The first movable plate and the second movable plate are connected to an operating member, The first movable plate is positioned between the first stationary plate and the second stationary plate, and the second movable plate is positioned between the second stationary plate and the base; A first flexible tube and a second flexible tube can be positioned between the base and the second movable plate, and a third flexible tube and a fourth flexible tube can be positioned between the first movable plate and the first stationary plate. The method further comprises the step of selectively moving the operating member to a first position and a second position of the pinch valve, thereby selectively moving the first movable plate and the second movable plate toward and away from the first and second stationary plate. The method according to claim 30.

33. The method according to claim 32, wherein, at the first position of the pinch valve, the second movable plate is positioned offset from the base by a distance equal to or greater than the outer diameter of the first and second flexible pipes, in order to allow the fluid to flow through the first and second flexible pipes.

34. The method according to claim 33, wherein, in the first position of the pinch valve, the first movable plate is positioned offset from the first stationary plate by an amount sufficient to compress the third and fourth flexible tubes in order to prevent the fluid from flowing through the third and fourth flexible tubes.

35. The method according to claim 32, wherein, at the second position of the pinch valve, the second movable plate is positioned offset from the base by an amount sufficient to compress the first and second flexible tubes in order to prevent the fluid from flowing through the first and second flexible tubes.

36. The method according to claim 35, wherein, at the second position of the pinch valve, the first movable plate is positioned offset from the first stationary plate by a distance equal to or greater than the outer diameter of the third and fourth flexible pipes, in order to allow the fluid to flow through the third and fourth flexible pipes.

37. The method according to claim 32, wherein the actuating member is connected to an actuator, and the actuator is controllable by a controller connected to the actuator.

38. Fluid storage container; A filter housing including a filter element disposed inside, the filter housing having a first end and a second end; A first pump connected between the fluid storage container and a single valve; A second pump connected between the fluid storage container and the single valve. Equipped with, The single valve is connected between the first pump and the second pump and the filter housing; The single valve is configured, in a first mode, to direct a unidirectional flow of fluid received from the first pump toward the second end of the filter housing for filtration within the filter housing; and the single valve is configured, in a second mode, to direct a unidirectional flow of fluid received from the second pump toward the first end of the filter housing for filtration within the filter housing; The single valve is further configured to receive fluid from the first or second end of the filter housing and return the received fluid to the fluid storage container. Fluid filtration system.

39. The fluid filtration system according to claim 38, further comprising a flow sensor for determining the actual flow rate from the discharge portion of at least one of the first pump and the second pump.

40. The fluid filtration system according to claim 39, further comprising the first pump, the second pump, the flow sensor, and a controller connected to the single valve for selectively controlling the fluid flow path through the fluid filtration system.

41. The fluid filtration system according to claim 40, further comprising a memory associated with the controller, the memory storing a plurality of preset positions of the single valve.

42. The fluid filtration system according to claim 41, wherein the controller is configured to adjust the speeds of the first pump and the second pump based on the sensed flow rate information received from the flow sensor.

43. The fluid filtration system according to claim 38, wherein the first pump and the second pump are low-shear pumps.

44. The fluid filtration system according to claim 38, wherein the filter element is a hollow fiber filter.

45. The fluid filtration system according to claim 38, wherein the fluid storage container is a bioreactor.

46. The fluid filtration system according to claim 38, wherein the single valve is selected from a list consisting of a three-way valve, a pinch valve, a rotary valve, and a shuttle valve.

47. The filter housing is further equipped with a permeate pump connected to the filter housing for removing permeate from the filter housing, wherein the permeate pump is connected to the controller, and the controller is programmed to adjust the operation of the permeate pump to perform at least one of the following: (a) synchronizing the flow rate of the permeate pump with the first and second pumps; (b) performing a backflow operation to inject the permeate back into the filter housing to purify the filter elements; and (c) performing a pulse flow operation to purify the filter elements. The fluid filtration system according to claim 40.

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