Tangential flow filter with combined permeate output and filtration method

Abstract

The tangential flow filter includes a first end cap and a second end cap, one end cap having a feed inlet and a retentate outlet and a permeate outlet; and one or more pairs of plates between the end caps. Each plate has a respective diaphragm bonded to each side. Forming a first series of openings through the first plate; forming a second series of openings through the second plate; forming a third series of openings through the first plate; and a fourth series of openings are formed through the second plate, and the fourth series of openings are in communication with the third series of openings. A third series of openings and a fourth series of openings are positioned in respective permeate channels in respective areas of one side of the first plate and one side of the second plate that are free of filter media. The permeate channel is in fluid communication with the permeate outlet.

Description

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

[0002] Embodiments of the technology disclosed herein relate to filters and filtration systems for use in bioprocessing. Background Art

[0003] Filtration via a membrane is a separation technique for laboratory-scale and process-scale purification of biomaterials. Different types of membranes are used in filtration, which can be classified as microfiltration membranes or ultrafiltration membranes according to pore size. Microfiltration membranes typically have a pore size between 0.1 micron (μm) and 10 μm. Ultrafiltration membranes have a smaller pore size, typically between 0.001 μm and 0.1 μm. Due to pore size differences, these membranes are used for different purposes. For example, microfiltration membranes are typically used for purification, sterilization, and removal of particulate matter, or for cell harvesting. Ultrafiltration membranes are typically used for fractionation, or for concentrating molecules (e.g., proteins, peptides, nucleic acids, carbohydrates, and other biomaterials). Ultrafiltration membranes are typically classified according to molecular weight cutoff (e.g., kilodaltons (kDa)), rather than pore size.

[0004] Microfiltration and ultrafiltration membranes use two main types of filtration modes or filtration processes. The first filtration mode is called normal flow filtration (NFF) mode, also known as "dead-end" filtration, which generally applies the feed stream perpendicular to the membrane face and attempts 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 face, with a portion passing through the membrane (i.e., permeate) while the remainder is retained and can be recycled back to the feed reservoir (i.e., retentate).

[0005] Tangential flow filtration (TFF) equipment, also known as cross-flow filtration equipment, has a feed inlet, a retentate outlet, and at least one permeate outlet. Tangential flow refers to a filtration configuration in which the flowing fluid is directed along the surface of the filter medium, approximately parallel (tangential) to the surface of the filter medium. In this configuration, solutes are adsorbed or absorbed onto the surface or pores of the membrane as the eluent flows across the surface. The purified portion of the fluid passing through the filter medium has a "transverse" velocity component, that is, perpendicular to the direction of fluid flow along the surface of the filter medium. In TFF, the retentate (or decantate) can be repeatedly recirculated to improve filtration efficiency and increase permeate yield. The recirculating retentate solution path extends parallel to the membrane surface and is pumped through the membrane at a sufficient rate to ensure surface cleaning. However, only a relatively small amount of permeate is collected during each retentate volume passage, and therefore, relatively long processing times are typically associated with TFF procedures. If the appropriate membrane is selected for the specific separation, a second liquid can be used to elute the material adsorbed or absorbed to the membrane for harvesting.

[0006] Cross-flow filtration or tangential filtration is a well-known filtration process. For example, reference can be made to U.S. Patents No. 5,681,464, No. 6,461,513, No. 6,331,253, No. 6,475,071, No. 5,783,085, No. 4,790,942, the disclosures of which are incorporated herein by reference.

[0007] For the purification of certain types of biological materials (e.g., biological materials with a size of 500 kDa or greater), TFF filtration is often preferred, where TFF is used for concentration and impurity removal. Most TFF processes use ultrafiltration membranes for concentration and buffer exchange steps, etc. An example of an ultrafiltration membrane used in the TFF format for the manufacture 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 a membrane to separate components in a liquid solution or suspension based on size, molecular weight or other differences. TFF is used to remove the target protein from a cell culture medium during the perfusion process while retaining the cells in the cell culture medium. During the TFF process, the fluid is pumped tangentially along the membrane surface, and particles, molecules or cells that are too large to pass through the membrane are rejected and returned to the processing tank. The TFF process may involve additional fluid crossings through the membrane (e.g., recirculation) until the process fluid is fully purified, concentrated or purified. The cross-flow properties of TFF minimize membrane fouling, thereby allowing high-capacity processing per batch. The membrane is contained in a filter element, which can have a variety of configurations, such as a spiral wound filter element and a cassette filter element.

[0009] Monoclonal antibodies (mAb) are used as the therapeutic agent of multiple indications, including for example cancer, transplant rejection and cardiovascular disease. There are various biopharmaceutical manufacturing technologies to produce and gather the crops mAb from host cells, including for example fed-batch process and perfusion process. In a fed-batch bioreactor system, cells are cultured in batches within a set time period (for example, within approximately 7 days to approximately 21 days), after which culture medium nutrients are consumed by host cells, and waste products are accumulated. After the cell culture cycle, the batch experience is harvested step, in which the protein of interest (for example, a product such as a monoclonal antibody or mAb) is separated from the cell mass. Compared with the fed-batch system, the perfusion bioreactor cultivates cells within a longer time period (for example, within a few weeks or months), continuously supplies fresh culture medium to the cells, removes spent culture medium and gathers the crops product simultaneously. Perfusion system provides several advantages over fed-batch system. For example, due to before the protein of interest is exposed to high-level waste, continuously gathers the crops and purified product, so in the perfusion system, product degradation reduces. In addition, perfusion bioreactors can produce product yields similar to those of fed-batch bioreactors while occupying significantly less space. Perfusion is becoming the preferred manufacturing technology in the biopharmaceutical industry due to its advantages over fed-batch processes. However, perfusion processes rely on maintaining a high density of host cells and continuous harvesting during each production run, which involves several filtration iterations and can cause physical damage to the host cells.

[0010] Conventional TFF equipment can be composed of multiple components, including pumps, feed solution reservoirs, filtration modules, and conduits for connecting these components. In use, the feed solution is directed from the feed solution reservoir to the filtration module, and the retentate from the filtration module is recirculated from the filtration module to the feed solution reservoir until the desired volume of retentate is obtained. Diaphragms are sandwiched between the top and bottom manifolds or retainers, which serve to provide precise mechanical restraint against the internal hydraulic pressure of the equipment and also to distribute the filtration stream across multiple flow paths within the equipment.

[0011] Prior art tangential flow filter devices incorporate a permeate output external to the filter housing or module. Furthermore, prior art tangential flow filter devices do not provide multiple internal permeate flow paths. A tangential flow filter having filter media on both sides of each end cap and any plates within the filter stack, wherein the permeate flows of each end cap and plate cooperate within the filter, thereby allowing 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 a fluid is disclosed, comprising: a first end cap and a second end cap, the first end cap having a fluid feed inlet, a retentate outlet, and a permeate outlet; at least a first plate and a second plate, each plate having a first side and an opposing second side, the first side of the first plate facing the first end cap and having a first effective filtration area, the second side of the first plate facing the first side of the second plate and having a second effective filtration area less than the first effective filtration area; filter 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 the first plate; and a second series of spaced-apart openings through the first plate. a second series of spaced-apart openings through the second plate aligned with or in fluid communication with the first series of spaced-apart openings in the first plate; a third series of spaced-apart openings through the first plate spaced apart from the first series of spaced-apart openings; a fourth series of openings through the second plate aligned with or in fluid communication with the third series of openings in the first plate; wherein the third series of spaced-apart openings and the fourth series of spaced-apart openings are positioned in corresponding permeate channels in corresponding areas of the second side of the first plate and the first side of the second plate that are free of filter media, the areas being opposite to the corresponding filter media on the first side of the first plate and the second side of the second plate; the permeate channels being in fluid communication with the permeate outlet. In some embodiments, the second effective filtration area can be equal to or greater than the first effective filtration area. In some embodiments, the membrane (and / or screen) on one side of the plate can extend laterally (i.e., the shorter axis of the device) a greater distance than the membrane and / or screen on the other side to accommodate the permeate flow channels.

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

[0014] In some embodiments, the filter 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 side of the first plate. In some embodiments, there may be a screen between the first membrane and the second membrane.

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

[0016] In some embodiments, the filter media between the first and second plates includes a third membrane attached to the second side of the first plate and a fourth membrane attached to the first side of the second plate. In some embodiments, fluid passing through the third and fourth membranes each 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 are multiple plate stacks between the first and second end caps. Thus, instead of the second plate being attached to the second end cap, it is attached to a third plate, which is one plate of a pair in the second plate stack, and the other plate of the pair is attached to the second end cap or a fifth plate (which is one plate of another pair), and so on.

[0018] Certain embodiments relate to a method for filtering a fluid sample. In some embodiments, a method for filtering a fluid sample is disclosed, comprising: introducing the fluid sample into a feed inlet of a first end cap; causing the introduced fluid sample to:

[0019] (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 the 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;

[0020] (b) contacting a second membrane attached to a first side of a first plate attached to a first end cap to form a second permeate stream and a second retentate stream, the second permeate stream flowing to a first plurality of spaced-apart permeate ports formed in the first plate and in fluid communication with the permeate channel and the first permeate outlet or the second permeate outlet, and the second retentate stream flowing to the first retentate outlet or the second retentate outlet;

[0021] (c) contacting a third membrane attached to a second side of the first plate to form a third permeate stream and a third retentate stream, the third permeate stream flowing to a second plurality of spaced-apart permeate ports formed in the first plate and combining with the second permeate stream before the second permeate stream enters the first plurality of spaced-apart permeate ports in fluid communication with the permeate channel and the first permeate outlet or the second permeate outlet, the third retentate stream flowing to the first retentate outlet or the second retentate outlet;

[0022] (d) contacting a fourth membrane attached to a first side of a second plate attached to the first plate to form a fourth permeate stream and a fourth retentate stream, the second plate being attached to the first plate, the fourth permeate stream flowing to a third spaced-apart plurality of permeate ports formed in the second plate and in fluid communication with a fourth spaced-apart plurality of ports, the fourth spaced-apart plurality of ports being in fluid communication with the permeate channel and the first permeate outlet or the second permeate outlet, and the fourth retentate stream flowing to the first retentate outlet or the second retentate outlet;

[0023] (e) contacting the fifth membrane attached to the second side of the second plate to form a fifth permeate stream and a fifth retentate stream, the fifth permeate stream flowing to the fourth plurality of spaced-apart permeate ports formed in the second plate in fluid communication with the permeate channel and the first permeate outlet or the second permeate outlet, and the fifth retentate stream flowing to the first retentate outlet or the second retentate outlet; and

[0024] (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 to a permeate conduit, conduit, or the like in fluid communication with the permeate channel and the first permeate outlet or the second permeate outlet, and the sixth retentate stream flowing to the first retentate outlet or the second retentate outlet; and

[0025] A permeate stream was collected from the permeate outlet.

[0026] For purposes of clarity, six retentate streams are defined above. However, it should be noted that the first stream and the second stream are actually the same stream, since they each flow between the gap between the first end cap and the diaphragm on the first side of the first plate. Neither passes through the diaphragm, so they enter the device as feed at one end of the diaphragm, flow through the device, and exit at the retentate outlet. They are separated from each other only by the open screen, 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 diaphragms, but there are actually only three retentate streams (see Figure 7 ).

[0027] In some embodiments, the retentate stream may be collected from the retentate outlet, recycled to the feed inlet, or both.

[0028] Some embodiments of the present disclosure describe a tangential flow filtration apparatus in which all permeate flows can be combined within the filter apparatus or housing, such as within an area defined between two end caps. Some embodiments of the present disclosure describe an apparatus in which all permeate flows exit through a single location. Some embodiments of the present disclosure describe an apparatus in which all permeate flows can be combined within the filter apparatus, and in which all permeate flows exit through a single location. Some embodiments of the present disclosure describe an apparatus in which external piping requirements are reduced, thereby eliminating the risk of flow restriction in one permeate output pipe, which would otherwise alter the flow pattern within the filter apparatus. Some embodiments of the present disclosure describe an apparatus in which there is an active membrane on each side of the end caps and plates, which contacts the fluid during operation of the apparatus.

[0029] In some embodiments, the TFF apparatus is used as part of a perfusion bioreactor, wherein a process medium flows through the TFF apparatus(es), entering via the feed input. The cells and process medium are returned to the bioreactor feeding the TFF apparatus via the retentate output, wherein the material produced by the cells (i.e., bioproduct) is collected via the permeate output.

[0030] In further embodiments, 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.

[0031] 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 by tangential flow filtration (TFF) in the filter element. A filter medium is provided that is capable of separating a liquid sample into a retentate stream and a permeate stream when the liquid sample enters the tangential flow filtration module through a feed inlet.

[0032] In another embodiment, a perfusion process for harvesting a target protein from a liquid feed comprising host cells is disclosed. The process includes transporting the liquid feed comprising the target protein and the host cell to a feed channel of at least one filter element, and separating the target protein from the host cell in at least one filter element. The target protein may, for example, be a monoclonal antibody, which may be separated from the host cell by TFF and recovered from at least one filter element. The perfusion process may also include recovering the host cell from at least one filter element, supplying a certain volume of fresh culture medium to the recovered host cell, and returning the recovered host cell to the bioreactor. The perfusion process may be run continuously, wherein the recovered host cell of the initial perfusion operation is the liquid feed for subsequent perfusion operations. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 is a perspective view of a tangential flow filtration assembly according to some embodiments of the present disclosure;

[0034] Figure 2 According to some embodiments of the present disclosure Figure 1 A perspective view of a tangential flow filtration assembly with the outer housing removed;

[0035] Figure 3A According to some embodiments of the present disclosure Figure 2 A front view of a tangential flow filtration assembly;

[0036] Figure 3B According to some embodiments of the present disclosure Figure 2 Top view of a tangential flow filtration assembly;

[0037] Figure 3C According to some embodiments of the present disclosure Figure 2 A bottom view of a tangential flow filtration assembly;

[0038] Figure 3D According to some embodiments of the present disclosure Figure 2 A first side view of a tangential flow filtration assembly;

[0039] Figure 3E According to some embodiments of the present disclosure Figure 2 a second side view of a tangential flow filtration assembly;

[0040] Figure 4 According to some embodiments of the present disclosure Figure 2 An exploded view of a tangential flow filtration assembly;

[0041] Figure 5A is a view of the underside of an end cap according to some embodiments of the present disclosure;

[0042] Figure 5B is according to some embodiments with a diaphragm attached Figure 5A A perspective view of the end cap;

[0043] Figure 5C yes Figure 5A A side view of the end cap;

[0044] Figure 6A is a top view of a first surface or face of an interior panel according to some embodiments of the present disclosure;

[0045] Figure 6B is a top view of a second surface or face of an interior panel according to some embodiments of the present disclosure;

[0046] Figure 7 is a cross-sectional view of a pair of interior plates sandwiched between two end caps according to some embodiments of the present disclosure;

[0047] Figure 8 is a cross-sectional view of an end cap permeate outlet and feed inlet showing permeate flow according to certain embodiments;

[0048] Figure 9A is a top view of an inner plate with a diaphragm according to certain embodiments;

[0049] Figure 9B yes Figure 9A a cross-sectional view of a portion of an interior panel;

[0050] Figure 10 is a cross-sectional view of a portion of a pair of interior plates sandwiched between two end caps according to some embodiments of the present disclosure;

[0051] Figure 11 According to some embodiments of the present disclosure Figure 10 A detailed view of a portion of

[0052] Figure 12A is a perspective view of a manifold connection assembly according to certain embodiments;

[0053] Figure 12B and Figure 12C yes Figure 12A A perspective view of the internal details of the manifold connection assembly;

[0054] Figure 13 is a view of an end cap with a strap attached, according to certain embodiments;

[0055] Figure 14 is a cross-sectional view of a portion of a pair of interior plates sandwiched between two end caps according to some embodiments of the present disclosure;

[0056] Figure 15A is a top view of an end cap according to certain embodiments;

[0057] Figure 15B yes Figure 15A The end cap along Figure 15A A side view taken along line BG-BG;

[0058] Figure 15C yes Figure 15A A magnified view of the details AZ;

[0059] Figure 15D yes Figure 15B A magnified view of the details of BB;

[0060] Figure 16A is a top view of a first surface or face of an interior panel according to some embodiments of the present disclosure;

[0061] Figure 16B According to some embodiments of the present disclosure Figure 16A a top view of a second surface or face of the interior panel;

[0062] Figure 16C yes Figure 16B a side view of the inner panel taken along line AP-AP;

[0063] Figure 16D yes Figure 16C A magnified view of the details of the AV; and

[0064] Figure 16E yes Figure 16A A magnified view of the detail AW. DETAILED DESCRIPTION

[0065] Although specific terms are used in the following description for clarity, these terms are intended only to refer to the specific structures of the embodiments selected for illustration in the accompanying drawings. In the drawings and the following description, it should be understood that like reference numerals refer to components having like functions.

[0066] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0067] As used in this specification, various devices and parts may be described as "including" other components. As used herein, the terms "comprises," "comprising," "having," "having," "may," "including" and variations thereof are intended to be open transitional phrases, terms or words that do not exclude the possibility of additional components.

[0068] All ranges disclosed herein are inclusive of the recited endpoints and are independently combinable (eg, a range "from 2% to 10%" includes the endpoints 2% and 10% and all intermediate values).

[0069] As used herein, approximation language may be applied to modify any quantitative representation that may vary without causing a change in the basic function to which it is related. Thus, in some cases, a value modified by one or more terms (such as "about" and "approximately") may not be limited to the exact value specified. The modifier "about" should also be considered to disclose a range defined by the absolute values ​​of the two endpoints. For example, the expression "from about 2 to about 4" also discloses a range of "from 2 to 4."

[0070] It should be noted that some of the terms used herein are relative terms. For example, the terms "upper" and "lower" are relative to each other in position, i.e., the upper component is located at a higher altitude than the lower component, and should not be construed as requiring a specific orientation or position of the structure. As another example, the terms "interior," "exterior," "inwardly," and "outwardly" are relative to the center and should not be construed as requiring a specific orientation or position of the structure.

[0071] The terms "top" and "bottom" are relative to an absolute reference, ie, the surface of the Earth. In other words, toward the surface of the Earth, a top location is always at a higher altitude than a bottom location.

[0072] "TFF module," "TFF system," and "TFF apparatus" are used interchangeably herein to refer to a tangential flow filtration system configured to operate in a recirculation mode, wherein at least a portion of the retentate is returned to the system as feed.

[0073] "Feed line" or "feed channel" refers to a conduit used to deliver feed from a feed source (eg, a feed vessel) to one or more processing units in a filtration module.

[0074] "Retentate line" or "retentate channel" refers to the conduit in a filtration module used to carry the retentate.

[0075] "Permeate line" or "permeate channel" refers to the conduit in a filtration module used to carry permeate.

[0076] "Filtration membrane" or "membrane" refers to a selective permeation membrane used to separate a feed into a permeate stream and a retentate stream using a 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. As used herein, the terms "ultrafiltration membrane" and "UF membrane" refer to membranes having a pore size in the range of about 1 nanometer to about 100 nanometers. As used herein, the terms "microfiltration membrane" and "MF membrane" refer to membranes having a pore size in the range of about 0.1 micrometer to about 10 micrometers.

[0077] Flat plate or cassette-type devices consist of or include membranes cast onto the plates; the plates are then securely stacked together. The devices may or may not include flexible screens in the feed channels to support the membranes. An attractive advantage of such configurations is their very compact design. However, channel height control, defined by plate-to-plate interaction and distance, must be carefully considered. Ties can be used to help achieve consistent channel height control.

[0078] Now turn Figure 1-4 According to some embodiments, a tangential flow filtration assembly or housing 10 includes two spaced apart end caps 14A, 14B with one or more pairs of plates 16 disposed between the end caps 14A, 14B, wherein each plate 16 has a first major side surface and a second major side surface. In some embodiments, each plate 16 is made of a fluid impermeable material (e.g., polypropylene) and may include a filter medium, such as a membrane 15 (e.g., a PVDF or PES membrane), disposed on each of the first major side surface and the second major side surface, such as by thermal bonding. In certain embodiments, a turbulence promoting screen 21 is juxtaposed with each membrane such that each flow channel includes a screen 21. Suitable screens 21 include those commercially available from EMD Millipore Corporation and include screens conventionally associated with The screens are those sold in boxes of 3, such as Type A screen (tight screen), Type C screen (coarse screen), and Type D screen (coarse screen for high viscosities). The screens also serve to prevent adjacent diaphragms from contacting each other. For assembly purposes, the screens can have appropriately positioned apertures to receive alignment pins or similar features on the end caps and inner plate, and the diaphragms can have rounded shoulder features to help properly position the diaphragms near the pins while avoiding wrinkling of the diaphragms. In some embodiments, there can be two different screen shapes, just as there can be two different diaphragm shapes; one for the end caps and one side of the inner plate, and a different shape for the other side of the inner plate. For simplicity, Figure 4 The reference numerals designated in the figures (15 for the diaphragm and 21 for the screen) do not reflect the different unique screen shapes and diaphragm shapes. The plates 16 are typically assembled in pairs in 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. In the device, up to 13 pairs or more pairs of plates may be suitable. Preferably, the plates 16 are equally sized. In some embodiments, the overall layout of the end caps and plates is similar or identical. To simplify manufacturing, the end caps 14A, 14B can all be identical and can include a plurality of ports 24, some of which may not be used and therefore blocked with suitable plugs (such as permeate plugs 22) and associated seals (such as (one or more) O-rings 23). For example, the operable ports 24 can be fitted with suitable barb fittings 19 and O-rings 23. The outer caps 8A, 8B ( Figure 1 ) (such as a hard plastic plate attached around the device with fasteners 7 such as bolts, etc.) to help prevent the device from bulging under operating pressure. In some embodiments, unused ports can be simply eliminated.

[0079] A biological fluid or other sample fluid feed enters the TFF apparatus 10 at the feed input or inlet 17, where it flows through the filter media in the apparatus or housing in a tangential flow pattern to a retentate outlet 18. In some embodiments, the filter media is a membrane that is capable of separating the fluid sample into a retentate stream and a permeate stream when the fluid sample enters the tangential flow filtration apparatus through the feed inlet 17. Regardless of which end cap 14A, 14B, or plate 16 the biological fluid flows through, the fluid (i.e., permeate) that passes through the filter media merges into a single location within the TFF apparatus. For each plate 16, the permeate streams (one or more) on both sides of the plate merge and flow into the permeate flow channel 77. Thus, regardless of which end cap or plate the permeate flows through, or if this occurs in both end caps or plates, all permeate streams are connected within the TFF apparatus and exit through a single location (e.g., permeate outlet 5), such as, for example, through a barbed fitting. In some embodiments, the TFF assembly 10 includes two end caps 14A, 14B. In some embodiments, end caps of the same configuration may be used, wherein one of the end caps has a feed input and a retentate outlet with barbs or similar structures, and the other end cap is closed, such as with a suitable plug, so that no feed or retentate fluid enters or exits at those locations, or the other end cap has no output location. The feed and retentate barb sizes can be modified to accommodate different flow rates.

[0080] Figure 5A and Figure 5B An embodiment of end cap 14A is shown, which may be identical to end cap 14B. In the embodiment shown, the visible surface or face is an interior surface or face (i.e., it faces inward in the assembled device) and has a functional geometry that provides the effective area for the diaphragm. Figure 4 As can be seen in FIG. 1 , the opposite or outer surface or face of end cap 14A does not contact the process fluid and, therefore, may be devoid of functional geometry such as ribs. In some embodiments, the functional geometry of the inner surface includes a plurality of spaced-apart ribs 26 that are elongated and extend above the inner surface and both support a diaphragm ( 12A ) bonded to or otherwise attached to end cap 14A. Figure 5B diaphragm shown in ), which in turn provides an area for fluid flow between the ribs 26 and the diaphragm. There may be gaps as shown between groups of ribs to improve flow. In some embodiments, a plurality of spaced-apart ribs 26 are arranged in spaced-apart columns, wherein each rib 26 in a column is spaced-apart from adjacent ribs 26 in the same column. In certain embodiments, the spacing and size of the ribs 26 in each column are equal, and the spacing between columns is equal. Other rib geometries 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 ribs) with a gap of 0.026" therebetween. Details of the ribs of the end cap 14A are shown in Figure 15A 、 Figure 15B、 Figure 15C and Figure 15D and details of the ribs of the inner plate 16 are shown in Figure 16A 、 Figure 16B and Figure 16C In. The end cap 14A can be attached to the inner plate 16 via a bonding rim 29, such as by means of thermal bonding, which is formed just inside the perimeter of at least a portion of the end cap 14A, and preferably spans the entire perimeter inside as shown. The bonding rim 29 extends upward from the inner face surface of the end cap. Therefore, this surface or face is configured to cooperate with the inner plate 16, as discussed in more detail below. When the permeate fluid flows through the diaphragm 15, it flows along the area between the lower side of the diaphragm 15 and a plurality of spaced ribs 26 to the opening 30, which leads to the permeate outlet 5 (and then, for example, through the barb 19) or to the permeate plug 22. For some openings 30 at the plug 22, in order to flow to the barb 19, the permeate flows to the permeate conduit feature 60 and then to the permeate flow channel 77. Therefore, the opening 30 is in fluid communication with the area between the rib 26 and the diaphragm 15 and with the permeate outlet 5 (or the permeate plug 22 at the fluid termination point). As shown, respective feed and retentate grooves, channels or cavities 127 , 128 may be provided in fluid communication with the feed inlet 17 and the retentate outlet 18 .

[0081] Figure 6A The first surface or face 180 of the plate 16 is shown having a functional geometry comprising a plurality of spaced apart elongated ribs that match the functional geometry of the inner surface of the end cap 14A or another first face of another pair of inner plates 16. In some embodiments, the first surface or face 180 of the inner plate 16 has an effective diaphragm area that is greater than the effective diaphragm area of ​​the second surface or face 160 of the inner plate 16 and has the same effective diaphragm area as the inner surface of the end cap 14A shown in FIG. 5 . Thus, as can be seen by comparing Figure 6A and Figure 6B It can be seen that the effective diaphragm area of ​​the first surface or face 180 (and therefore the plurality of ribs 26) is closer to the center of the diaphragm than the effective area of ​​the second surface or face 160 of the inner plate 16 (and therefore the plurality of ribs 26'). Figure 6A, extending laterally about the outer perimeter on the left side of the inner plate 16. Like the ribs 26 of the end cap 14A discussed above, a plurality of spaced-apart ribs 26 are formed on a surface or face 180, extending upwardly therefrom, and arranged in spaced-apart columns, wherein each rib 26 in a column is spaced apart from adjacent ribs 26 in the same column. In certain embodiments, the spacing and size of the ribs 26 in each column are equal, and the spacing between the columns is equal. In certain embodiments, the ribs 26 are larger than the ribs 26'; there are fewer ribs 26 per column height than ribs 26'. The first face 180 of the inner plate 16 is configured to be joined or otherwise attached to another second face of the end cap 14A or another pair of inner plates 16, such as via a joining rim 29 formed just inside the perimeter 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 ( Figure 4 ); Each flow channel typically includes a screen 21. In some embodiments, one or more narrow plastic (e.g., polypropylene) straps 400, etc. ( Figure 13 , shown on the end caps) are positioned above the septum and attached to the plate surface outside the active septum area to achieve more uniform and / or consistent channel height (e.g., between each pair of components, such as between an end cap and a plate, or between two plates) and better device performance. In some embodiments, the straps are thermally bonded to the top of the septum. In some embodiments, two straps may be used per septum.

[0082] Figure 6B An embodiment of the inner plate 16 is shown. In the embodiment shown, the visible surface or face is the second surface or face 160 and has a functional geometry including a plurality of spaced apart ribs 26' that support a diaphragm (not shown). In some embodiments, the second surface or face 160 of the inner plate 16 has a thickness less than Figure 5A The effective diaphragm area of ​​the inner surface of the end cap 14A shown in FIG (and similarly, less than Figure 6A). The second surface or face 160 is configured to mate and bond with a corresponding surface or face of the second plate 16, such as by thermal bonding, to form a pair of plates. Like the ribs 26 of the end cap 14A discussed above, a plurality of elongated, spaced-apart ribs 26' are formed on the surface or face 160 and are arranged in spaced-apart columns, wherein each rib 26' in a column is spaced apart from adjacent ribs 26' in that column. In some embodiments, the ribs 26' in each column are of equal spacing and size, and the spacing between columns is equal. In some embodiments, the ribs 26' are smaller than the ribs 26; there are more ribs 26' per column height than ribs 26. In some embodiments, the second surface or face 160 also includes an additional bonding rim 29' that traverses the length of the inner plate 16. The additional bonding rim 29' separates a first plurality or series of permeate ports 75 positioned along a row of ribs within the effective diaphragm area from a second plurality or series of permeate ports 76 positioned laterally spaced apart from the first plurality of permeate ports 75 and outside the effective diaphragm area. In certain embodiments, the first plurality of permeate ports are linearly aligned with one another. In certain embodiments, the second plurality of ports 76 can be linearly aligned with one another. When two plates 16 are assembled into a pair, the number of ports 75 in the first of the two plates can match the number of ports 75 in the second of the two plates, with each port 75 in the first plate aligned with a corresponding port 75 in the second plate, and the number of ports 76 in the first of the two plates can match the number of ports 76 in the second of the two plates, with each port 76 in the first plate aligned with a corresponding port 76 in the second plate. In other embodiments, the spaced plurality of ports 76 may not be linearly aligned. Furthermore, in other embodiments, the number of ports 75 may be different from the number of ports 76. The additional bonding rim 29' defines the permeate flow channel 77 and keeps the unfiltered feed / retentate liquid out of this longitudinal channel where it 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 permeate flow channel 77 should be large enough to avoid occlusion by molten plastic that may seep from the bonding rim when the plates are bonded together.

[0083] Now turn Figure 7 , showing the flow of sample feed and retentate according to certain embodiments. The feed enters the feed input 17 as depicted by arrow 117 and flows through the end cap 14A and the surface of the inner plate 16, through the flow channel defined by the septum 15 (and screen 21, if present) as shown by arrows 117A, 117B and 117C, and through the retentate outlet ( Figure 7 The permeate flow is not shown in Figure 7 middle.

[0084] Figure 8 The permeate flow is shown from the feed inlet 17 to the permeate outlet 5. The feed flow, depicted by arrow 200, enters the feed inlet 17, such as through the feed barb, and flows through the surface of the end cap 14A and through the membrane 15 and screen (if present) ( Figure 8 Filtered permeate liquid, depicted by arrows 201 and 202, flows toward the permeate outlet 5 as shown.

[0085] Figure 9A and Figure 9B Also shown is the permeate flow now through a pair of inner plates 16 according to certain embodiments. As shown, the permeate flow is depicted by arrows 200 and 205 through the end caps ( Figure 9A and Figure 9B The feed liquid entering through the opening 17' in fluid communication with the feed inlet 17 of the inner plate 16 (not shown) flows through the first surface or face 180 (arrow 200) of the inner plate 16 and the second surface or face 160 (arrow 205) of the inner plate 16. With respect to the permeate flow on one side of the second surface 160 (shown by arrow 205), the fluid flows along the small rib structure 26' (at Figure 9B 2 (not visible in the figure) flows through the membrane 15 of each plate 16 to the permeate port 75 and flows through the permeate port 75 to the side of the first surface 180 of each plate 16 as depicted by arrow 202. With respect to the permeate flow on one side of the first surface 180, the permeate fluid flows through the membrane 15 along the area of ​​the small rib structure 26' to the plurality of permeate ports 76 as depicted by arrow 204. Thus, all permeate fluid (whether from the first surface 180 or the second surface 160) flows through the plurality of ports 76 into the open area on one side of the second surface 160 and then flows longitudinally in the channel 77 until it reaches the permeate conduit feature 60, thereby allowing it to flow to the permeate outlet 5 in fluid communication with the permeate channel 77. In this way, the permeate fluid flows through the membrane 15 are combined and flow toward the permeate outlet 5.

[0086] Figure 10 and Figure 11 Further details of the permeate fluid flow are shown. Arrow 300 depicts the feed stream entering through the feed inlet (not shown), after which it flows through the end caps 14A, 14B and the surfaces of the corresponding internal plates 16, and through the membrane 15 and the screen 21 associated therewith. The resulting filtered permeate flowing through the membrane 15 is combined and flows to the permeate outlet 5, as indicated by Figure 10303 in FIG. More specifically, the permeate fluid flows through the membrane 15 to the permeate port 75 (arrow 302), and flows through the permeate port 75 to one side of the second surface. With respect to the permeate flow on one side of the first surface 180, the permeate fluid flows through the membrane 15 along the area of ​​the small rib structure 26' to the plurality of permeate ports 76, as depicted by arrows 204. Thus, all permeate fluid (whether from the first surface 180 or the second surface 160) flows through the plurality of ports 76 into the open area on one side of the second surface 160, and then flows longitudinally in the channel 77 until it reaches the permeate conduit feature 60, thereby allowing it to flow to the permeate outlet 5 in fluid communication therewith. In this way, the permeate fluid flows through the membrane 15 merge and flow toward the permeate outlet 5.

[0087] Figure 14 Still further illustrated is the permeate flow through a pair of internal plates 16, now near the end of the device having the permeate plug, away from the permeate barbs. Feed stream 300 entering through the feed barbs flows through the end caps 14A, 14B and the surfaces of the internal plates 16, and through the membrane 15 and screen 21. The resulting permeate flows through the membrane 15 combine and flow to the permeate channels between the internal plates 16, and then flow through the permeate channels to the permeate barbs 19 at the other end of the device, as depicted by the arrows.

[0088] In some embodiments, as Figure 12A 、 Figure 12B and Figure 12C As shown in FIG, two or more apparatuses 10 may be manifolded together, such as to achieve higher throughput or capacity. External piping (partially shown in FIG) may be used. Figure 12B In some embodiments, the feed and retentate lines are located at the center of the device and are split to the two filters. In some embodiments, a manifold tee 605 separates the feed and retentate flows for the two filters and connects to the piping system ( Figure 12B ). Figure 12B and Figure 12C Also shown is a center support plate 602 sandwiched between the two filters 10 to support internal pressure.

[0089] Although various aspects and embodiments have been disclosed herein, other aspects, embodiments, modifications, and variations will become apparent to those skilled in the art after reading and understanding the foregoing detailed description. The various aspects and embodiments disclosed herein are for illustrative purposes only and are not intended to be limiting. The present disclosure is intended to be construed as including all such aspects, embodiments, modifications, and variations as come within the scope of the appended claims or their equivalents.

Claims

1. A tangential flow filter for filtering a fluid, comprising: a first end cap and a second end cap, and each of a fluid feed inlet, a retentate outlet, and a permeate outlet on the first end cap or the second end cap; at least a first plate and a second plate, each plate having a first side and an opposing second side, the first side of the first plate facing the first end cap and having a first effective filter area, the second side of the first plate facing the first side of the second plate and having a second effective filter area; filter 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 the second plate in fluid communication with the first series of openings; a third series of spaced-apart openings through the first plate, spaced apart from the first series of spaced-apart openings; a fourth series of openings through the second plate in fluid communication with the third series of openings; wherein the third series of spaced-apart openings and the fourth series of spaced-apart openings are positioned in respective permeate channels in respective areas of the second side of the first plate and the first side of the second plate that are free of filter media, the areas being opposite respective filter media on the first side of the first plate and the second side of the second plate; The permeate channel is in fluid communication with the permeate outlet.

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

3. The tangential flow filter according to claim 1, wherein The openings in the third series of spaced apart openings are linearly aligned with one another. The tangential flow filter according to claim 1 , wherein: The filter 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 the first side of the first plate. The tangential flow filter of claim 4 , further comprising a screen between the first membrane and the second membrane. The tangential flow filter according to claim 4 , wherein: Fluid passing through the second membrane flows through the third series of spaced-apart openings and into the permeate channels.

7. The tangential flow filter according to claim 4, wherein Fluid passing through the first membrane enters the permeate outlet.

8. The tangential flow filter according to claim 1, wherein The filter media between the first plate and the second plate includes a third membrane attached to the second side of the first plate and a fourth membrane attached to the first side of the second plate.

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

10. The tangential flow filter of claim 1 further comprising filter media between the second side of the second plate and the second end cap.

11. A tangential flow filter for filtering a fluid, comprising: a first end cap and a second end cap, a fluid feed inlet, a retentate outlet, and a permeate outlet on the first end cap or the second end cap; a plurality of pairs of plates between the first end cap and the second end cap; each of the pair of the plurality of plates comprises at least a first plate and a second plate, each of the first plate and the second plate having a first side and an opposing second side, the first side of the first plate having a first effective filtration area, the second side of the first plate facing the first side of the second plate and having a second effective filtration area; filter media on the first side and the second side of each of the first plate and the second plate; a first series of spaced-apart openings through said first plate; a second series of openings through the second plate; a third series of spaced-apart openings through the first plate, spaced apart from the first series of spaced-apart openings; a fourth series of openings through the second plate in fluid communication with the third series of openings in the first plate; wherein the third series of spaced-apart openings and the fourth series of spaced-apart openings are positioned in respective permeate channels in respective areas of the second side of the first plate and the first side of the second plate that are free of filter media, the areas being opposite respective filter media on the first side of the first plate and the second side of the second plate; The permeate channel is in fluid communication with the permeate outlet.

12. A method of filtering a fluid sample, comprising: introducing the fluid sample into the feed inlet of the first end cap; causing the 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 the 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 attached to a first side of a first plate attached to the first end cap to form a second permeate stream and a second retentate stream, the second permeate stream flowing to a first plurality of spaced-apart permeate ports formed in the first plate and in fluid communication with the permeate channel and the first permeate outlet or the second permeate outlet, and the second retentate stream flowing to the first retentate outlet or the second retentate outlet; (c) contacting a third membrane attached to a second side of the first plate to form a third permeate stream and a third retentate stream, the third permeate stream flowing to a second plurality of spaced-apart permeate ports formed in the first plate and combining with the second permeate stream before the second permeate stream enters the first plurality of spaced-apart permeate ports in fluid communication with the permeate channel and the first permeate outlet or the second permeate outlet, the third retentate stream flowing to the first retentate outlet or the second retentate outlet; (d) contacting a fourth membrane attached to a first side of a second plate attached to the first plate to form a fourth permeate stream and a fourth retentate stream, the second plate being attached to the first plate, the fourth permeate stream flowing to a third spaced-apart plurality of ports formed in the second plate and in fluid communication with a fourth spaced-apart plurality of ports, the fourth spaced-apart plurality of ports being in fluid communication with the permeate channel and the permeate outlet, and the fourth retentate stream flowing to either the first retentate outlet or the second retentate outlet; as well as (e) contacting a fifth membrane attached to a second side of the second plate to form a fifth permeate stream and a fifth retentate stream, the fifth permeate stream flowing to the fourth plurality of spaced-apart permeate ports formed in the second plate in fluid communication with the permeate channel and the first permeate outlet or the second permeate outlet, and the fifth retentate stream flowing to the first retentate outlet or the second retentate outlet; as well as (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 conduit in fluid communication with the permeate channel and the first permeate outlet or the second permeate outlet, and the sixth retentate stream flowing to the first retentate outlet or the second retentate outlet; and A permeate stream is collected from the permeate outlet.

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

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

15. The tangential flow filter according to claim 1, wherein The second effective filter area is smaller than the first effective filter area.

16. The tangential flow filter according to claim 1, wherein The second series of openings are aligned with the first series of openings.

17. The tangential flow filter according to claim 1, wherein The third series of openings are aligned with the fourth series of openings.

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