Filtration system with optimized retentate / permeate flow sequencing

Abstract

A fluid filtration system includes a fluid storage vessel such as a bioreactor, a filter housing including a filter element disposed therein, a pump coupled between the fluid storage vessel and the filter housing, and a valve disposed between the pump and the filter housing. The pump is configured to move fluid from the fluid storage vessel through the filter element, and the valve is configured for selectively directing fluid received from the pump to the 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. A controller controls the pump and valve to achieve a predetermined stroke profile during each of the first and second modes of operation.

Description

INTERNATIONAL PATENT APPLICATIONFORFILTRATION SYSTEM WITH OPTIMIZEDRETENT ATE / PERME ATE FLOW SEQUENCINGINVENTOR:RUDOLF PAVLIKPREPARED BY:KDW FIRM PLLC 2601 WESTON PARKWAY SUITE 103CARY, NC 27513(609) 270-4983FILTRATION SYSTEM WITH OPTIMIZEDRETENT ATE / PERMEATE FLOW SEQUENCINGCross-Reference to Related Applications

[0001] This application claims priority to pending U.S. provisional patent application serial number 63 / 656,854, filed June 6, 2024, the entirety of which is incorporated by reference herein .Field of the Disclosure

[0002] Embodiments of the disclosure relate generally to filtration systems, and more particularly to a filtration system for optimizing retentate and permeate flows during alternating tangential flow filtration.Discussion of Related Art

[0003] Filtration is often performed to separate, clarify, modify, and / or concentrate a fluid solution, mixture, or suspension. In the biotechnology, pharmaceutical, and medical industries, filtration is vital for the successful production, processing, and analysis of drugs, diagnostics, and chemicals as well as many other products. As examples, filtration may be used to sterilize fluids and to clarify a complex suspension into a filtered “clear” fraction and an unfiltered fraction. Similarly, constituents in a suspension may be concentrated by removing or “filtering out” the suspending medium. Further, with appropriate selection of filter material, filter pore size and / or other filter variables, many other specialized uses have been developed. These uses may involve selective isolation ofconstituents from various sources, including cultures of microorganisms, blood, as well as other fluids that may be solutions, mixtures, or suspensions.

[0004] Biologies manufacturing processes have advanced through substantial process intensification. Both eukaryotic and microbial cell culture to produce recombinant proteins, virus-like particles (VLP), gene therapy particles, and vaccines now include cell growth techniques that can achieve 100e6 cells / ml or higher. This is achieved using cell retention devices that remove metabolic waste products and refresh the culture with additional nutrients. One common means of cell retention is to perfuse a bioreactor culture using hollow fiber filtration using alternating tangential flow (ATF).

[0005] Commercial and development scale processes use a device that controls a pump to perform ATF through a hollow fiber filter. In some arrangements the flow direction through the hollow fiber filter can be periodically / cyclically changed so that in a first phase flow moves from a first end of the filter to a second end of the filter, and in a second phase flow moves in the reverse direction from the second end of the filter to the first end of the filter. Such flow direction changes, which are characteristic of ATF processes, can have an adverse impact on cell culture wellbeing during the flow' transitions.

[0006] It would be desirable, therefore, to provide an improved system and method for ATF processes that improves cell culture viability even for the most sensitive cell culture strains.Summary of the Disclosure[00G7] Methods of alternating flow through hollow fiber filters are known, in which one or more valves are used to direct flow through the hollow fibers in an alternatingfashion from each end of the filter. Examples of such arrangements are disclosed in U.S. Patent No. 11,673,083, assigned to Repligen Corporation. The present disclosure recognizes that these flow direction changes can have an impact on cell culture wellbeing during flow transitions, and thus the disclosure provides one or more event sequences implemented during the flow direction changes that improve cell culture viability.

[0008] ATF processes include control of retentate and permeate flow (ml. or L per minute), control of duration between flow direction changes (which depends on holdup volume and time to its fall exchange), speed of flow7direction change (i.e., the transition period between flow direction changes) which are typically on the order of milliseconds). Manipulation of the aforementioned variables just before, during and shortly after flow direction change provides the ability to smooth out, mitigate instantaneous flow and pressure peaks.

[0009] In some embodiments the disclosure provides one directional cell culture flow and its redirection by a valve to alternate entry to both filter ends. Embodiments provide adjustments to fluid dynamics between related devices, including a retentate pump, a permeate pump, and a flow redirecting valve. Timing / sequencing of starting and stopping devices can minimize negative impact on cell culture. Timing / sequencing can include ramp up / down profile of pumps’ pumping delivery, speed of cell culture flow direction change, and volume of pass through the valve at the time of flow direction change.

[0010] A fluid filtration system is disclosed, and can include a fluid storage vessel, a filter housing including a filter element disposed therein, the filter housing having first and second ends, a pump coupled between the fluid storage vessel and the first and secondends of the filter housing for moving fluid from the fluid storage vessel through the filter housing, a valve disposed between the pump and the filter housing, the valve configured to selectively direct fluid received from the pump to the first or second end of the filter housing, and a controller programmed to execute instructions for controlling the pump and the valve to selectively transition the system between first and second modes of operation. In the first mode of operation the fluid travels 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 travels from the second end of the filter housing to the first end of the filter housing, The controller is further programmed to execute instructions to achieve a predetermined stroke profile during each of the first and second modes of operation.

[0011] In some embodiments the predetermined stroke profile has a sinusoidal shape. In some embodiments the predetermined stroke profile has a trapezoidal shape. In some embodiments the stroke profile includes first and second parabolic portions and a central linear portion. In some embodiments the stroke profile includes a flow direction change portion in which no flow occurs between the pump and the filter housing. In some embodiments the pump comprises first and second pumps. In some non-limiting example embodiments the valve is a rotary valve.

[0012] In some embodiments the system includes a first pressure sensor disposed in the filter permeate line to measure filter condition, a second pressure sensor disposed adjacent the first end of the filter housing for sensing a pressure of the fluid entering and exiting the first end of the filter housing, and a third pressure sensor disposed adjacent the second end of the filter housing for sensing a pressure of the fluid entering and exiting thesecond end of the filter housing. Use of additional pressure sensors may be considered one of which may be connected to the output from the retentate pump.

[0013] In some embodiments the system includes a permeate pump coupled to the filter housing for removing permeate from the filter housing, wherein the permeate pump is coupled to the controller, the controller programmed to execute instructions for reducing or stopping flow through the permeate pump at or near an end of a first stroke and for increasing or beginning flow through the permeate pump at or near a beginning of a second stroke.

[0014] In some embodiments the controller is programmed to execute instructions for cycling the valve between the first and second modes of operation during a period between the end of the first stroke and the beginning of the second stroke.

[0015] A method of operating a fluid filtration system is disclosed. The method can include: controlling a pump to move a fluid between a fluid storage vessel and a filter housing, controlling a valve disposed downstream of the pump to selectively direct the fluid from the pump to either a first end or a second end of the filter housing, the valve further configured to direct the fluid received from the filter housing to the fluid storage vessel via a fluid return line, controlling the valve to selectively transition the system between first and second modes of operation, wherein in the first mode of operation the fluid travels 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 travels from the second end of the filter housing to the first end of the filter housing, and controlling the pump to achieve a predetermined stroke profile during each of the first and second modes of operation.

[0016] In some embodiments the predetermined stroke profile has a sinusoidal shape. In some embodiments the predetermined stroke profile has a trapezoidal shape. In some embodiments the predetermined stroke profile includes first and second parabolic portions and a central linear portion. In some embodiments the stroke profile includes a flow direction change portion in which no flow occurs between the pump and the filter housing.

[0017] In some embodiments the step of controlling the pump comprises controlling first and second pumps such that each discharges the fluid at a flow rate that is half of a total system flowrate. In some embodiments the valve is a rotary valve.

[0018] In some embodiments the method also includes monitoring a pump discharge pressure, monitoring a pressure of the fluid entering and exiting the first end of the filter housing, and monitoring a pressure of the fluid entering and exiting the second end of the filter housing; and using said moni tored pressures to control a speed of the pump.

[0019] In some embodiments the method also includes controlling a permeate pump coupled to the filter housing to remove permeate from the filter housing, said controlling a permeate pump including reducing or stopping flow through the permeate pump at or near an end of a first stroke and for increasing or beginning flow through the permeate pump at or near a beginning of a second stroke.

[0020] In some embodiments the method also includes cycling the valve between the first and second modes of operation during a period between the end of the first stroke and the beginning of the second stroke.Brief Description of the Drawings

[0021] The accompanying drawings illustrate preferred embodiments of the disclosed method so far devised for the practical application of the principles thereof, and in which:

[0022] FIG. 1 is a schematic view of an example pump and filter system according to the present disclosure operating in a first flow mode.

[0023] FIG. 2 is a schematic view of the example pump and filter system of FIG. 1 operating in a second flow mode.

[0024] FIG. 3 is a schematic view of another example pump and filter system according to the present disclosure.

[0025] FIG. 4 i s a schematic view of a further example pump and fil ter system according to the present disclosure.

[0026] FIG. 5 is a graphical view of an example flow run curve obtained using one or more of the pump and filter systems of FI GS. 1~4.

[0027] FIGS. 6-8 are graphical views of example run flow curves obtaining using one or more of the pump and filter systems of FIGS. 1-4.

[0028] FIG. 9 is a graphical view of a system trend before deployment of sequencing steps according to the present disclosure.

[0029] FIG. 10 is a graphical view of a system trend after deployment of sequencing steps according to the present disclosure.

[0030] FIG. 11 is a schematic of a control system for use with the systems ofFIGS. 1-4.Description of Embodiments

[0031] A system is disclosed, comprising a bioreactor, a pump and a filter. The pump moves fluid in alternating directions through the filter via associated piping and a flow diverter such as, but not limited to, a rotaiy valve, a three-way valve, a pinch valve, or a shuttle valve. The system can be employed for conducting a rapid, low sheer, Alternating Tangential Flow (ATF) of fluid through the filter, which in some embodiments is a hollow fiber filter. Such a system has applications in perfusion of cultured animal cells as well as other varied filtration applications.

[0032] As will be discussed in greater detail later, the disclosed assembly can reduce the amount of time cell cultures reside outside the bioreactor and can also provide a more uniform use of the filter as well as reduced fouling, compared to current systems. In some embodiments, operational control of the pump and valve can be based on an algorithm which causes relatively gentle transitions between flow directions in order to minimize the impact on the cell cultures entrained in the flow. These and other advantage will be discussed below.

[0033] FIGS. 1 and 2 illustrate an example system 1 which can include a fluid storage vessel 2 (referred to herein as “vessel”) coupled to a pump 4 and a filter housing 6. The pump 4 is arranged to take suction from the vessel 2 via a suction line 8 disposed at or near the bottom of the vessel 2. The pump 4 is coupled to a discharge line 10, which in turn is coupled to a first port 12 of a flow diverter, which in the illustrated embodiment is avalve 21. In some embodiments a flowmeter 36 may be disposed in the discharge line 10 between the pump 4 and the valve 21. A second port 16 of the valve 21 is coupled to a first filtration line 18, which in tarn is coupled to a first end 20 of the filter housing 6. A third port 22 of the valve 21 is coupled to a second fil tration line 24 which is coupled to a second end 26 of the filter housing 6. A fourth port 25 of the valve 21 is coupled to a return line 28 which is coupled to the vessel 2. As will be appreciated, the valve 21 can be operated to selectively fluidly connect the ports 12, 16, 22, and 25 so that flow of system fluid can be selectively directed -from the pump 4 to either the first or second end 20, 26 of the filter housing, thereby achieving ATF in the manner previously mentioned.

[0034] To effect flow through the filter housing 6 (and filter) in the direction of arrow' “A” (i.e., the first mode of operation, illustrated in FIG. 1, in which the system 1 is configured to direct flow from the vessel 2 to the first end 20 of the filter housing 6 via first filtration line 18), the valve 21 is operated to fluidly connect the first and second ports 12, 16 to thereby direct flow from the pump discharge 10 to the first filtration line 18. In this position (shown in FIG. 1), the valve 21 also fluidly connects the third and fourth ports 22, 25 so that flow from the second filtration line 24 is directed to the return line 28 and then to the vessel 2. Thus configured, fluid flows from the vessel 2, through the pump 4, through the val ve 21 , then through the first filtration fine 18 where it enters the first end 20 of the filter housing 6. Fluid travels through the filter housing 6 in the direction of arrow “A” and exits the second end 26 of the filter housing. Fluid is filtered w'ithin the filter housing 6 and a portion of the fluid (e.g., permeate) can be evacuated from the filter housing 6 via permeate discharge line 38 and permeate pump 39. The remaining portion of fluid (e.g.,retentate) is returned to the vessel 2 via the second filtration line 24, valve 21, and return line 28.

[0035] To effect flow through the filter housing 6 (and filter) in the direction of arrow “B” (i.e., the second mode of operation, shown in FIG. 2, in which the system 1 is configured to direct flow from the vessel 2 to the second end 26 of the filter housing 6 via second filtration line 24), the valve 21 is positioned to fluidly connect the first port 12 to the third port 22 to direct flow from the pump discharge 10 to the second filtration line 24. In this configuration, the valve 21 also fluidly connects the second port 16 to the fourth port 25 to direct flow from the first filtration line 18 to the return line 28. Thus configured, fluid flows from the vessel 2, through the pump 4, through the valve 21, then through the second filtration line 24 where it enters the second end 26 of the filter housing 6. Fluid travels through the filter housing 6 in the direction of arrow “B” and exits the first end 20 of the filter housing. Fluid is filtered within the filter housing 6 and a portion of the fluid (e.g., permeate) can be evacuated from the filter housing 6 via permeate discharge line 38 and permeate pump 39. The remaining portion of fluid (e.g., retentate) is returned to the vessel 2 via the first filtration line 18, valve 21, and first return line 28.

[0036] FIG. 3 illustrates an example placement of pressure sensors for monitoring pressure trends in the system of FIGS. 1 and 2. Thus, a first pressure sensor 40 is disposed in the discharge line 10 of the pump 4, while second and third pressure sensors 42, 44 are disposed in the first and second filtration lines 18, 24 adjacent the first and second ends 20, 26, respectively, of the filter housing 6. The presented system illustrates a Universal Perfusion Platform capable of running in two basic perfusion modes (although other modesare also possible.) Historically, ATF mode does not include pressure sensors on the filter ends, rather, tangential flow filtration (TFF) does. The pressure sensors in TFF mode measure trans-membrane pressure (TMP) of the filter. In ATF mode, the pressure sensors provide monitoring information. In TFF mode, the pressure sensors provide process control information to the controller 50 (FIG. 11) for use in controlling system operation.

[0037] FIG. 4 illustrates an arrangement in which two pumps 4A, 4B are used for circulating fluid (i.e., retentate) between the vessel 2 and the filter housing 6. Retentate cell culture pumping can be enhanced during high volume pumping conditions by deploying two parallel retentate pumps. As will be appreciated, cell culture is sensitive to high pump speeds, so the use of two pumps reduces the pumping demand for each pump by half Operation of the first and second pumps 4A, 4B can be continuous, synchronized, according to a timed schedule, and / or manually switched by a user. In a first mode of operation, the first and second pumps 4 A, 4B are the same and a flow setpoint of both pumps is the same. The first and second pumps 4A, 4B are arranged for flow to occur in the same direction (i.e., drawing suction from the vessel 2 and discharging toward the filter housing 6).

[0038] The two-pump arrangement can also be used with a setup in which one pump is a primary pump and the second pump is a backup pump in case the primary pump fails. The first and second pumps 4A, 4B can be electronically connected. The electronic connection in general allows for several different modes of operation. In one mode, where a flow drop of the primary7pump is experienced, the backup pump can start pumping, In another mode, where one pump cannot deliver a required volume, die backup pump canprovide the additional required flow. In yet another mode, both pumps can be ran simultaneously at equal volume to lower the need for volume delivery of each pump individually.

[0039] With the disclosed system 1 , a single pump 4 can be used to continuously pump cell culture from the vessel 2 (bioreactor) based on a user-defined flow rate. The cell culture flows through the filter housing 6 and filter element in a single direction (First mode “A” or Second mode “B”) or selectively in two opposing directions (First Mode “A” and Second Mode “B”) based on a selected operation mode.

[0040] The time of flow in one direction (which may be referred to as “flow stroke”) is the time when a single particulate (cell) travels from the vessel 2 (e.g., bioreactor) through the entire loop of piping (tubing), through the filter 6, and returns to the vessel. This time depends on the flow rate set by the pump(s) 4.

[0041] A controller 50 (FIG. 11) can be used to control the speed of the pump 4 and the posi tion of the valve 21 to affect a desired flow stroke and flow direction through the filter 6. An algorithm performed by the controller 50 can calculate the time required for the cells to make the complete loop. The same time is than applied to flow of cells the opposite direction. When the pump 4 is set to run at a low flowrate, it will take relatively longer for the cells to make a complete loop in one direction, while setting the pump to run at a higher flowrate will result in a shorter time for the cells to make a complete loop in one direction. The disclosed alternating flow arrangement (i.e., flow through the loop in a first direction follow by flow through the loop in a second, opposite, direction), can be effective in preventing premature filter clogging. Flow through the permeate discharge line 38 canbe adjusted by adjusting the speed of the associated permeate pump (not shown) and may be based on the flow rate of a retentate pump (not shown). Retentate and permeate pump flow rate can be periodically increased for a short time period to further help with the cleaning of the filter and to increase its life.

[0042] FIG. 5 illustrates the steps in an example flow redirection sequence according to the present disclosure. As will be appreciated the sequence of steps can occur automatically without interaction from the user, under command from the controller 50 (FIG. 11). The controller 50 can command the steps for each flow re-direction.

[0043] As mentioned, “flow stroke” refers to die time it takes the cell culture to be removed from the vessel 2, passed through the filter housing 6, and then returned to the vessel 2. In ATF arrangements two flow strokes constitute a “cycle.” As shown in FIG. 5, and FIG. 11, just before a stroke ends (i.e., “prior stroke”), at sequence step 100 the controller 50 commands the permeate pump 39 to slow down or stop. At sequence step 110, while the permeate pump is slowing down or stopped, the controller 50 commands the retentate pump (i.e., pump 4) to slow down or stop. In some embodiments the pump 4 may must remain energized while slowing / stopped. At sequence step 120, while the pump 4 slows down / stops, the controller 50 commands the valve 21 to change the flow direction at an adjustable speed of transition (i.e., from the first mode of operation to the second mode of operation, or vice versa). At sequence step 130, the controller 50 commands the pump 4 to increase speed (RPM) until a commanded flowrate is reached. At sequence step 140, when the pump achieves the commanded flow rate, the controller 50 commands the permeate pump 39 to increase flow, and the next flow stroke starts.

[0044] FIG. 6 illustrates an example retentate pump sinusoidal pumping profile obtained with the system 1 operating in ATF mode. The sinusoidal profile shows a gentle increase / decrease in flow rate during each flow stroke. As can be seen, the flow strokes are interrupted for a minimal time period during the transition from one flow direction to the next. All of the associated steps are achieved through appropriate command of the pump 4 and valve 21 by the controller 50.

[0045] FIG. 7 illustrates an example retentate pump trapezoidal pumping profile obtained with the system 1 operating in ATF mode. The trapezoidal profile shows a linear increase / decrease in flow rate at the beginning and end of each flow stroke, and a constant flow rate in the central portion of the flow stroke. The slope of the flow profile at the beginning and end of each flow stroke can be adjusted to any appropriate value to achieve a desired rate of flow increase / decrease. In addition, the slope of the flow increase can be different from the slope of the flow decrease. As can be seen, the flow strokes are interrupted for a minimal time period during the transition from one flow direction to the next. All of the associated steps are achieved through appropriate command of the pump 4 and valve 21 by the controller 50.

[0046] FIG. 8 illustrates an example retentate pump trapezoidal pumping profile obtained with the system 1 operating in a soft zero flow ATF mode. The profile of this embodiment shows a parabolic increase / decrease in flow rate at the beginning and end of each flow stroke, and a constant flow rate in the central portion of the flow stroke. The shape of the parabola at the beginning and end of each flow stroke can be adjusted to any appropriate value to achieve a desired rate of flow increase / decrease. In addition, the shapeof the parabola during the flow increase can be different from the shape of the parabola during the flow decrease. As can be seen, the flow strokes are interrupted for a minimal time period during the transition from one flow direction to the next. All of the associated steps are achieved through appropriate command of the pump 4 and valve 21 by the controller 50.

[0047] FIG. 9 illustrates system trend profiles without the sequencing steps according to the present disclosure. As can be seen, flow reversals (i.e., transitioning from the first mode of operation to the second mode of operation, or vice versa) are substantially square shaped which represent abrupt changes in flow direction that can adversely impact cell cultures.

[0048] By comparison, FIG. 10 illustrates system trend profiles when the sequencing steps according to the present disclosure are implemented. As can be seen, the instantaneous flow and pressure peaks evident in FIG. 9 are minimized or eliminated. As will be appreciated, cell culture is sensitive to pressure changes, and thus reduction or complete elimination of pressure changes is critical. The action sequencing as described in relation to FIG. 5 provides even pressure characteristics.

[0049] Referring now to FIG. 11, the pump 4, permeate pump 39, valve 21, and pressure sensors 40, 42, 44 can be controlled by the controller 50 to enable the system 1 to be operated in a variety of sequences and manners. The controller 50 may include a processor or microprocessor configured to run an operating system, an application-specific integrated circuit (ASIC), a field-programmable gate array (FPGA), etc., or combinations thereof. The controller may include memory 52 which 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 program instructions. The memory may include a memory chip, Electrically Erasable Programmable Read-Only Memory (EEPROM), erasable programmable read only memory (EPROM), flash memory', or any other suitable memory from which the controller can read instructions. The instructions may include code from any suitable programming language.

[0050] In some embodiments, the processor of the controller 50 may execute instructions (e.g., a subroutine) to actuate the valve 21 to reconfigure the system between the first and second operating modes. As will be appreciated, the controller 50 may also control the speed of the pump(s) 4, 39 to adjust flow through the system. In some embodiments the controller 50 adjusts the speed(s) of the pumps 4, 39 to achieve the flow profiles described in relation to FIGS. 6-8. A variety of set points and operating positions can be stored in controller memory 52 and executed by the processing portion of the controller 68 upon user command or automatically.

[0051] As previously mentioned, the controller 50 can include a processor and associated memory 52 for storing information regarding the pumps 4, 39, the valve 21, the filter element and / or other aspects of the system. The memory can include instructions executable by the processor for controlling operation of the pumps 4, 39 and the valve 21 to thereby control flow of fluid between the vessel 2 and the filter housing 6 and filter element, and to ensure concurrent flow of retentate and recirculated permeate in any of a variety of desired manners. The controller 50 can also include a user interface for allowing a user to input information into the controller and / or operate the system in a desiredmanner. Controller 50 can be connected to a network with a full SCADA and visualization platform.

[0052] In various embodiments, a user interface is provided where users of the disclosed systems can input and / or monitor various facets of the system and operation of associated pumps and valves. For example, the user interface may be programmed to display one or more graphical outputs of data, received and analyzed by controller 50. The user interface may also display other data stored in the memory of controller 50, including type and size of filter, flow direction mode, permeate pump mode (normal, cleaning), TFF mode, ATF mode, system flow, system pressure, and system status (running, off). Further still, additional parameters that may be displayed to the user at the user interface include a flow rate and a cycle time for one or more process steps.

[0053] Further still, the user interface of certain exemplary embodiments permits the user to control starting or stopping of a control process carried out by the controller 50.In some embodiments, starting and stopping functions may be controlled via. buttons provided on a touch-screen display, for example. The user interface also allows for input(entry) of specified control parameters.

[0054] As will be appreciated by one of ordinary skill in the art, the filter housing6 encloses a filter element (not shown), which in one non-limiting exemplary embodiment is a hollow fiber filter, although this is not critical and any of a variety of other filter elements can be used. The filter housing 6 can be made from plastic, metal, such as stainless steel, glass, and the like. 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, or1 , 2, 3, or 4 microns, or about 500 to 1000 kD, e.g., 550, 600, 650, 700, 750, 800, 850, 900, or 950 kD.

[0055] To minimize the negative impact of pumping on the cells within the pumped fluid, a specialized pump type is desirable. In the illustrated embodiments the pumps 4, 39 are appropriate low-shear pump types, examples of which include Levitronix pumps (www.levitronix.com), and Quattrofiow pumps manufactured by Holland Applied Technologies (www.hollandapt.com). Peristaltic pumps can be used for non-cell culture applications. Permeate pumps can be peristaltic pumps.

[0056] The vessel 2 may be any suitable container for housing a fluid to be filtered. For example, the fluid vessel may be a bioreactor, a fermentor or any other vessel, nonexclusively including vats, barrels, tanks, botles, flasks, containers, and the like which can contain liquids. The vessel may be composed of any suitable material such as plastic, metal such as stainless steel, glass, or the like.

[0057] Tn some embodiments the filter element is a hollow fiber filter. In some embodiments the fluid storage vessel is a bioreactor. In some embodiments the fluid comprises cell cultures.

[0058] The disclosed systems and methods have applications in perfusion of cultured animal cells as well as other varied filtration applications. Cultured animal cells can mean mammalian cells suspended in a liquid culture medium. Cultured animal cells can have a cell density of greater than about 0.1 x 106cells / mL (e.g., greater than about 1 x 106cells / mL, greater than about 5x106cells / mL, greater than about 1 Ox 106cells / mL, greater than about 15x10scells / mL, greater than about 20x106cells / mL, greater than about25xl06cells / mL, greater than about 30*10&cells / mL, greater than about 35xl()6cells / mL, greater than about 40x106cells / mL, greater than about 45 x 106cells / mL, greater than about 50^106cells / mL, greater than about 55xl06cells / mL, greater than about 60x106cells / mL, greater than about 65xl06cells / mL, greater than about 70x106cells / mL, greater than about 75xl06cells / mL, greater than about 80x I (}6celis / mL, greater than about 85x106 cells / mL, greater than about 90x10scells / mL, greater than about 95xl06cells / mL, or greater than 100x10scells / mL).

[0059] While the present invention has been disclosed with reference to certain embodiments, numerous modifications, alterations and changes to the described embodiments are possible without departing from the spirit and scope of the invention, as defined in the appended claims. Accordingly, it is intended that the present invention not be limited to the described embodiments, but that it has the fall scope defined by the language of the following claims, and equivalents thereof.

Claims

CLAIMSWhat is claimed is1. A fluid filtration system, comprising: a fluid storage vessel; a filter housing including a filter element disposed therein, the filter housing having first and second ends; a pump coupled between the fluid storage vessel and the first and second ends of the filter housing for moving fluid from the fluid storage vessel through the filter housing; a valve disposed between the pump and the filter housing, the valve configured to selectively direct fluid received from the pump to the first or second end of the filter housing: a controller programmed to execute instructions for controlling the pump and the valve to selectively transition the system between first and second modes of operation, wherein in the first mode of operation the fluid travels 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 travels from the second end of the filter housing to the first end of the filter housing; wherein the controller is further programmed to execute instructions to achieve a predetermined stroke profile during each of the first and second modes of operation.

2. The fluid filtration system of claim 1, wherein the predetermined stroke profile has a sinusoidal shape.

3. The fluid filtration system of claim 1, wherein the predetermined stroke profile has a trapezoidal shape.

4. The fluid filtration system of claim 1, wherein the stroke profile includes first and second parabolic portions and a cental linear portion.

5. The fluid filtration system of claim 1, wherein the stroke profile includes a flow direction change portion in which no flow occurs between the pump and the filter housing.

6. The fluid filtration system of claim 1, wherein the pump comprises first and second pumps.

7. The fluid filtration system of claim 1, wherein the valve is a rotary valve.

8. The fluid filtration assembly of claim 1, further comprising a first pressure sensor disposed in a filter permeate line coupled to the filter housing, the first pressure sensor operable to determine a filter condition, a second pressure sensor disposed adjacent the first end of the filter housing for sensing a pressure of the fluid entering and exiting the first end of the filter housing, and a third pressure sensor disposed adjacent the second end of the filter housing for sensing a pressure of the fluid entering and exiting the second end of the filter housing.

9. The fluid filtration system of claim 1, further comprising a permeate pump coupled to the filter housing for removing permeate from the filter housing, wherein the permeate pump is coupled to the controller, the controller programmed to execute instructions for reducing or stopping flow through the permeate pump at or near an end ofa first stroke and for increasing or beginning flow through the permeate pump at or near a beginning of a second stroke.

10. The fluid filtration system of claim 1, wherein the controller is programmed to execute instructions for cycling the valve between the first and second modes of operation during a period between the end of the first stroke and the beginning of the second stroke.

11. A method of operating a fluid filtration system, the method comprising: controlling a pump to move a fluid between a fluid storage vessel and a filter housing; controlling a valve disposed downstream of the pump to selectively direct the fluid from the pump to either a first end or a second end of the filter housing, the valve further configured to direct the fluid received from the filter housing to the fluid storage vessel via a fluid return line; controlling the valve to selectively transition the system between first and second modes of operation, wherein in the first mode of operation the fluid travels 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 travels from the second end of the filter housing to the first end of the filter housing: and controlling the pump to achieve a predetermined stroke profile during each of the first and second modes of operation.

12. The method of claim 11 , wherein the predetermined stroke profile has a sinusoidal shape.

13. The method of claim 11 , wherein the predetermined stroke profile has a trapezoidal shape.

14. The method of claim 11, wherein the predetermined stroke profile includes first and second parabolic portions and a central linear portion.

15. The method of claim 11 , wherein the stroke profile includes a flow direction change portion in which no flow occurs between the pump and the filter housing.

16. The method of claim 11 , wherein the step of controlling the pump comprises controlling first and second pumps such that each discharges the fluid at a flow rate that is half of a total system flowrate.

17. The method of claim 11, wherein the valve is a rotary valve.

18. The method of claim 11 , further comprising monitoring a pump discharge pressure, monitoring a pressure of the fluid entering and exiting the first end of the filter housing, and monitoring a pressure of the fluid entering and exiting the second end of the filter housing; and using said monitored pressures to control a speed of the pump.

19. The method of claim 11, further comprising controlling a permeate pump coupled to the filter housing to remove permeate from the filter housing, said controlling a permeate pump including reducing or stopping flow through the permeate pump at ornear an end of a first stroke and for increasing or beginning flow through the permeate pump at or near a beginning of a second stroke.

20. The method of claim 19, farther comprising cycling the valve between the first and second modes of operation during a period between the end of the first stroke and the beginning of the second stroke.

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