Tangential flow filtration manifold

Abstract

A tangential flow filtration manifold takes a modular form for interconnection in a manifolded arrangement for aggregating a total filtration area of the aggregate filter (membrane) surface. A plurality of modular TFF cassette filters may be or stacked on the TFF manifold such that it allows the number of interconnected filters, as well as the membrane surface area within each cassette, to be readily reconfigured. A single output, or filtrate connection on the TFF manifold simplifies fluidic plumbing connections for directing and gathering the filtrate (permeate) produced as output.

Claims

1. In a tangential flow filtration (TFF) apparatus for directing a feed across a filter membrane to a permeate passing through the filter and an unfiltered retentate, a manifold device for directing the feed, retentate and permeate to a filter assembly defined by stack of filter cassettes, comprising: a manifold surface having a first side and a second side, the first side opposed from the second side; a feed channel fluidically coupling a feed port to a feed outlet for fluid communication with the filter assembly, the feed outlet on the manifold surface adjacent to the first side; a retentate channel fluidically coupling a retentate inlet to a retentate port, the retentate inlet configured for fluidic communication for receiving retentate from the filter assembly, the retentate inlet on the manifold surface adjacent to the second side; at least two permeate inlets on the manifold surface and configured to receive permeate from the filter assembly in a respective plurality of permeate channels through the manifold, including at least one of the permeate inlets adjacent to the first side and at least one permeate inlet adjacent to the second side, each of the permeate inlets aligned with corresponding orifices on the filter assembly, the permeate channels fluidically coupled to a single, aggregate permeate port for output of the permeate via a common outflow; a union fluidically coupling each of the plurality of permeate channels from each of the permeate inlets to the common outflow for output of the permeate from the filter assembly via the single, aggregate permeate port, each permeate channel receiving the permeate from the filter assembly via a respective permeate inlet, each of the permeate inlets adjacent to the first side or the second side of the manifold; the permeate channels further comprising a junction channel, the junction channel extending under the manifold surface continuously from the at least one permeate inlet adjacent the second side to the at least one permeate inlet adjacent the first side, the junction channel forming fluidic communication with the plurality of permeate inlets and the common outflow.

2. The device of claim 1 wherein the permeate inlets are positioned on the manifold based on a correspondence to permeate orifices on the filter assembly.

3. The device of claim 1 further comprising a filter cassette stack defining the filter assembly, the filter cassette stack including one or more filter cassettes, each filter cassette having aligned feed, retentate, and permeate orifices adapted to form continuous feed, retentate and permeate paths through the filter cassette stack.

4. The device of claim 1 wherein at least one of the permeate channels passes between a surface of the manifold and at least one of the feed channel or the retentate channel.

5. The device of claim 3 wherein the filter cassette stack includes an endplate for sealing an opposed end of each the feed, retentate and permeate paths for forming a closed fluidic system.

6. The device of claim 1 further comprising a row of feed outlets, a row of retentate inlets and one or more rows of permeate inlets, the row of feed outlets, row of retentate inlets and the row of permeate inlets defined by a predetermined position of orifices on the filter assembly.

7. The device of claim 1 wherein each of the feed port, retentate port and permeate port have a port diameter and terminus defined by a flange having a flange diameter greater than the port diameter and adapted for engagement by a tri-clamp.

8. The device of claim 1 further comprising a plug aligned with the tubular channel for directing the permeate to the aggregate permeate port.

9. The method of claim 1 wherein the plurality of permeate inlets are aligned in a plurality of linear rows, each linear rows and permeate inlets aligned with corresponding orifices on the filter assembly, and a first row of permeate inlets are adjacent the first opposed side; and a second row of permeate inlets are adjacent the second opposed side.

10. The device of claim 1, further comprising: a plurality of permeate inlets forming a linear arrangement adjacent to and parallel to the first side; and a plurality of permeate inlets forming a linear arrangement adjacent to and parallel to the second side.

11. The device of claim 1 wherein the junction channel extends more than half the longest dimension of the manifold.

12. In a tangential flow filtration (TFF) apparatus for directing a feed across a filter membrane to a permeate passing through the filter and an unfiltered retentate, a manifold device for directing the feed, retentate and permeate to a filter assembly defined by stack of filter cassettes, comprising: a manifold surface having a first side and a second side, the first side opposed from the second side; a feed channel fluidically coupling a feed port to a feed outlet for fluid communication with the filter assembly, the feed outlet on the manifold surface adjacent to the first side; a retentate channel fluidically coupling a retentate inlet to a retentate port, the retentate inlet configured for fluidic communication for receiving retentate from the filter assembly, the retentate inlet on the manifold surface adjacent to the second side; at least two permeate inlets on the manifold surface and configured to receive permeate from the filter assembly in a respective plurality of permeate channels through the manifold, including at least one of the permeate inlets adjacent to the first side and at least one permeate inlet adjacent to the second side, each of the permeate inlets aligned with corresponding orifices on the filter assembly, the permeate channels fluidically coupled to a single, aggregate permeate port for output of the permeate via a common outflow; and a union fluidically coupling each of the plurality of permeate channels from each of the permeate inlets to the common outflow for output of the permeate from the filter assembly via the single, aggregate permeate port, the permeate channels further comprising a junction channel, the junction channel extending under the manifold surface from the at least one permeate inlet adjacent the second side to the at least one permeate inlet adjacent the first side; the junction channel forming fluidic communication with the plurality of permeate inlets and the common outflow in communication with the permeate port.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The foregoing and other objects, features and advantages of the invention will be apparent from the following description of particular embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.

(2) FIG. 1 is a context view of a tangential flow filtration (TFF) manifold assembly suitable for use in configurations herein;

(3) FIG. 2 is a schematic view of a TFF manifold assembly of FIG. 1;

(4) FIGS. 3A and 3B show an example configuration of a lab scale filter cassette based on the approach of FIGS. 1 and 2;

(5) FIGS. 4A-4B show a process scale filter cassette and differences from the lab scale cassette;

(6) FIGS. 5A-5B show transparent and exploded views of a particular configuration of the lab filter cassette as in FIGS. 3A-3B;

(7) FIG. 6 shows a transparent view of a process filter cassette as in FIGS. 4A-4B;

(8) FIG. 7 shows a method of manufacturing the lab scale cassette of FIGS. 3A-3B;

(9) FIGS. 8A-8B show an alternative, additive manufacturing approach for the cassette of FIG. 7;

(10) FIG. 9 shows a method of manufacturing a process scale cassette as in FIGS. 4A-4B;

(11) FIG. 10 shows an example setup of the filter cassette engaged in a lab application; and

(12) FIG. 11 shows an example of a full manifold filter assembly as in FIG. 10 for a process scale cassette.

DETAILED DESCRIPTION

(13) Tangential Flow Filtration (TFF) is a type of filtration where the feed stream passes parallel to the membrane face as one portion of the flow passes through the membrane (permeate). Simultaneously, the remainder of the flow (retentate) recirculates back to the feed reservoir. The benefit of TFF versus normal flow filtration, e.g., a typical house water filter, is that the parallel flow across the membrane surface promotes cleaning by way of a sweeping actoon at the membrane's surface, which allows for higher volumetric throughput. Furthermore, the claimed manifold provides particular benefits specific to TFF flat sheet membrane that is laid flat and stacked in alternating layers.

(14) These layers are then bound into a discrete unit using an adhesive to form the cassette device or filter. Next, to use the filter, one must have fluid a manifold to direct fluids into and out of the filter. The manifold will be lodged with the filter inside a clamping device designed to seal and compress the cassettes. Configurations herein illustrate improvements in the manifold. As the industry has generally migrated to plastics and single-use technologies, the prior art manifolds are no exception. Currently, plastic or single-use manifolds require four external connections, one inlet, and three outlets, two of which direct fluids from the permeate layers. The disclosed approach improves usability by reducing the number of permeate outlets without impacting filtration performance.

(15) A conventional TFF manifold, therefore, employs at least two external connections. Configurations herein reduced this to a single permeate port without compromising effectiveness in the preferred embodiment. Since the TFF manifold has two internal permeate fluid passages, each connected separately to one of the two external permeate connections, the preferred embodiment connects fluid paths defined by channels within the manifold to exit through the single connection described above. Conversely, conventional approaches require the combination of the two permeate fluid streams outside of the TFF manifold using peripheral tubing and fittings. Indeed, one could choose to use only one external permeate connection of the prior art approach while leaving the other closed, but doing so affects filtration performance. Instead of having two exit points for permeate flow, one at each cassette end, there would be only one. By blocking one permeate connection on a prior art manifold, permeate fluid from the blocked end is forced to travel further across the membrane and through the cassette to exit. Since the cassette layers are tightly packed, this presents additional flow resistance.

(16) FIG. 1 is a context view of a tangential flow filtration (TFF) manifold assembly 130 suitable for use in configurations herein. In a TFF manifold assembly, a feed flow 102 delivers a feed fluid 113 into a manifold assembly 130. The manifold assembly 130 includes a manifold and one or more filter cassettes, discussed further below. The manifold assembly directs the feed flow across a retentate side 109 of a filter surface 140. A permeate side 110 of the filter surface 140 receives substances that pass through the filter surface as the feed fluid 113 passes across the filter surface, while unfiltered material passes to the retentate flow 103. The filtrate on the permeate side 110 passes to the permeate flow 104. The manifold assembly determines the area of the filter surface and flow rate based on the delivery rate of the feed fluid 113 and the number and type of cassettes stacked to form the manifold assembly 130.

(17) FIG. 2 is a schematic view of a TFF manifold assembly of FIG. 1. Referring to FIG. 2, the full manifold assembly 130 is defined by a manifold 160 and one or more cassettes 162-1 . . . 162-N (162 generally) in a fluidically coupled arrangement to define the feed 102, retentate 103, and filtrate 104 flows. In the example configurations herein, the tangential flow filtration process includes a membrane filter 150, from which substances in the feed fluid 113 permeate thought the membrane filter 150 for gathering permeate on the permeate side 110; different filter and/or membrane types may result in a different filtrate composition on the permeate side 110.

(18) The manifold includes a feed port 2, retentate port 3, and permeate port 4, for the respective flows. Each of the ports is adapted for connection to fluidic vessels for performing the desired filtration process. A typical arrangement is a tri-clamp flange for attachment to established laboratory and/or production fluid vessels, typically a tubing setup. In the tri-clamp setup, each of the feed port, retentate port and permeate port have a port diameter and terminus define by a flange having a flange diameter greater than the port diameter and adapted for engagement by the tri-clamp. A barbed attachment may also be employed. The manifold includes a feed channel 202 for receiving the feed fluid 113 from the feed port 2, and a retentate channel 203 for delivering the retentate to the retentate port 3, typically for recirculation via the aforementioned tubing and/or other laboratory or process setup.

(19) The permeate flows from the permeate side 110 to a plurality of permeate passages 11-1 . . . 11-2 (11 generally) from the collective array of filter cassettes 162. In contrast to conventional approaches, the permeate passages 11 aggregate at a junction 111 to merge with a common outflow 204 leading to the permeate port 4. The plurality of permeate passages 11 may be formed, drilled or molded in the manifold 160, and emanate from various orifices on the filter cassettes so that fluid pressure and balance across the membrane filter 150 is not disturbed. In other words, the manifold 160 redirects and channels the permeate to the individual permeate port 4 without imposing any changes on the filter cassette design or flow orifices; the junction 111 and associated permeate passages are formed within the manifold 160.

(20) FIGS. 3A and 3B show an example configuration of a lab scale filter cassette based on the approach of FIGS. 1 and 2. Referring to FIGS. 1-3B, in a tangential flow filtration (TFF) apparatus for directing a feed across a filter membrane to a permeate passing through the filter and an unfiltered retentate, a manifold device for directing the feed, retentate and permeate includes a feed channel 202 fluidically coupling a feed port 2 to a feed outlet adapted to engage a filter assembly, and a retentate channel 203 fluidically coupling a retentate inlet to retentate port 3. The retentate inlet is adapted to receive retentate from the filter assembly through one or more retentate apertures 9. A plurality of permeate inlets align with permeate apertures 10 and are adapted to receive permeate from the filter assembly in a respective plurality of permeate channels 11, such that the permeate channels fluidically couple to the permeate port 4. The junction 111 defines a union fluidically coupling the plurality of permeate channels 11 for consolidating the flow into the individual permeate port 4.

(21) A manifold 1 may be fabricated by a subtractive (machining) or additive manufacturing processes, preferably from polypropylene or like material that has been tested and approved for appropriate material handling. The manifold 1 dimensions will vary by size but range from 3 to 9 inch wide by 81 inch long by to 3 inch thick. The manifold 1 will generally include fluid passageways defining the feed port 2 operable as the inlet for unfiltered material, retentate port 3 as the outlet for an unfiltered recirculation loop, and permeate port 4 providing the outlet for filtered material. A particular configuration uses a biopharmaceutical grade tri-clamp connection or an equally robust barbed connection to facilitate external links to the three fluid streams. FIGS. 3A and 3B show the tri-clamp type of connection flange 5.

(22) Continuing to refer to FIGS. 1-3B, in operation the feed port connection 2 on the side of the manifold 1 is in fluid communication with at least one, and as many as twenty, feed apertures 6 on the manifold surface 7. The retentate port 3 on the side of the manifold is in fluid communication with at least one, and as many as twenty of the retentate apertures 9 on the manifold surface 7. Although not limited to the locations shown, a particular configuration positions the feed 2 and retentate 3 ports on the same side of the manifold for enhanced user accessibility.

(23) The permeate port 4 on the side of the manifold will be in fluid communication with at least two, and as many as thirty-two, permeate apertures 10 on the manifold surface(s) 7 and 8 (FIGS. 4A,4B). Furthermore, the permeate apertures corresponding to the feed and retentate ends of the manifold will be in fluid communication through tubular passages 11 within the manifold and collectively exit through the permeate port 4. Should the fabrication process be subtractive, i.e., machining, then the internal passageways connecting the permeates will require up to three external drill access ports 12, plus a corresponding sealing plug 13. The number of drill access ports 12 will depend on the location of the permeate port 4. Conversely, should the fabrication process be additive, i.e., 3D printed, external drill access ports may still be used but are not required. Sealing plugs 13, if needed, can be threaded inserts, bonded with adhesive, or welded in place using ultrasonics or similar techniques

(24) The manifold surface 7 has an array of orifices positioned for surface alignment and fluidic engagement with the filter cassette. The permeate inlets (apertures) 10 are positioned on the manifold 1 based on a correspondence to permeate orifices on the manifold filter assembly 130, and the union 111 couples the permeate channels 11 from each of the permeate inlets to the common outflow 204 fluidically coupled to the permeate port 4.

(25) Due to the alignment of the feed 6, retentate 9 and permeate 10 orifices, a filter cassette stack of a suitable size may define the manifold filter assembly 130. The filter cassette stack includes one or more filter cassettes, each filter cassette having aligned feed, retentate, and permeate orifices adapted to form continuous feed, retentate and permeate paths through the filter cassette stack.

(26) FIGS. 4A-4B show a process scale filter cassette and differences from the lab scale cassette. Process scale cassettes are intended for a production volume and also provide similar membrane filtration according to the concepts of FIGS. 1 and 2. A corresponding process scale manifold 1 may include a row of feed outlets, a row of retentate inlets and one or more rows of permeate inlets, such that the row of feed outlets, row of retentate inlets and the row of permeate inlets are defined by a predetermined position of orifices on the filter assembly 130 based on the cassette used. Process scale cassettes are larger and the surface 8 includes an array of feed 6, retentate 9 and permeate apertures 10 as described above. Both the lab and process manifolds arrange orifices to correspond to the respective feed, retentate and permeate flows.

(27) FIGS. 5A-5B show transparent and exploded views of a particular configuration of the lab filter cassette as in FIGS. 3A-3B. Referring to FIGS. 1-5B, in a particular arrangement, the ports include a feed 2 and a retentate 3, such that the feed and retentate are in fluidic communication on a particular (same) side of the manifold 1, further comprising the tangential flow path between the feed and retentate for forming a unidirectional fluid flow between the feed and retentate. This typically defines a recirculation loop, where the recirculation loop provides a fluidic connection for fluid exiting the retentate for directing the exiting fluid back to the feed. An iterative filtration cycle is established for achieving variable degrees of condensing the input via the filtrate. It is apparent that the union 111 couples each of a plurality of permeate channels 11 to a single, aggregate permeate port 4, such that each permeate channel receives the permeate from the filter assembly via a respective permeate flow 104.

(28) In general, configurations herein depict that the union 111 is fluidically coupled to the permeate port 4 via a common outflow 204, and the permeate port is disposed at a predetermined position based on a position of the feed port and the retentate port, typically centered between on the same side or located on an opposed side. Other suitable configurations may fabricate the permeate port 4 and related channels 11 and union 111 at alternate locations.

(29) In FIGS. 5A and 5B, the central flanked permeate port configuration of the lab-scale format of the manifold 1 is shown. One of the features of the disclosed approach is the internal routing of fluid from the two permeate orifices on the manifold surface to the single permeate outlet, or permeate port 4. It should also be understood that the feed orifice 6 and feed port 2 are in fluid communication, as are the retentate orifice 9 and retentate port 3. Thus, regardless of size, whether lab-scale or process-scale, these links between the external ports and manifold surface orifices are consistent.

(30) In FIG. 5B, an exploded view of the filter and cover plate are shown for reference. This sketch further illustrates the lines of fluid flow through the manifold. As can be seen, the two separate permeate orifices at the surface of the manifold connect within the manifold and exit through a common outflow 204. The position of the permeate fitting connection, as shown, is believed to be the most versatile; however, one should note that fitting connections could be placed on either side of the manifold and off-center.

(31) FIG. 6 shows a transparent view of a process filter cassette as in FIGS. 4A-4B. Referring to FIGS. 4A-6, FIG. 6 illustrates aa process-scale format. In FIG. 6, the internal routing of fluid from the two permeate orifices and respective channels 11-1 . . . 11-2 leads from the manifold surface 8 to the single permeate port 4. As shown, this manifold receives cassettes only on one side; alternate configurations employ orifices and channels for engaging cassettes on both sides for enabling a larger number of cassettes in a flow through manifold assembly 130.

(32) FIG. 7 shows a method of manufacturing the lab scale cassette of FIGS. 3A-3B, and FIGS. 8A-8B show an alternative, additive manufacturing approach for the cassette of FIG. 7. Referring to FIG. 3A-8B, the manifolds 1 and 1 may be fabricated by one of several approaches. FIGS. 7-8B illustrate various alternative designs and the respective manufacturing method. A more traditional manufacturing process includes both manual and computer-controlled milling and turning. Alternatively, a 3D printing additive manufacturing process may also be invoked, where the material is added one layer at a me. Additive processes include but are not limited to fused deposition and UV-cured resin technologies. Fused deposition has an additional advantage in that the technology is available that would allow for finished parts in both plastic and metal. Multiple passes or fusing of individual portions may also be performed, as opposed to a single continuous deposition/printing pass. An alternative approach is through milling and/or drilling in a so-called of subtractive manufacturing, or machining, from a single block of material or aggregations thereof.

(33) FIG. 7 shows a drilling path 11 for a permeate passage 11 for joining a first permeate orifice 10-1 to a second permeate orifice 10-2. The drilling path 11 commences at a sidewall 164, maintains a trajectory to intersect a passage from the second permeate orifice to meet a permeate passage 11 from the first orifice 10-1 and define the junction 111. A plug or seal 13 is then inserted to close the drilled entry 166 and form a closed fluid system. Precise trajectory of the drill path 11 is employed to ensure an accurate meeting and junction 111 of the passages 11.

(34) FIGS. 8A and 8B depict another lab-scale manifold designed for additive manufacturing. FIGS. 8A and 8B show internally connected permeate bores without requiring any external port for drill access. Furthermore the permeate port 4 is located in a same-side center orientation with the feed 2 and retentate 3 ports. The use of additive manufacturing also allows for additional material savings through pockets or voids 168 absent of print medium in non-critical areas.

(35) A further feature shown in FIGS. 8A and 8B are positioning the permeate port 4 on the same side of the manifold between the feed port 2 and the retentate port 3 to maximize user accessibility and convenience during use. However, since user convenience is subjective and will vary by individual, there is no performance disadvantage by locating the permeate port 4 on the side opposite the feed and retentate Port Connections, as illustrated in FIGS. 8A and 8B.

(36) FIG. 9 shows a method of manufacturing a process scale cassette as in FIGS. 4A-4B. Referring to FIGS. 2, 3 and 9, the machined process-scale manifold 1 is shown with the permeate port 4 located on the same side as the feed 2 and retentate 3. Because this is a machined component, and the permeate connection is located on the same side as the feed and retentate connections, three plug 13 locations are employed; one for each of the permeate orifice arrays with channels 11-1 and 11-2, and a third 11 drill bore that locates permeate passage 11-3 at an angle to pass above the retentate passage 203 and meet permeate passage 11-1 to define the junction 111 on the path 11 aligned to intersect permeate passage 11-2. Therefore, the bore trajectory 11 for the permeate channel 11-1 is drilled to pass between the surface 7 of the manifold and at least one of the feed channel 202 or the retentate channel 203. In general, as the number of feed and retentate orifices increases, permeate passages 11 leading to the union encounter tighter tolerances and more complex routing to avoid the retentate loop.

(37) In various configurations, the manifold is formed from a substrate for forming the feed channel, the retentate channel and the plurality of permeate channels from either additive printing or extrusion, or from controlled boring of a monolithic substrate.

(38) FIG. 10 shows an example setup of the filter cassette engaged in a lab application. A feed pump 170 recirculates the feed fluid 113 from a recirculation vessel 172 to the feed port 2 and receives the retentate from the retentate port 3. The manifold assembly 130 directs the filtrate to the single filtrate port 4 and into a collection vessel 174.

(39) FIG. 11 shows an example of a full manifold filter assembly as in FIG. 10 for a process scale cassette. Referring to FIGS. 10 and 11, the filter clamp is a device that is designed to create a constant compression force on the manifold assembly 130 including a manifold 1 and one or more filter cassettes 160. Clamping force can either be generated using manual techniques, most commonly with threaded nuts and rods 179 as shown below, or through the use of hydraulic cylinders. A filter clamp can be a simple device made from two rigid plates through which alignment rods are threaded. The rods 179 will allow for the manifold 1 and cassette(s) to be stacked in alignment while the compression force is applied. Each cassette will be sealed using a gasket 178 or integral sealing feature. For single use applications, all fluid contact items must be disposable; therefore, a plate or gasket that isolates the last cassette from a clamp endplate 176 is employed. The full manifold assembly 130 includes the filter cassette stack and the endplate 176 for sealing an opposed end of each the feed, retentate and permeate paths for forming a closed fluidic system.

(40) While the system and methods defined herein have been particularly shown and described with references to embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.