Tangential flow filter with combined permeate output and filtration method - Patent Application 20070122997

Abstract

The tangential flow filter includes first and second end caps, one of which has a feed inlet, a retentate outlet, and a permeate outlet, with one or more pairs of plates between the end caps. Each plate has a respective membrane bonded to its respective surface. A first series of openings is formed through the first plate; a second series of openings is formed through the second plate; a third series of openings is formed through the first plate; and a fourth series of openings is formed through the second plate, fluidly communicating with the third series of openings. The third and fourth series of openings are located in respective permeate channels in regions of one side of the first plate and one side of the second plate that are free of filtration media. The permeate channels are fluidly connected to the permeate outlet.

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Application No. 63 / 436,781, filed January 3, 2023, the disclosure of which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION Embodiments of the presently disclosed technology relate to filters and filtration systems useful in bioprocessing. [Background technology]

[0003] Membrane filtration is a separation technique used in bench-scale and process-scale purification of biological materials. There are various types of membranes used for filtration, classified as microfiltration or ultrafiltration membranes based on their pore size. Microfiltration membranes generally have pore sizes ranging from 0.1 microns (μm) to 10 μm. Ultrafiltration membranes have smaller pore sizes, typically ranging from 0.001 to 0.1 μm. Due to the different pore sizes, these membranes are used for different purposes. For example, microfiltration membranes are commonly used for purification, sterilization, and particulate removal, or for cell harvesting. Ultrafiltration membranes are commonly used for the fractionation or concentration of molecules (e.g., proteins, peptides, nucleic acids, carbohydrates, and other biological materials). Ultrafiltration membranes are generally classified by molecular weight cutoff, e.g., kilodaltons (kDa), rather than pore size.

[0004] There are two main types of filtration modes or processes used with microfiltration and ultrafiltration membranes. The first filtration mode is called normal flow filtration (NFF) mode, also known as "dead-end" filtration, in which the feed stream is generally applied perpendicular to the membrane plane, attempting to force 100% of the fluid through the membrane. The second filtration mode is called tangential flow filtration (TFF), in which the feed stream is parallel to the membrane plane, with a portion passing through the membrane (i.e., permeate) and the remainder being retained and may be recycled back to the feed reservoir (i.e., retentate).

[0005] Tangential flow filtration (TFF) devices, also known as crossflow filtration devices, have one feed inlet, one retentate outlet, and at least one permeate outlet. Tangential flow refers to a filtration configuration in which the flowing fluid flows along the surface of the filter medium, substantially parallel (tangential) to the surface of the filter medium. In this configuration, solutes are adsorbed or absorbed onto the membrane surface or pores as the eluent flows over the membrane surface. The purified portion of the fluid passing through such a filter medium has a "lateral" velocity component, i.e., perpendicular to the direction of the fluid flow along the surface of such a filter medium. In TFF, the retentate (or decantation) can be repeatedly recycled to improve filtration efficiency and permeate yield. The recycled retentate solution path runs parallel to the membrane surface and is pumped through the membrane at sufficient velocity to ensure surface cleaning. However, because the amount of permeate collected in each retentate volume pass is relatively small, significant processing time is typically associated with the TFF procedure. If an appropriate membrane is selected for a particular separation, a second liquid can be used to elute and collect the material adsorbed or absorbed onto the membrane.

[0006] Cross-flow or tangential flow filtration is a well-known filtration process, see for example U.S. Patent Nos. 5,681,464, 6,461,513, 6,331,253, 6,475,071, 5,783,085, and 4,790,942, the disclosures of which are incorporated herein by reference.

[0007] TFF filtration is often suitable for the purification of certain types of biological materials, such as biological materials with a size of 500 kDa or greater, where TFF is used for concentration and impurity removal. Most TFF processes use ultrafiltration membranes for concentration and buffer exchange steps. One example of an ultrafiltration membrane used in TFF mode for the production of certain biological materials (e.g., proteins, vaccines, and virus-like particles) is a solution-cast ultrafiltration membrane made of polyethersulfone (PES).

[0008] Tangential flow filtration (TFF) is a separation process that uses membranes to separate components in a liquid solution or suspension based on size, molecular weight, or other differences. TFF is used in perfusion processes to remove target proteins from cell culture media while retaining the cells within the media. In the TFF process, fluid is pumped tangentially along the membrane surface, rejecting particles, molecules, or cells too large to pass through the membrane and returning them to the process tank. The TFF process can involve passing the fluid through additional membranes (e.g., recirculating) until the process fluid is sufficiently clarified, concentrated, or purified. The cross-flow characteristics of TFF minimize membrane fouling, thereby enabling the processing of large volumes per batch. The membrane is contained within a filter element, which can be in a variety of configurations, such as spiral-wound filter elements and cassette filter elements.

[0009] Monoclonal antibodies (mAbs) are used as therapeutic agents for a variety of conditions, including cancer, transplant rejection, and cardiovascular disease. Various biopharmaceutical manufacturing techniques exist for producing and harvesting mAbs from host cells, including fed-batch and perfusion processes. In fed-batch bioreactor systems, cells are cultured in batches for a period of time, e.g., about 7 to about 21 days, after which nutrients in the culture medium are consumed by the host cells and waste products accumulate. After the cell culture period, the batch undergoes a harvesting process, in which the protein of interest (e.g., a product such as a monoclonal antibody, or mAb) is separated from the cell mass. In contrast to fed-batch systems, perfusion bioreactors culture cells for extended periods of time, e.g., weeks or months, while continuously supplying cells with fresh medium, removing spent medium, and harvesting the product. Perfusion systems offer several advantages over fed-batch systems. For example, perfusion systems reduce product degradation because the product is continuously harvested and purified before the protein of interest is exposed to high levels of waste. Furthermore, perfusion bioreactors can produce product yields comparable to fed-batch bioreactors while occupying a much smaller space. Perfusion has become a preferred manufacturing technology in the biopharmaceutical industry due to its advantages over batch-fed processes. However, perfusion processes rely on high host cell densities maintained throughout each manufacturing run and continuous harvesting, which involves multiple filtration cycles and can cause physical damage to the host cells.

[0010] A conventional TFF device may consist of multiple elements, including a pump, a feed solution reservoir, a filtration module, and conduits connecting these elements. In use, a feed solution is directed from the feed solution reservoir to the filtration module, while the retentate from the filtration module is recirculated from the filtration module to the feed solution reservoir until a desired amount of retentate is obtained. The membrane is sandwiched between upper and lower manifolds or holders, which serve to provide precise mechanical constraints against the internal hydraulic pressure of the device and to distribute the filtrate flow among multiple flow paths within the device.

[0011] Prior art tangential flow filter devices combine permeate outputs external to the filter housing or module. Also, prior art tangential flow filter devices do not provide multiple internal permeate flow paths. A tangential flow filter with filtration media on each end cap and on both sides of any plate in the filter stack, where the permeate flows of each end cap and plate are cooperative within the filter, allowing for a single permeate output from the filter, represents an advancement in the art. Summary of the Invention

[0012] In some embodiments, a tangential flow filter housing or module for filtering fluids comprises first and second end caps, the first end cap having a fluid feed inlet, a retentate outlet, and a permeate outlet; at least first and second plates, each plate having a first face and an opposite second face, the first face of the first plate facing the first end cap and having a first effective filtration area, and the second face of the first plate facing the first face of the second plate and having a second effective filtration area smaller than the first effective filtration area; filtration media between the first end cap and the first plate, between the first plate and the second plate, and between the second plate and the second end cap; a first series of spaced apart openings extending through the first plate; and a second series of spaced apart openings extending through the second plate and connecting to the first plate. A tangential flow filter housing or module for filtering a fluid is disclosed, comprising: a second series of spaced openings aligned with or in fluid communication with a first series of spaced openings in the first plate; a third series of spaced openings extending through the first plate and spaced apart from the first series of spaced openings; a fourth series of openings extending through the second plate and aligned with or in fluid communication with the third series of openings in the first plate; wherein the third and fourth series of spaced openings are located in respective permeate channels in regions of the second face of the first plate and the first face of the second plate that are free of filtration media, the regions being opposite the filtration media on the first face of the first plate and the second face of the second plate; and the permeate channels are in fluid communication with a permeate outlet. In some embodiments, the second effective filtration area may be the same as or greater than the first effective filtration area. In some embodiments, the membrane (and / or screen) on one side of the plate may extend a greater distance laterally (i.e., along the short axis of the device) than the membrane and / or screen on the opposite side to accommodate the permeate flow channels.

[0013] In some embodiments, the openings in the first series of spaced apart openings are aligned with one another, and in some embodiments, the openings in the third series of spaced apart openings are aligned with one another.

[0014] In some embodiments, the filtration media between the first end cap and the first plate includes a first membrane attached to the end cap and a second membrane attached to a first surface of the first plate, and in some embodiments, a screen may be between the first and second membranes.

[0015] In some embodiments, the fluid passing through the second membrane flows through a third series of spaced openings and enters a permeate channel. In some embodiments, the fluid passing through the first membrane enters a permeate outlet.

[0016] In some embodiments, the filtration media between the first plate and the second plate comprises a third membrane attached to the second face of the first plate and a fourth membrane attached to the first face of the second plate. In some embodiments, fluid passing through the third and fourth membranes enters the respective first and second series of spaced apart openings and flows to the third and fourth series of spaced apart openings.

[0017] In some embodiments, there may be a stack of plates between the first end cap and the second end cap, so that rather than the second plate being attached to the second end cap, it is attached to a third plate, which is one of a pair of plates in the second stack of plates, the other of which is attached to the second end cap or a fifth plate that is one of yet another pair of plates, etc.

[0018] Certain embodiments relate to methods for filtering a fluid sample. In some embodiments, a method for filtering a fluid sample comprises: introducing a fluid sample into a feed inlet of a first end cap; (a) contacting a first membrane attached to a first end cap to form a first permeate stream and a first retentate stream, the first permeate stream flowing to a first permeate outlet of the first end cap or a second permeate outlet of a second end cap, and the first retentate stream flowing to a first retentate outlet of the first end cap or a second retentate outlet of said second end cap; (b) contacting a second membrane mounted on a first face of a first plate mounted on the first end cap to form a second permeate stream and a second retentate stream, the second permeate stream flowing into a first plurality of spaced apart permeate ports formed in the first plate in fluid communication with the permeate channels and said first or second permeate outlet, and the second retentate stream flowing into the first or second retentate outlet; (c) contacting a third membrane attached to a second surface of the first plate to form a third permeate stream and a third retentate stream, the third permeate stream flowing into a second plurality of spaced apart permeate ports formed in the first plate, the second permeate stream combining with the second permeate stream before entering said permeate channel and a first plurality of spaced apart permeate ports in fluid communication with said first or second permeate outlet, and the third retentate stream flowing into the first or second retentate outlet; (d) contacting a fourth membrane attached to a first surface of a second plate attached to the first plate to form a fourth permeate stream and a fourth retentate stream, wherein the fourth permeate stream flows into a third plurality of spaced apart permeate ports formed in the second plate and in fluid communication with said permeate channel and a fourth plurality of spaced apart ports in fluid communication with said first or second permeate outlet, and wherein said fourth retentate stream flows into said first or second retentate outlet; (e) contacting said fifth membrane attached to the second surface of a second plate to form a fifth permeate stream and a fifth retentate stream, wherein the fifth permeate stream flows into said fourth plurality of spaced apart permeate ports formed in the second plate in fluid communication with said permeate channels and said first or second permeate outlet, and wherein the fifth retentate stream flows into said first or second retentate outlet; and (f) contacting a sixth membrane attached to the second end cap to form a sixth permeate stream and a sixth retentate stream, the sixth permeate stream flowing into a permeate pipe, conduit, or the like, in fluid communication with said permeate channel and said first or second permeate outlet, and the sixth retentate stream flowing into said first or second retentate outlet; collecting a permeate stream from a permeate outlet; A method is disclosed, comprising:

[0019] For clarity, six retentate streams are defined above. Note, however, that the first and second streams are essentially the same stream because they each flow through the gap between the membranes on the first end cap and the first face of the first plate. Because neither passes through the membrane, they enter the device as feed at one end of the membrane, flow across it, and exit at the retentate outlet. They are separated from each other only by open screens, if present. The same is true for the third and fourth retentate streams and the fifth and sixth retentate streams. Thus, a device with a pair of plates has a total of six permeate streams passing through six membranes, but effectively only three retentate streams (see FIG. 7).

[0020] In some embodiments, the retentate stream may be collected from the retentate outlet, recycled to the feed inlet, or both.

[0021] Some embodiments of the present disclosure describe tangential flow filtration devices in which all permeate streams can combine within a filter device or housing, for example, within a defined area between two end caps. Some embodiments of the present disclosure describe devices in which all permeate streams exit through a single location. Some embodiments of the present disclosure describe devices in which all permeate streams can combine within the filter device and all permeate streams exit through a single location. Some embodiments of the present disclosure describe apparatus that reduces the need for external tubing, eliminating the risk of restricting flow in one permeate output tube, which would otherwise alter the flow pattern within the filter device. Some embodiments of the present disclosure describe devices in which there is an active membrane on each side of the end caps and plates that contact the fluid during operation of the device.

[0022] In some embodiments, the TFF device is used as part of a perfusion bioreactor, where the process medium flows through one or more TFF devices and enters via a feed input, the cells and process medium are returned via a retentate output to the bioreactor that feeds the TFF device, and the material produced by the cells, i.e., the biological product, is collected via a permeate output.

[0023] In a further embodiment, a perfusion system is disclosed that includes at least one filter element as described herein and a pump configured to control the flow of a liquid feed through the at least one filter element.

[0024] In yet another embodiment, a perfusion process is disclosed that includes passing a liquid feed through a feed channel of at least one filter element and separating the liquid feed into a permeate and a retentate within the filter element by tangential flow filtration (TFF). A filtration medium is provided that is capable of separating a liquid sample into a retentate stream and a permeate stream as said liquid sample enters the tangential flow filtration module through a feed inlet.

[0025] In another embodiment, a perfusion process for harvesting a target protein from a liquid feed containing host cells is disclosed. The process includes passing the liquid feed containing the target protein and host cells into a feed channel of at least one filter element and separating the target protein from the host cells within the at least one filter element. The target protein can be, for example, a monoclonal antibody, which can be separated from the host cells by TFF and recovered from the at least one filter element. The perfusion process further includes recovering the host cells from the at least one filter element, feeding the recovered host cells with a volume of fresh medium, and returning the recovered host cells to the bioreactor. The perfusion process can be performed continuously, where the host cells recovered in a first perfusion run are the liquid feed for subsequent perfusion runs. [Brief explanation of the drawings]

[0026] [Figure 1] FIG. 1 is a perspective view of a tangential flow filtration assembly according to some embodiments of the present disclosure. [Figure 2] FIG. 2 is a perspective view of the tangential flow filtration assembly of FIG. 1 with the outer housing removed according to some embodiments of the present disclosure. [Figure 3A] FIG. 3 is a front view of the tangential flow filtration assembly of FIG. 2 according to some embodiments of the present disclosure. [Figure 3B] FIG. 3 is a top view of the tangential flow filtration assembly of FIG. 2 according to some embodiments of the present disclosure. [Figure 3C] FIG. 3 is a bottom view of the tangential flow filtration assembly of FIG. 2 according to some embodiments of the present disclosure. [Figure 3D] FIG. 3 is a first side view of the tangential flow filtration assembly of FIG. 2 according to some embodiments of the present disclosure. [Figure 3E] FIG. 3 is a second side view of the tangential flow filtration assembly of FIG. 2 according to some embodiments of the present disclosure. [Figure 4] FIG. 3 is an exploded view of the tangential flow filtration assembly of FIG. 2 according to some embodiments of the present disclosure. [Figure 5A]FIG. 10 is a view of the underside of an end cap according to some embodiments of the present disclosure. [Figure 5B] FIG. 5B is a perspective view of the end cap of FIG. 5A with a membrane attached according to some embodiments. [Figure 5C] FIG. 5B is a side view of the end cap of FIG. 5A. [Figure 6A] FIG. 1B is a top view of a first surface or face of an inner plate according to some embodiments of the present disclosure. [Figure 6B] FIG. 10 is a top view of a second surface or face of the inner plate according to some embodiments of the present disclosure. [Figure 7] 1 is a cross-sectional view of a pair of inner plates sandwiched between two end caps according to some embodiments of the present disclosure. FIG. [Figure 8] FIG. 1 is a cross-sectional view of the permeate outlet and feed inlet of an end cap showing the permeate flow according to certain embodiments. [Figure 9A] FIG. 10 is a top view of an inner plate with a membrane according to certain embodiments. [Figure 9B] FIG. 9B is a cross-sectional view of a portion of the inner plate of FIG. 9A. [Figure 10] 1 is a cross-sectional view of a portion of a pair of inner plates sandwiched between two end caps according to some embodiments of the present disclosure. FIG. [Figure 11] FIG. 11 is a detailed view of a portion of FIG. 10 according to some embodiments of the present disclosure. [Figure 12A] FIG. 1 is a perspective view of a manifold assembly according to certain embodiments. [Figure 12B] FIG. 12B is a perspective view of the internal details of the manifold assembly of FIG. 12A. [Figure 12C] FIG. 12B is a perspective view of the internal details of the manifold assembly of FIG. 12A. [Figure 13] 12A and 12B are diagrams of end caps with attached straps according to certain embodiments. [Figure 14] 1 is a cross-sectional view of a portion of a pair of inner plates sandwiched between two end caps according to some embodiments of the present disclosure. FIG. [Figure 15A] FIG. 10 is a top view of an end cap according to certain embodiments. [Figure 15B] 15B is a side view of the end cap of FIG. 15A taken along line BG-BG of FIG. 15A. [Figure 15C] FIG. 15B is an enlarged view of detail AZ of FIG. 15A. [Figure 15D] FIG. 15C is an enlarged view of detail BB of FIG. 15B. [Figure 16A] FIG. 1B is a top view of a first surface or face of an inner plate according to some embodiments of the present disclosure. [Figure 16B] FIG. 16B is a top view of a second surface or face of the inner plate of FIG. 16A according to some embodiments of the present disclosure. [Figure 16C] FIG. 16C is a side view of the medial plate of FIG. 16B taken along line AP-AP. [Figure 16D] FIG. 16D is an enlarged view of detail AV of FIG. 16C. [Figure 16E] FIG. 16B is an enlarged view of detail AW of FIG. 16A. DETAILED DESCRIPTION OF THE INVENTION

[0027] In the following description, specific terminology is used for the sake of clarity, but these terms are intended to refer only to the specific structure of the embodiment selected for illustration in the drawings. In the drawings and the following description, like numerical designations will be understood to refer to components of like function.

[0028] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0029] As used herein, various devices and components may be described as "comprising" other elements. As used herein, the terms "comprise(s)," "include(s)," "having," "has," "can," "contain(s)," and variations thereof, are intended to be open-ended phrases, terms, or words that do not exclude the possibility of additional elements.

[0030] All ranges disclosed herein are inclusive of the recited endpoints and are independently combinable (e.g., the range "2% to 10" includes the endpoints 2% and 10%, and all intermediate values).

[0031] As used herein, approximation can be applied to modify expressions relating to any quantity that can vary without resulting in a change in the basic function to which it pertains. Thus, values ​​modified by one or more terms such as "about" or "substantially" may not be limited to the exact value specified in some cases. The modifier "about" should also be considered to disclose a range defined by the absolute values ​​of the two endpoints. For example, the expression "about 2 to about 4" also discloses a range of "2 to 4."

[0032] It should be noted that some of the terms used herein are relative terms. For example, the terms "upper" and "lower" are relative in position to one another, i.e., an upper component is located higher than a lower component, and should not be construed as requiring a particular orientation or position of a structure. As a further example, the terms "interior," "exterior," "inward," and "outward" are relative to the center and should not be construed as requiring a particular orientation or position of a structure.

[0033] The terms "top" and "bottom" are absolute references, i.e., relative to the surface of the Earth. In other words, a top location is always higher, toward the surface of the Earth, than a bottom location.

[0034] "TFF assembly," "TFF system," and "TFF apparatus" are used interchangeably herein and refer to a tangential flow filtration system configured to operate in a recirculation mode in which at least a portion of the retentate is returned to the system as feed.

[0035] "Feed line" or "feed channel" refers to a conduit for carrying feed from a feed source (eg, a feed vessel) to one or more processing units within a filtration assembly.

[0036] "Retentate line" or "retentate channel" refers to a conduit within a filtration assembly for carrying retentate.

[0037] "Permeate line" or "permeate channel" refers to a conduit within a filtration assembly for carrying permeate.

[0038] "Filtration membrane" or "membrane" refers to a selectively permeable membrane for separating a feed into a permeate stream and a retentate stream using an SPTFF or TFF process. Filtration membranes include, but are not limited to, ultrafiltration (UF) membranes, microfiltration (MF) membranes, reverse osmosis (RO) membranes, and nanofiltration (NF) membranes. The terms "ultrafiltration membrane" and "UF membrane" are used herein to refer to membranes having pore sizes ranging from about 1 nanometer to about 100 nanometers. The terms "microfiltration membrane" and "MF membrane" are used herein to refer to membranes having pore sizes ranging from about 0.1 micrometer to about 10 micrometers.

[0039] Flat plate or cassette devices contain or consist of membranes cast onto plates, where the plates are securely stacked. The device may or may not have flexible screens in the feed channels to support the membranes. An attractive advantage of such a configuration is a very compact design. However, channel height control, which is determined by the interaction and distance between the plates, requires very careful consideration. Straps can be used to help achieve consistent channel height control.

[0040] 1-4, according to some embodiments, a tangential flow filtration assembly or housing 10 includes two spaced-apart end caps 14A, 14B and one or more pairs of plates 16 disposed between the end caps 14A, 14B, each plate 16 having a first major surface and a second major surface. In some embodiments, each plate 16 is made of a fluid-impermeable material (e.g., polypropylene) and may include a filtration medium, such as a membrane 15 (e.g., a PVDF or PES membrane), disposed on each of the first and second major surfaces, e.g., by thermal bonding or the like. In certain embodiments, a turbulence-promoting screen 21 is juxtaposed to each membrane, such that every flow path includes a screen 21. Suitable screens 21 include those commercially available from EMD Millipore Corporation and commonly sold in PELLICON® 3 cassettes, such as an A screen (tight screen), a C screen (coarse screen), and a D screen (coarse screen for high viscosity). The screen also serves to prevent contact between adjacent membranes. For assembly, the screen may have openings in appropriate locations to receive alignment pins or similar features in the end caps and inner plates, while the membrane may have features such as rounded shoulders to help properly position the membrane near the pins while preventing membrane wrinkling. In certain embodiments, there may be two different screen shapes, just as there may be two different membrane shapes; one for the end caps and one side of the inner plates, and a different shape for the other side of the inner plates. For simplicity, the reference numbers assigned in FIG. 4 (15 for membrane, 21 for screen) do not reflect the different specific screen and membrane shapes. The plates 16 are generally assembled in pairs within the stack, for example, one pair of plates 16, two pairs of plates 16, three pairs of plates 16, or any suitable number of pairs of plates. As many as thirteen or more pairs of plates may be suitable for a device. Preferably, the plates 16 are identical in size. In some embodiments, the overall layout of the end caps and plates is similar or identical.For ease of manufacturing, the end caps 14A, 14B may all be identical and may include multiple ports 24, some of which may be unused and therefore blocked with appropriate plugs, such as permeate plugs 22, and associated seals, such as one or more O-rings 23. Operable ports 24 may be fitted with appropriate barb fittings 19 and O-rings 23, for example. Overcaps 8A, 8B (FIG. 1), such as rigid plastic plates, bonded around the device using fasteners 7, such as bolts, may also be used to help prevent the device from expanding when under operating pressure. In some embodiments, unused ports may be removed.

[0041] A feed of biological or other sample fluid enters TFF device 10 at feed input or inlet 17 and flows in a tangential flow mode across a filtration medium within the device or housing to retentate outlet 18. In some embodiments, the filtration medium is a membrane capable of separating a fluid sample into a retentate stream and a permeate stream as the fluid sample enters the tangential flow filtration device through feed inlet 17. The fluid passing through the filtration medium, i.e., the permeate, combines at a single location within the TFF device, regardless of whether the biological fluid passed through end caps 14A, 14B, or plate 16. At each plate 16, one or more permeate streams on either side of the plate combine and flow into permeate channel 77. As a result, regardless of whether the permeate passes through an end cap or plate or where this occurs within each end cap or plate, the one or more permeate streams are all combined within the TFF device and exit at a single location, e.g., permeate outlet 5, through, for example, a barbed fitting. In some embodiments, TFF assembly 10 includes two end caps 14A, 14B. In some embodiments, identical end caps can be used, with one end cap having a feed input and a retentate outlet with barbs or similar structures, and the other end cap being closed with a suitable plug or the like, so that the feed or retentate fluids do not enter or exit at those locations, or the other end cap has no output locations. The barb sizes for the feed and retentate can be varied to accommodate different flow rates.

[0042] 5A and 5B show one embodiment of end cap 14A, which may be identical to end cap 14B. In the illustrated embodiment, the visible surface or face is the interior surface or face (i.e., it faces inward in the assembled device) and has a functional feature that provides effective membrane area. As seen in FIG. 4, the opposite or outer surface of end cap 14A does not contact the process fluid and may therefore be devoid of functional features such as ribs. In some embodiments, the functional feature of the interior surface includes a plurality of spaced ribs 26 extending upwardly along the interior surface, which support a membrane bonded or otherwise attached to end cap 14A (as shown in FIG. 5B) and provide an area for fluid flow between the ribs 26. Gaps shown between groups of ribs may be present to enhance flow. In some embodiments, the plurality of spaced ribs 26 are arranged in spaced rows, with each rib 26 in a row spaced apart from adjacent ribs 26 in the same row. In certain embodiments, the ribs 26 within each row are equally spaced and sized, and the spacing between rows is also equal. Other rib shapes and configurations may be used. In certain embodiments, the ribs 26 may be 0.020" high and 0.026" wide (in the narrow direction across the rib), with a 0.026" gap between them. Details of the ribs on the end cap 14A are shown in Figures 15A, 15B, 15C, and 15D, and details of the ribs on the inner plate 16 are shown in Figures 16A, 16B, and 16C. The end cap 14A may be attached to the inner plate 16, such as by thermal bonding, via a mating rim 29 formed just inside the periphery of at least a portion of the end cap 14A, which preferably extends inward around the entire periphery as shown. The mating rim 29 extends upward from the inner surface of the end cap. This surface or face is therefore configured to mate with the inner plate 16, as described in more detail below. As the permeate fluid flows through membrane 15, it flows along the area between the underside of membrane 15 and the plurality of spaced ribs 26 to permeate outlet 5 (and then, for example, through barb 19) or to opening 30 leading to permeate plug 22.At a particular opening 30 in plug 22, the permeate flows to permeate pipe feature 60, then to permeate flow channel 77, and then to barb 19. Opening 30 is therefore in fluid communication with the region between rib 26 and membrane 15 and permeate outlet 5 (or fluid dead-end permeate plug 22). As shown, feed and retentate grooves, troughs, or cavities 127, 128 can be provided in fluid communication with feed inlet 17 and retentate outlet 18, respectively.

[0043] 6A shows a first surface or face 180 of plate 16 having a functional shape including a plurality of spaced apart elongated ribs that match the functional shape of the inner surface of end cap 14A or another first face of a further pair of inner plates 16. In some embodiments, first surface or face 180 of inner plate 16 has a larger effective membrane area than second surface or face 160 of inner plate 16, and has the same effective membrane area as the inner surface of end cap 14A shown in FIG. 5A. Thus, as can be seen by comparing FIGS. 6A and 6B, the effective membrane area of ​​first surface or face 180 (and therefore ribs 26) extends laterally closer to the periphery on the left side of FIG. 6A than the effective area of ​​second surface or face 160 of inner plate 16 (and therefore ribs 26′). Similar to the ribs 26 of the end cap 14A described above, a plurality of spaced ribs 26 are formed on a surface or face 180, extend upward therefrom, and are arranged in spaced rows, with each rib 26 in a row spaced apart from adjacent ribs 26 in the same row. In certain embodiments, the ribs 26 in each row are equally spaced and sized, and the spacing between rows is also equal. In certain embodiments, the ribs 26 are larger than the ribs 26'; the number of ribs 26 per row height is less than the number of ribs 26'. The first face 180 of the inner plate 16 is configured to be bonded or otherwise attached to another second face of the end cap 14A or a further pair of inner plates 16, such as via a joining rim 29 formed just inside the periphery of at least a portion of the inner plate 16 as shown. The first surface or face 180 of the inner plate 16 may also have a screen 21 (FIG. 4) located above the membrane; all flow channels generally include a screen 21. In some embodiments, to achieve a more uniform and / or consistent channel height (e.g., the height between each pair of members, e.g., between an end cap and a plate, or between two plates) and better device performance, one or more narrow plastic (e.g., polypropylene) straps 400 or the like (shown in FIG. 13, on an end cap) may be placed over the membrane and secured to the plate surface outside the active membrane area. In some embodiments, the straps are heat-bonded to the top of the membrane.In some embodiments, two straps per membrane may be used.

[0044] FIG. 6B illustrates one embodiment of the inner plate 16. In the illustrated embodiment, the visible surface or face is the second surface or face 160, which has a functional configuration including a plurality of spaced-apart ribs 26′ that support a membrane (not shown). In some embodiments, the second surface or face 160 of the inner plate 16 has a smaller effective membrane area than the inner surface of the end cap 14A shown in FIG. 5A (which in turn is smaller than the effective membrane area of ​​the opposite or first surface or face 180 of the inner plate 16 shown in FIG. 6A). The second surface or face 160 is configured to mate and join, such as by thermal bonding, with a corresponding surface or face of the second plate 16 to form a pair of plates. Similar to the ribs 26 of the end cap 14A described above, a plurality of elongated, spaced-apart ribs 26′ are formed on the surface or face 160 and arranged in spaced-apart rows, with each rib 26′ in a row being spaced apart from an adjacent rib 26′ in the row. In certain embodiments, the ribs 26' in each row are equally spaced and sized, and the spacing between rows is also equal. In certain embodiments, the ribs 26' are smaller than the ribs 26; the number of ribs 26' per row height is greater than the number of ribs 26. In some embodiments, the second surface or face 160 also includes an additional joining rim 29' that traverses the length of the inner plate 16. The additional joining rim 29' separates a first plurality or series of spaced apart permeate ports 75 located along a row of ribs within the effective membrane area from a second plurality or series of spaced apart permeate ports 76 spaced laterally from the first plurality of spaced apart permeate ports 75 outside the effective membrane area. In certain embodiments, the first plurality of spaced apart permeate ports are aligned with one another. In certain embodiments, the second plurality of spaced apart ports 76 may also be aligned with one another.When two plates 16 are assembled in a pair, the number of ports 75 on the first of the two plates may match the number of ports 75 on the second of the two plates, with each port 75 on the first plate aligned with each port 75 on the second plate, and the number of ports 76 on the first of the two plates may match the number of ports 76 on the second of the two plates, with each port 76 on the first plate aligned with each port 76 on the second plate. In other embodiments, the spaced ports 76 may not be aligned in a line. Also, in other embodiments, the number of ports 75 may differ from the number of ports 76. An additional joining rim 29′ defines a permeate flow channel 77, directing unfiltered feed / retentate liquid away from the longitudinal channel. In this channel, the permeate liquid can flow toward the permeate “pipe” or pipe feature 60 and ultimately toward the permeate outlet 5 in fluid communication therewith, as indicated by arrow 206. The width of the permeation channels 77 should be sufficient to avoid closure by molten plastic that may seep out from the joint rim when the plates are joined together.

[0045] Referring to Figure 7, the flow of sample feed and retentate is shown according to certain embodiments. The feed enters feed input 17, as indicated by arrow 117, flows across the surface of end cap 14A and inner plate 16, flows across the flow path defined by membrane 15 (and screen 21, if present), as indicated by arrows 117A, 117B, and 117C, and exits through the retentate outlet (not shown in Figure 7). The permeate stream is not shown in Figure 7.

[0046] Figure 8 shows the permeate flow from feed inlet 17 to permeate outlet 5. The feed flow, represented by arrow 200, enters feed inlet 17, for example, through a feed barb, flows across the surface of end cap 14A, and flows across membrane 15 and a screen, if present (not shown in Figure 8). Filtered permeate liquid, represented by arrows 201 and 202, flows toward permeate outlet 5 as shown.

[0047] 9A and 9B further illustrate the permeate flow, here passing through a pair of inner plates 16 according to certain embodiments. Feed liquid entering through opening 17' in fluid communication with feed inlet 17 in an end cap (not shown in FIGS. 9A and 9B), indicated by arrows 200 and 205, flows across first surface or face 180 (arrow 200) of one or more inner plates 16 and second surface or face 160 (arrow 205) of one or more inner plates 16, as shown. For the permeate flow on the second surface 160 side, indicated by arrow 205, the fluid flows through membrane 15 of each plate 16, along small rib structure 26' (not visible in FIG. 9B), to permeate port 75, and then through permeate port 75 to the first surface 180 side of each plate 16, as indicated by arrow 202. With respect to the permeate streams on one or more of the first surfaces 180, the permeate flows through the membrane 15 along the area of ​​the small rib structure 26′, as indicated by arrows 204, to the plurality of permeate ports 76. Thus, all of the permeate (whether from the first surface 180 or the second surface 160) flows through the plurality of ports 76 to the open area on the second surface 160, and then flows longitudinally within the channels 77 until it reaches the permeate pipe feature 60, allowing it to flow to the permeate outlet 5, which is in fluid communication with the permeate channels 77. In this manner, the permeate fluid streams passing through the membrane 15 are combined and flow toward the permeate outlet 5.

[0048] 10 and 11 illustrate further details of the permeate fluid flow. Arrow 300 indicates a feed stream entering through a feed inlet (not shown), which then flows across the surfaces of end caps 14A, 14B and their respective inner plates 16, and across membrane 15 and its associated screen 21. The resulting filtered permeate from flowing through membrane 15 is combined and flows toward permeate outlet 5, as indicated by arrow 303 in FIG. 10. More specifically, the permeate fluid passes through membrane 15 to permeate port 75 (arrow 302) and through permeate port 75 to the second surface. For permeate streams on one or more first surfaces 180, the permeate fluid flows through membrane 15 along the area of ​​small rib structure 26′ to multiple permeate ports 76, as indicated by arrow 204. Thus, all of the permeate fluid (whether from first surface 180 or second surface 160) is allowed to flow through the plurality of ports 76 to the open area at second surface 160, and then flow longitudinally within channel 77 until it reaches permeate pipe feature 60 and into permeate outlet 5, which is in fluid communication therewith. In this manner, the permeate fluid streams passing through membrane 15 are combined and flow toward permeate outlet 5.

[0049] 14 further illustrates the permeate stream passing through a pair of inner plates 16, away from the permeate barbs, near the end of the device with the permeate plug. The feed stream 300 entering through the feed barbs flows across the surfaces of the end caps 14A, 14B and inner plates 16, and across the membranes 15 and screen 21. The resulting permeate flows through the membranes 15, combines, and flows toward the permeate channel between the inner plates 16, then flows through the permeate channel toward the permeate barbs 19 at the other end of the device, as indicated by the arrows.

[0050] In some embodiments, two or more devices 10 can be manifolded together, as illustrated in Figures 12A, 12B, and 12C, for example, for high throughput or capacity. External tubing (partially shown in Figure 12B) can be used to connect the permeate output stream from each device and combine these two streams together. In some embodiments, the feed and retentate lines are located in the center of the device and split to the two filters. In some embodiments, a manifold tee 605 splits the feed and retentate streams for the two filters and connects them to the tubing (Figure 12B). Figures 12B and 12C also show a central support plate 602 sandwiched between the two filters 10 to support the internal pressure.

[0051] While various aspects and embodiments have been disclosed herein, other aspects, embodiments, modifications, and variations will be apparent to those skilled in the art upon reading and understanding the foregoing detailed description. The various aspects and embodiments disclosed herein are for purposes of illustration and not limitation. It is intended that the present disclosure be construed as including all such aspects, embodiments, modifications, and variations insofar as they come within the scope of the appended claims or the equivalents thereof.

Claims

1. 1. A tangential flow filter for the filtration of a fluid, comprising: first and second end caps, wherein a fluid feed inlet, a retentate outlet, and a permeate outlet are on said first or said second end cap, respectively; at least first and second plates, each plate having a first surface and an opposite second surface, the first surface of the first plate facing the first end cap and having a first effective filtration area, and the second surface of the first plate facing the first surface of the second plate and having a second effective filtration area; filtration media between the first end cap and the first plate, between the first plate and the second plate, and between the second plate and the second end cap; a first series of spaced apart openings through said first plate; a second series of openings through said second plate and in fluid communication with said first series of openings; a third series of spaced apart openings through said first plate spaced apart from said first series of spaced apart openings; a fourth series of openings through said second plate and in fluid communication with said third series of openings; Equipped with the third and fourth series of spaced apart openings are located in respective permeate channels in regions of the second face of the first plate and the first face of the second plate that are free of filtration media, the regions being on opposite sides of the first face of the first plate and the second face of the second plate that are free of filtration media; A tangential flow filter, wherein the permeate channel is in fluid communication with the permeate outlet.

2. 10. The tangential flow filter of claim 1, wherein the openings in the first series of spaced apart openings are aligned with one another.

3. 10. The tangential flow filter of claim 1, wherein the openings in said third series of spaced apart openings are aligned with one another.

4. 10. The tangential flow filter of claim 1, wherein the filtration media between the first end cap and the first plate comprises a first membrane attached to the end cap and a second membrane attached to the first surface of the first plate.

5. 5. The tangential flow filter of claim 4, further comprising a screen between the first membrane and the second membrane.

6. 5. The tangential flow filter of claim 4, wherein fluid passing through said second membrane flows through said third series of spaced apart openings and enters said permeate channel.

7. 5. The tangential flow filter of claim 4, wherein fluid passing through the first membrane enters the permeate outlet.

8. 2. The tangential flow filter of claim 1, wherein the filtration media between the first plate and the second plate comprises a third membrane attached to the second surface of the first plate and a fourth membrane attached to the first surface of the second plate.

9. 9. The tangential flow filter of claim 8, wherein fluid passing through the third and fourth membranes enters the respective first and second series of spaced apart openings and flows to the third and fourth series of spaced apart openings.

10. 10. The tangential flow filter of claim 1, further comprising a filtration media between the second face of the second plate and the second end cap.

11. 1. A tangential flow filter for the filtration of a fluid, comprising: first and second end caps, a fluid feed inlet, a retentate outlet, and a permeate outlet on the first or second end cap; a plurality of pairs of plates between the first and second end caps, each pair of the plurality of pairs of plates comprising at least a first and a second plate, each of the first and second plates having a first surface and an opposite second surface, the first surface of the first plate having a first effective filtration area, and the second surface of the first plate facing the first surface of the second plate having a second effective filtration area; a filtration medium on the first and second surfaces of each of the first and second plates; a first series of spaced apart openings through said first plate; a second series of openings through said second plate; a third series of spaced apart openings through said first plate spaced apart from said first series of spaced apart openings; a fourth series of openings through the second plate and in fluid communication with the third series of openings in the first plate; Equipped with the third and fourth series of spaced apart openings are located in respective permeate channels in regions of the second face of the first plate and the first face of the second plate that are free of filtration media, the regions being on opposite sides of the first face of the first plate and the second face of the second plate that are free of filtration media; A tangential flow filter, wherein the permeate channel is in fluid communication with the permeate outlet.

12. 1. A method of filtering a fluid sample, comprising: introducing the fluid sample into a feed inlet of a first end cap; and subjecting said introduced fluid sample to: (a) contacting a first membrane attached to the first end cap to form a first permeate stream and a first retentate stream, the first permeate stream flowing to a first permeate outlet of the first end cap or a second permeate outlet of a second end cap, and the first retentate stream flowing to a first retentate outlet of the first end cap or a second retentate outlet of the second end cap; (b) contacting a second membrane mounted on a first face of a first plate mounted on the first end cap to form a second permeate stream and a second retentate stream, the second permeate stream flowing into a first plurality of spaced apart permeate ports formed in the first plate in fluid communication with the permeate channels and the first or second permeate outlet, and the second retentate stream flowing into the first or second retentate outlet; (c) contacting a third membrane attached to a second surface of the first plate to form a third permeate stream and a third retentate stream, the third permeate stream flowing into a second plurality of spaced apart permeate ports formed in the first plate, the second permeate stream combining with the second permeate stream before entering the first plurality of spaced apart permeate ports in fluid communication with the permeate channel and the first or second permeate outlet, and the third retentate stream flowing into the first or second retentate outlet; (d) contacting a fourth membrane attached to a first surface of a second plate attached to the first plate to form a fourth permeate stream and a fourth retentate stream, the fourth permeate stream flowing into a third plurality of spaced apart ports formed in the second plate and in fluid communication with the permeate channel and a fourth plurality of spaced apart ports in fluid communication with the permeate outlet, and the fourth retentate stream flowing into the first or second retentate outlet; and (e) contacting a fifth membrane attached to a second surface of the second plate to form a fifth permeate stream and a fifth retentate stream, the fifth permeate stream flowing into the fourth plurality of spaced apart permeate ports formed in the second plate in fluid communication with the permeate channel and the first or second permeate outlet, and the fifth retentate stream flowing into the first or second retentate outlet; and (f) contacting a sixth membrane attached to a second end cap to form a sixth permeate stream and a sixth retentate stream, the sixth permeate stream flowing to a permeate pipe in fluid communication with the permeate channel and the first or second permeate outlet, and the sixth retentate stream flowing to the first or second retentate outlet; collecting a permeate stream from said permeate outlet; A method comprising:

13. 13. The method of claim 12, further comprising collecting a retentate stream from the retentate outlet.

14. 13. The method of claim 12, further comprising recycling a retentate stream from the retentate outlet to the feed inlet.

15. 2. The tangential flow filter of claim 1, wherein the second effective filtration area is smaller than the first effective filtration area.

16. 10. The tangential flow filter of claim 1, wherein the second series of openings is aligned with the first series of openings.

17. 2. The tangential flow filter of claim 1, wherein the third series of openings is aligned with the fourth series of openings.

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