Chromatography Devices

Abstract

- at least one chromatographic material unit (203) comprising a convection-based chromatographic material, the at least one chromatographic material unit (203) being substantially rectangular having a length (L) and a width (W); - at least one fluid distribution system (207) configured to distribute fluid into and from at least one chromatographic material unit (203), the fluid distribution system (207) comprising a distribution device (209a) and a collection device (209b) sandwiching the chromatographic material unit (203); A chromatography device comprising: A chromatography device, wherein the distribution device (209a) comprises a plurality of parallel grooves (255) for distributing fluid passing through the chromatographic material unit (203), and the collection device (209b) comprises a plurality of parallel grooves (255) for collecting fluid passing through the chromatographic material unit (203), the parallel grooves spanning substantially the entire length (L) of the chromatographic material unit (203) and distributed over substantially the entire width (W) of the chromatographic material unit (203).

Description

[Technical field]

[0001] The present invention relates to a chromatographic device that includes a convection-based chromatographic material. [Background technology]

[0002] Historically, conventional packed bed chromatography using porous beads has been a very powerful separation tool. In porous bead-based systems, the binding events between the target molecules / impurities and the solid phase rely on diffusion into the porous beads. Therefore, there is a strong correlation between the interaction of the molecules with the solid phase of the porous bead-based system and the residence time, and therefore the flow rate, given. Thus, the binding capacity decreases as the residence time decreases. This type of chromatography can be called diffusion-based chromatography. Any matrix included in diffusion-based chromatography materials is made of particles and essentially exhibits a diffusion limitation of mass transfer in that the rate of the adsorption / desorption process is determined by the diffusion rate of the substance as a result of the diffusion coefficient of the substance into and out of the particle, which is quite highly dependent on the size or molecular weight of the substance and the accessibility of the particle's pores in terms of the size, structure and depth of the particle's pores.

[0003] As an alternative to porous bead-based systems, monoliths or membranes are sometimes used. The flow through these materials and the mechanism by which molecules interact with the solid phase is convection rather than diffusion, and therefore the binding capacity of monoliths or membranes to flow is much lower than that of porous bead-based systems. These materials can be operated at much higher flow rates than porous bead-based materials. In (membrane) adsorption chromatography, components of the fluid, e.g. individual molecules, satellites or particles, bind to the surface of the solid in contact with the fluid by diffusion without the need to pass through pores, and the active surface of the solid phase is accessible to the molecules by convective transport. The advantage of membrane adsorbers over packed chromatography columns is that they are compatible with operation at much higher flow rates. This is also called convection-based chromatography. Convection-based chromatographic materials include any matrix in which the application of a hydraulic pressure difference between the inflow and outflow of the matrix forces perfusion of the matrix, achieving substantial convective transport of substances between the matrix and the surface of the matrix intended to interact with said substances, whereby interaction is achieved very rapidly at high flow rates.

[0004] Convection-based chromatography and membrane adsorber are described, for example, in U.S. Patent Application Publication No. 20140296464A1 (Patent Document 1), U.S. Patent Application Publication No. 20160288089A1 (Patent Document 2), WO 2018011600A1 (Patent Document 3), and WO 2018037244A1 (Patent Document 4), which are incorporated by reference in their entireties.

[0005] However, membrane adsorbers have the problem that the total accessible surface area of ​​the support for interaction with the target molecules is smaller compared to porous beads. Therefore, the binding capacity may also be reduced. This is due to the fact that the porous bead structure, due to the large surface area inside the beads, promotes a large binding capacity for substances that are closer to the porous structure by the slow diffusion mechanism described. To increase the surface area and capacity with convection-based membrane adsorbers and compensate for the lack of area provided by the diffusion pores, the size of the convection pores of the membrane adsorbers can be reduced. This allows for more convection pores and, by providing a larger volume of convection pores for a specific surface area, the total accessible surface area for interaction between the substance and the matrix is ​​also larger. This can significantly improve the binding capacity of the convection matrix.

[0006] However, as a result of the smaller convective pores with the membrane adsorber, the hydrodynamic resistance to flow increases compared to a conventional packed bed. However, the membrane adsorber can still be constructed to a very low height compared to a packed bed, so that the increased hydrodynamic resistance can be compensated for by the lower height of the matrix. Also, membrane adsorber has the advantage that a low matrix height can be achieved by design, since the matrix consists of a continuous sheet of membrane material. This is a considerable advantage compared to conventional chromatographic beds packed from individual beads, where the geometry and bed height are limited for practical reasons of obtaining a stable and uniform packed bed.

[0007] Although membrane adsorber can provide high throughput and binding capacity due to small convective pores, and the adsorber geometry can compensate for the large hydrodynamic resistance due to its low height, the overall performance is limited by the efficiency in distributing (and collecting) fluid across the inlet and outlet of the matrix. This is especially important when large-scale distribution and collection of liquid is required across matrices with large inlet and outlet areas.

[0008] Thus, one of the remaining problems in taking advantage of convective matrices and membrane adsorber systems is the efficient distribution and collection of liquids and materials at the inlet and outlet faces of the matrix so that chromatographic efficiency can be increased. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] US Patent Application Publication No. 20140296464A1 [Patent Document 2] US Patent Application Publication No. 20160288089A1 [Patent Document 3] International Publication No. 2018011600A1 [Patent Document 4] International Publication No. 2018037244A1 Summary of the Invention [Problem to be solved by the invention]

[0010] It is an object of the present invention to provide an improved chromatography device that includes a convection-based chromatographic material.

[0011] It is a further object of the present invention to provide a chromatography device including a convection-based chromatography material that allows high flow rates and can withstand high operating pressures and high internal loads to support a desired material thickness of the chromatography material.

[0012] It is a further object of the present invention to provide a chromatography device that allows high flow rates, can withstand high operating pressures and high internal loads, at a desired material thickness, to support convection-based chromatography materials in a disposable paradigm.

[0013] It is a further object of the present invention to provide a chromatographic device that enables high chromatographic performance through uniform and simultaneous efficient liquid distribution and collection, thereby enabling uniform flow through the chromatographic material and uniform residence time distribution of substances through the chromatographic material.

[0014] It is a further object of the present invention to provide a chromatographic device that allows for high chromatographic performance by providing a device with low liquid holdup.

[0015] It is a further object of the present invention to provide a chromatography device having an improved liquid distribution and collection system that is easy to wash and clean. [Means for solving the problem]

[0016] This is achieved by a chromatography device as claimed in claim 1.

[0017] According to one aspect of the present invention, - at least one chromatography material unit, the chromatography material unit including a convection-based chromatography material and having a length (L) and a width (W), the chromatography material unit being substantially rectangular; - at least one fluid distribution system configured to distribute fluid into and from at least one chromatographic material unit, the fluid distribution system comprising a distribution device and a collection device sandwiching said chromatographic material unit; - Entrance and - at least one fluid inlet channel connecting an inlet to each chromatographic material unit via a fluid distribution system; - Exit, - at least one fluid outlet channel connecting an outlet to each chromatographic material unit via a fluid distribution system; A chromatography device is provided, comprising: The distribution device has a plurality of parallel grooves for distributing fluid passing through the chromatographic material unit, the plurality of parallel grooves being fluidly connected to an inlet via a common inlet rail of the distribution device, and the collection device has a plurality of parallel grooves for collecting fluid passing through the chromatographic material unit, the plurality of parallel grooves being fluidly connected to an outlet via a common outlet rail of the collection device, the parallel grooves spanning substantially the entire length (L) of the chromatographic material unit from a first end to a second end of the parallel grooves and distributed across substantially the entire width (W) of the chromatographic material unit, the common inlet rail and the common outlet rail being fluid channels arranged in a direction substantially perpendicular to the direction of the parallel grooves and fluidly connected to the first end of each of the parallel grooves.

[0018] This results in a chromatographic device that allows high chromatographic performance through uniform and efficient liquid distribution and collection over the chromatographic material. One advantage of providing parallel grooves for fluid distribution and collection over the chromatographic material according to the present invention is that it provides the chromatographic material with efficient mechanical support in addition to the mechanical forces resulting from the support of the chromatographic material at the desired thickness to withstand the mechanical forces imposed on the material due to pressure losses in the flow direction. This is achieved by providing large walls and contact areas for the chromatographic material between the grooves, distributing the mechanical load over as large a surface area as possible, thereby ensuring the homogeneity and integrity of the chromatographic material over many load and pressure cycles.

[0019] Another advantage of providing parallel channels for fluid distribution and collection across a chromatographic material according to the present invention is that it allows for uniform and simultaneous distribution and collection of liquid across the material, by providing the parallel channels with appropriate spacing and cross-sectional area.

[0020] Another advantage of providing parallel channels for fluid distribution and collection according to the present invention is that said liquid distribution and collection can be achieved with minimal liquid hold-up volume, which is achieved by optimizing and tailoring the channel shape in terms of width and depth.

[0021] Prior art distribution systems in chromatography generally refer to distribution systems that provide a tortuous flow path, e.g. a number of grooves or the like in a tortuous pattern, where the liquid to be applied to the chromatographic matrix can choose various separate migration paths between the inlet and the outlet. A disadvantage of the tortuous paths of the prior art designs is that the overall holdup is necessarily larger than with the subject of the present invention. Another disadvantage of the tortuous paths of the prior art designs is that the support area of ​​the walls, i.e. the area not included in the distributor's open channels, is necessarily smaller compared to the present invention, providing less mechanical support to the chromatographic matrix and less possible loads and operating pressures.

[0022] In one embodiment of the present invention, the distribution device comprises a distribution plate in contact with the inlet face of the chromatographic material unit, the distribution plate having parallel grooves for distributing fluid supplied from the inlet of the chromatographic device to the chromatographic material unit, and the collection device comprises a collection plate provided in contact with the outlet face of the chromatographic material unit, the collection plate having parallel grooves for collecting fluid from the chromatographic material unit.

[0023] In one embodiment of the invention, each of the parallel grooves has a cross-sectional area that decreases from the first end to the second end.

[0024] In one embodiment of the present invention, the inlet common rail and the outlet common rail are provided across substantially the entire width (W) of the chromatographic material unit from a first end to a second end of the inlet common rail and the outlet common rail, the inlet fluid channel is connected to the first end of the inlet common rail so that fluid is supplied to the distribution device from a first corner of the fluid distribution system, and the outlet fluid channel is connected to the first end of the outlet common rail so that fluid from a second corner of the fluid distribution system is collected from the collection device, the second corner being diagonally opposite the first corner.

[0025] In one embodiment of the invention, the inlet and outlet common rails are provided along opposite edges of the chromatographic material unit.

[0026] In one embodiment of the invention, the inlet common rail has a cross-sectional area that decreases from the first end to the second end of the inlet common rail.

[0027] In one embodiment of the invention, the total combined area of ​​the wall surfaces between the parallel grooves in the distribution / collection device facing the chromatographic material unit is twice as large as the total combined area of ​​the grooves facing the chromatographic material unit.

[0028] In one embodiment of the invention, the parallel grooves each have a width of less than 1.5 mm and are spaced apart by more than 2 mm.

[0029] In one embodiment of the invention, the holdup volume of the chromatography device is less than 1.6 times, such as 1.5 times, the volume of the membrane of the chromatography unit.

[0030] In one embodiment of the present invention, the outlet common rail has a larger fluid capacity than the inlet common rail.

[0031] In one embodiment of the invention, the chromatography device comprises at least one cassette, each cassette comprising a fluid distribution system and a chromatographic material unit.

[0032] In one embodiment of the invention, the chromatography device comprises at least two cassettes stacked together, each with a portion of an inlet fluid channel fluidly connected to a common inlet rail provided on the cassette, which may be in fluid communication with an inlet of the chromatography device, optionally via one or more of the other cassettes of the chromatography device, each with a portion of an outlet fluid channel fluidly connected to a common outlet rail provided on the cassette, which may be in fluid communication with an outlet of the chromatography device, optionally via one or more of the other cassettes of the chromatography device.

[0033] In one embodiment of the invention, the chromatography device further comprises a first end plate and a second end plate between which the at least two cassettes are provided, and the chromatography device further comprises a locking member configured to lock the first end plate and the second end plate to one another.

[0034] In one embodiment of the invention, the chromatography device further comprises an elastomeric seal provided on the outer periphery of the chromatographic material unit surrounding the parallel grooves for sealing the distribution device and the collection device.

[0035] In one embodiment of the invention, each chromatographic material unit comprises at least one adsorbent membrane, in one embodiment of the invention, said adsorbent membrane is a polymer nanofiber membrane.

[0036] In one embodiment of the present invention, each chromatographic material unit comprises at least one adsorbent membrane sandwiched between at least one top spacer layer and at least one bottom spacer layer, or at least two adsorbent membranes stacked on top of each other with a spacer layer between them, sandwiched between at least one top spacer layer and at least one bottom spacer layer. [Brief description of the drawings]

[0037] [Figure 1] 1 is an exploded perspective view of a chromatography device according to one embodiment of the present invention. [Figure 2a] FIG. 2 shows a first side of a distribution or collection device according to one embodiment of a distribution system that may be provided in a chromatography device according to the present invention. [Figure 2b] FIG. 2 shows the opposite second side of a distribution or collection device according to one embodiment of a distribution system that may be provided in a chromatography device according to the present invention. [Figure 2c] FIG. 2b is a cross-sectional view of the distribution or collection device shown in FIG. 2a along line AA. [Figure 2d] FIG. 2b is a cross-sectional view of the distribution or collection device shown in FIG. 2a along line BB. [Figure 3a] 2 shows a front or rear view of the chromatographic device of the present invention shown in FIG. 1 when assembled. [Figure 3b] FIG. 3b is a cross-sectional view along CC of the chromatographic device of FIG. 3a. [Figure 3c] FIG. 3b is a cross-sectional view along DD of the chromatographic device of FIG. 3a. [Figure 4a] 1 is a perspective view of a chromatography device according to another embodiment of the present invention, in which a plurality of the chromatography devices shown in Figures 1 and 3a-3c are assembled and connected in parallel. [Figure 4b] FIG. 4b is a cross-sectional view of the chromatographic device shown in FIG. 4a. [Figure 4c]FIG. 4b shows a portion of the cross section in more detail. [Figure 5a] FIG. 4 is a schematic diagram of the flow path of a chromatographic device similar to that shown in Figures 4a-4c, in which eight chromatographic devices similar to those shown in Figures 1 and 3a-3c are connected in parallel. [Figure 5b] FIG. 4 is a schematic diagram of the flow path of another chromatographic device similar to that shown in Figures 4a-4c, in which eight chromatographic devices similar to those shown in Figures 1 and 3a-3c are connected in parallel. [Figure 6a] 2 is a schematic perspective view of a fluid distribution system according to another embodiment of the present invention; [Figure 6b] 2 is a schematic perspective view of a fluid distribution system according to another embodiment of the present invention; [Figure 6c] 1 is a schematic perspective view of a fluid distribution system according to yet another embodiment of the present invention; DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] FIG. 1 is an exploded perspective view of a chromatography device 201 according to an embodiment of the present invention. The chromatography device 201 comprises at least one chromatography material unit 203, which comprises a convection-based chromatography material. The chromatography material unit is suitably an axial flow device and may comprise a flat sheet membrane material. The chromatography material unit is substantially rectangular in shape having a length L and a width W. By substantially rectangular, it would be meant that the chromatography material unit may have, for example, chamfered or beveled corners or curved side walls. "Substantially rectangular" may also include more elliptical or diamond shaped chromatography materials.

[0039] As discussed above, convection-based chromatographic materials can be, for example, adsorbent membranes, where the flow through such materials is convective rather than diffusive. Adsorbent membranes can be, for example, polymer nanofiber membranes, such as, for example, cellulose, cellulose acetate, and cellulose fibers that have been treated for use as adsorbents. Adsorbent membranes can alternatively be conventional membranes made of standalone materials or by emulsion.

[0040] Optionally, the adsorbent membrane comprises polymer nanofibers. The polymer nanofibers may have an average diameter of 10 nm to 1000 nm. For some applications, polymer nanofibers having an average diameter of 200 nm to 800 nm are appropriate. For certain applications, polymer nanofibers having an average diameter of 200 nm to 400 nm may be appropriate. Optionally, the polymer nanofibers are provided in the form of one or more nonwoven sheets, each comprising one or more polymer nanofibers. Optionally, the adsorbent chromatographic medium is formed from one or more nonwoven sheets, each comprising one or more polymer nanofibers. The nonwoven sheets comprising one or more polymer nanofibers are mats of one or more polymer nanofibers, each nanofiber being essentially randomly oriented, i.e., the nanofibers are not fabricated to adopt a particular pattern. Optionally, the chromatographic material unit comprises one or more spacer layers. A spacer layer may be provided to add structural integrity to the adsorbent chromatographic medium. In particular, the spacer layer can be mechanically stiffer than the nonwoven sheet of nanofibers. The spacer layer can assist in mitigating deformation of the adsorptive chromatographic media to keep the channels formed at the flow head open during manufacture and / or use of the chromatographic system. Ideally, the spacer layer should be incompressible or mostly incompressible to allow for alternating layering of compressible polymer nanofibers to allow the porosity of this stack to be maintained at higher flow rates than a stack of compressible nanofibers alone. The format and composition of the spacer material is not particularly limited, but it should be more porous than the nanofiber layers and of minimal thickness to reduce the dead volume of the stack. Suitable materials are 10-120 (g / m 2 ) non-woven polypropylene.

[0041] The chromatographic device 201 according to the invention further comprises at least one fluid distribution system 207 configured to distribute fluid into and out of at least one chromatographic material unit 203. In the embodiment of Fig. 1, only one chromatographic material unit 203 and one fluid distribution system 207 are provided. In Figs. 4-5 a chromatographic device 201' is shown comprising eight chromatographic material units 203 and eight fluid distribution systems 207. Now referring to Figs. 1-3, the fluid distribution system 207 comprises a distribution device 209a and a collection device 209b, between which said chromatographic material unit 203 is sandwiched.

[0042] When a total number of chromatographic material units, spacer layers or sheets of any type of chromatographic material are used, the chromatographic material units are sealed at or near the periphery by an elastomeric seal 281 such that fluid communication is provided between the layers sandwiched between each other without significantly affecting the surface area of ​​the sorbent material. A preferred embodiment of the chromatographic material unit 203 is constructed with a mechanically bonded (encapsulated) elastomeric seal 281, which serves to provide fluid communication both between the layers of the chromatographic material unit 203 and the distribution device 209a and between the layers of the chromatographic material unit 203 and the collection device 209b.

[0043] Figures 2a and 2b show a first side 2a and an opposite second side 2b of a distribution device 209a or a collection device 209b, respectively, according to one embodiment of a distribution system that may be provided in a chromatographic device 201 according to the invention, whereby the distribution device 209a and the collection device 209b may be identical.

[0044] 2c and 2d are cross-sectional views of the distribution device 209a or collection device 209b shown in FIG. 2a along lines AA and BB, respectively.

[0045] Figures 3a to 3c are views of the chromatography device 201 of the present invention shown in Figure 1 when assembled, where Figure 3a is a view showing the front or back of the chromatography device 201 shown in Figure 1 when assembled, Figure 3b is a cross-sectional view along CC of the chromatography device 201 of Figure 3a, and Figure 3c is a cross-sectional view along DD of the chromatography device 201 of Figure 3a.

[0046] The chromatography device 201, 201' further comprises an inlet 215, 215' and an outlet 219, 219'. With reference to Figures 1-3, there is only one chromatography material unit 203, which may be called a cassette 205, and one fluid distribution system 207, with the inlet and outlet designated 215 and 219, respectively, which are connection ports to and from the chromatography device 201. With reference to Figures 4-5, in the chromatography device 201', eight cassettes 205 are stacked and connected in parallel, with the inlets and outlets designated 215' and 219', respectively. The chromatographic device 201, 201' according to the present invention further comprises at least one inlet fluid channel 217 connecting the inlets 215, 215' to the respective chromatographic material units 203 via the fluid distribution system 207, and at least one outlet fluid channel 221 connecting the outlets 219, 219' to the respective chromatographic material units 203 via the fluid distribution system 207.

[0047] According to the invention, the distribution device 209a and the collection device 209b each comprise a number of parallel distribution and collection channels 255 for passing the respective fluids through the chromatographic material unit. The parallel channels 255 are fluidly connected to the inlets 215, 215' through the inlet common rail 256a of the distribution device 209a and to the outlets 219, 219' through the outlet common rail 256b of the collection device 209b. The parallel channels 255 may extend substantially over the entire length L of the chromatographic material unit 203 from the first end 257a to the second end 257b of the parallel channels 255 and are distributed substantially over the entire width W of the chromatographic material unit 203. "Substantially over the entire length L" or "substantially over the entire width W" means, for example, more than 80% or 90% of the entire length L or width W. Suitably, the distance between the outermost channels and the edge of the chromatographic material is equal to or less than the distance between the channels. Also, the distance between the end of the groove and the edge of the chromatographic material unit may be approximately the same as the distance between the grooves, for example 80-120% or 90-110% of the distance between the grooves. Moreover, if the chromatographic material unit is not rectangular but more elliptical or some of the grooves have rounded corners, for example, the grooves located very close to the edge of the chromatographic material unit may be shorter than the remaining grooves. This does not necessarily require all grooves to be of the same length. In one embodiment, the grooves are arranged to substantially cover a sufficient surface area of ​​the chromatographic material (e.g. at least 80%, such as at least 90% of the surface area) such that all positions on the surface area of ​​the material are supplied with fluid by grooves that are no further away than the average distance of equally spaced grooves in the center of the distributor. In some embodiments, curved or bent grooves may be applied to accommodate peripheral shapes of the material that deviate from a strictly rectangular shape.

[0048] The inlet common rail 256a and the outlet common rail 256b are fluid channels oriented substantially perpendicular to the direction of the parallel grooves 255 and fluidly connect with the first ends 257a of each of the parallel grooves 255. "Substantially perpendicular" may mean, for example, that the direction of the inlet common rail 256a and the outlet common rail 256b is at an angle of at least 80 degrees or at least 85 degrees to the direction of the parallel grooves 255. However, if the chromatographic material unit is not rectangular but is more elliptical, the inlet common rail 256a and the outlet common rail 256b may be curved somewhat to follow the curved edges of the chromatographic material.

[0049] By distributing the parallel grooves over substantially the entire surface area of ​​the chromatographic material unit 203, the fluid flow supplied to the chromatographic device through the chromatographic material unit 203 can be effectively distributed over the entire area of ​​the chromatographic material unit 203. Moreover, by providing an inlet common rail and an outlet common rail substantially perpendicularly connected to the first ends of the parallel grooves, the fluid flow can be efficiently distributed to all the parallel grooves 255.

[0050] In some embodiments of the invention, each of the parallel grooves 255 has a cross-sectional area that decreases from the first end 257a to the second end 257b. This reduces the residence time difference between fluid entering the chromatographic material near the inlet / outlet common rail and fluid entering the chromatographic material further from the inlet / outlet common rail, so that the fluid flow can be more evenly distributed over the length L of the chromatographic material unit 203. The cross-sectional view of the groove is defined by the groove width, which represents the open fluid contact surface with the chromatographic material, and the groove depth. In some embodiments, the groove is rectangular in shape. In other embodiments, the groove may have a rounded bottom. In some embodiments, the groove may have a cross-sectional area that decreases from the first end to the second end, which is achieved by decreasing the groove depth, decreasing the groove width, or a combination of a decrease in the groove depth and width. In a suitable embodiment, the cross-sectional area of ​​the groove is decreased by decreasing the groove depth over the length of the groove.

[0051] By providing a chromatography device 201 with a distribution device (209a) and a collection device (209b) according to the invention providing parallel grooves for fluid distribution, a hygienic design is realized that allows efficient flushing and cleaning of all wetted surfaces. Moreover, the fluid distribution system according to the invention allows for a cost-effective design and manufacture of said devices, since the pattern of parallel grooves can be directly imparted to the internal walls and surfaces of the distribution and collection devices during manufacture, for example by injection molding.

[0052] With reference to Fig. 1, the chromatography device 201 according to an embodiment of the present invention will be described in more detail. The distribution device 209a comprises a distribution plate 251a provided in contact with the inlet face 253a of the chromatographic material unit 203. The distribution plate 251a comprises parallel grooves 255 for distributing the fluid supplied from the inlet 215 of the chromatographic device 201 to the chromatographic material unit. The collection device 209b comprises a collection plate 251b provided in contact with the outlet face 253b of the chromatographic material unit 203, said collection plate 251b comprising parallel grooves 255 for collecting the fluid from the chromatographic material unit 203. Moreover, the inlet common rail 256a and the outlet common rail 256b are provided across substantially the entire width W of the chromatographic material unit 203 from the first end 258a to the second end 258b of the inlet common rail 256a and the outlet common rail 256b. "Across substantially the entire width W of the chromatographic material unit 203" may mean, for example, at least 80% or at least more than 90% of the entire width W of the chromatographic material unit 203. The inlet fluid channel 217 is connected to a first end 258a of the inlet common rail 256a so that fluid is supplied from a first corner 261a of the fluid distribution system 207 to the distribution device 209a, and the outlet fluid channel 221 is connected to a first end 258a of the outlet common rail 256b, the second corner 261b being diagonally opposite the first corner 261a, so that fluid from a second corner 261b of the fluid distribution system 207 is collected from the collection device 209b. The inlet common rail 256a and the outlet common rail 256b are provided along opposite edges of the chromatographic material unit 203. By introducing fluid into the distribution device 209a from a first corner 261a of the fluid distribution system 207 and collecting fluid from a collection device 209b from a second corner 261b of the fluid distribution device 207 that is diagonally opposite the first corner 261a, a uniform residence time can be achieved for all fluid passing through the cassette 205.As an example, two different fluid elements passing through cassette 205 at different locations will travel similar total lengths, resulting in similar residence times when adding up the total distance and volume the fluid elements need to travel from the inlet to the outlet of the device. If the fluid were instead introduced to distribution device 209a at a more central location, such as the center of the inlet common rail, the overall travel path lengths of the different fluid elements through cassette 205 at different locations would be different, thereby resulting in substantially different residence times for the fluid elements.

[0053] Uniform residence times for all fluid elements through the device are advantageous in minimizing the amount of liquid required to flush, rinse, and clean the chromatography device and cassette 205 when applying a series of different fluids during a separation process. As an example, uniform residence times allow a step change in tracer material at the inlet of the device to result in a nearly uniform, clear, and sharp step response signal at the outlet of the device. With a sharper step response signal at the outlet, better binding capacity can be utilized, more effective fluids can be exchanged, and chromatography efficiency will be greater overall.

[0054] In some embodiments of the invention, the inlet common rail 256a may have a cross-sectional area that decreases from the first end 258a to the second end 258b of the inlet common rail 256a. This may improve fluid flow distribution across the distribution device 209a by reducing the liquid hold-up volume and reducing residence time differentials, resulting in a sharper signal response at the device outlet. Similarly, the outlet common rail 256b may have a cross-sectional area that decreases from the first end 258a to the second end 258b.

[0055] The parallel grooves 255 in the distribution device 209a and collection device 209b may have a width of less than 1.5 mm. In one embodiment, the parallel grooves have a width of 1.2 mm or less. This optimizes the mechanical support and stabilization of the chromatographic material unit 203, since the width and distance of the unsupported regions are minimized.

[0056] The spacing of the parallel grooves 255 in the distribution device 209 a and collection device 209 b may be greater than 2 mm, and in some embodiments greater than 3 mm, thereby providing excellent mechanical support and stabilization of the chromatographic material unit 203 .

[0057] The total combined area of ​​the walls of the surfaces between the parallel grooves 255 facing the chromatographic material unit 203 may be more than twice the total combined area of ​​the grooves 255 of the chromatographic material unit 203. In one embodiment, the total combined area of ​​the walls of the surfaces between the parallel grooves 255 facing the chromatographic material unit 203 may be more than three times the total combined area of ​​the grooves 255 of the chromatographic material unit 203.

[0058] Prior art systems often have a network of channels in the distribution system instead of a single (unidirectional) channel according to the present invention, which has the disadvantages of increasing holdup and reducing the support surface area for the matrix.

[0059] The grooves according to the invention have the additional advantage that the liquid volume of the distributor can be minimized, reducing the liquid hold-up volume in the device. In one embodiment of the invention, the liquid volume in the entire device from inlet to outlet is less than 1.5 times the volume of the membrane (<1.5MV).

[0060] In some embodiments of the invention, the outlet common rail 256b has a wider dimension than the inlet common rail 256a, which results in a larger fluid capacity. This can be advantageous in larger device sizes when the flow of liquid in the common rail is completely turbulent. One such embodiment is shown in FIG. 5b. The outlet common rail 256b with a larger fluid capacity than the inlet common rail 256a compensates for the dynamic pressure build-up required when collecting fluids exiting the cassette at low speed under laminar flow conditions, accelerating the fluids into a high speed turbulent regime. This allows the pressure and pressure loss changes at the inlet side of the common rail to match the pressure and pressure loss changes at the outlet side of the common rail. By matching the pressure loss profiles at the inlet and outlet common rails, a more uniform velocity of the fluids across the chromatographic device can be achieved, resulting in a more uniform distribution of residence times across the device, and therefore a more efficient chromatography.

[0061] The chromatographic device 201, 201' according to the invention comprises at least one cassette 205, each cassette 205 comprising a fluid distribution system 207 and a chromatographic material unit 203. In the chromatographic device 201 shown in Figures 1 and 3 only one cassette 205 is provided, in the chromatographic device 201' shown in Figures 4-5 eight cassettes 205 are provided. However, the number of cassettes 205 can of course be varied. If several cassettes 205 are provided, the cassettes 205 can be stacked together as shown in Figures 4a-4c. Each cassette 205 includes a portion of an inlet fluid channel 217 in fluid communication with an inlet common rail 256a provided on that cassette 205, which may be in fluid communication with an inlet 215, 215' of the chromatographic device 201, 201', possibly via one or more other cassettes 205 of the chromatographic device 201, 201'. Each cassette 205 also includes a portion of an outlet fluid channel 221 in fluid communication with an outlet common rail 256b provided on that cassette 205, which may be in fluid communication with an outlet 219, 219' of the chromatographic device 201, 201', possibly via one or more other cassettes 205 of the chromatographic device 201, 201'.

[0062] A chromatography device 201' comprising a plurality of cassettes 205, as shown, for example, in Figures 4a-4c, further comprises a first end plate 271a and a second end plate 271b sandwiching the at least two cassettes 205. The chromatography device 201' may further comprise a locking member 273 configured to lock the first end plate 271a and the second end plate 271b together. Seals may be provided between the cassettes and between the outermost cassette and the end plates 271a, 271b.

[0063] When the cassette 205 is installed, an elastomeric seal 281 can be mechanically bonded to the outer circumference of the chromatographic material unit 203, providing a fluid connection both between the layer of the chromatographic material unit 203 and the distribution device 209a and between the layer of the chromatographic material unit 203 and the collection device 209b. The elastomeric seal 281 will surround the parallel groove 255. When the chromatographic material unit 203 is sandwiched between the distribution device 209a and the collection device 209b over the range of separation between the distribution device 209a and the collection device 209b of the fluid distribution system 207, the elastomeric seal 281 will ensure a sealed connection between the fluid distribution system 207 and the chromatographic material unit 203. The elastomeric seal 281 fluidly connects the dispensing device 209a and the collection device 209b and surrounds the parallel grooves over the extent of the separation distance between the dispensing device 209a and the collection device 209b.

[0064] Each chromatographic material unit 203 may comprise at least one adsorbent membrane, which may be a polymer nanofiber membrane.

[0065] In some embodiments of the invention, each chromatographic material unit 203 may comprise at least one sorbent membrane 41 sandwiched between at least one top spacer layer 45a and at least one bottom spacer layer 45b, or at least two sorbent membranes 41 sandwiched between at least one top spacer layer 45a and at least one bottom spacer layer 45b, stacked on top of each other with a spacer layer 43 between them. This is seen in FIG. 3c. The top spacer layer 45a and / or the bottom spacer layer 45b may comprise one or more layers of spacer material of similar or different properties, the main properties being porosity and hydrodynamic resistance. In the case of multiple sorbent or spacer layers, the chromatographic material unit 203 is sealed with an elastomer at or near the periphery so that a fluid connection is formed between each sandwiched layer without significantly affecting the surface area of ​​the sorbent material.

[0066] In one embodiment, the chromatographic material unit 203 and the elastomeric seal 281 are mechanically joined, for example by encapsulation.

[0067] In one embodiment, the top and bottom spacer layers 45a, 45b have a much lower hydrodynamic resistance than the adsorbent membrane, and therefore a lower pressure drop per unit length at a given flow rate, which facilitates uniform horizontal distribution of liquid from the grooves to the entire surface of the adsorbent membrane.

[0068] As seen in Fig. 5a, the fluid flow through the chromatographic device 201' according to the invention can be fed by first passing the chromatographic material unit 203 by the inlet fluid channel 217 to feed the chromatographic material unit 203 with the fluid flow from the rear side of the chromatographic material unit. Thus, the fluid is collected from the front side of the chromatographic material unit. As a result, the direction of the fluid flow when passing through the chromatographic material unit 203 is opposite to the direction of the fluid flow in the inlet fluid channel 217 and the outlet fluid channel 221. This structure allows to reduce the dead legs at the ends of the inlet and outlet fluid channels (X och Y). Conventional mechanisms of devices that deliver fluid at the front of the chromatographic material unit result in fluid flow through the chromatographic material unit 203 in the same direction as the fluid flow in the inlet fluid channel 217 and outlet fluid channel 221, resulting in larger dead legs that require additional design elements and / or additional assembly steps during manufacture of the device to plug the larger dead legs. These dead legs should generally be avoided as they represent pockets of fluid that are difficult to flush or clean, thereby reducing overall chromatographic and process efficiency.

[0069] In one embodiment, the chromatography device 201' is prepared pre-assembled (compare FIG. 4a) and comprises one or several chromatography devices 201 and chromatography unit material 203 sandwiched and locked between a first end piece 271a and a second end piece 271b so as to obtain a fluid-tight assembly. In one embodiment, the locking is achieved by a fixed length locking member 273, see FIG. 4a. In another embodiment, the locking is achieved by a length-adjustable locking member, allowing to (re)tighten and compress the assembly of the chromatography device 201'. In another embodiment of the invention, locking means consisting of a snap or latch mechanism are provided for assembling and locking the chromatography device 201' or its parts to each other.

[0070] In one embodiment, the chromatography device 201' and its end pieces 271a, 271b are arranged such that the inlet 215 and outlet 219 are provided substantially at the top of the device, to minimise the spillage and / or loss of liquid or leakage of liquid from the device when connecting and / or disconnecting the device.

[0071] In one embodiment, a chromatography device 201' is provided that is pre-sterilized, for example by gamma irradiation. The chromatography device is suitably a disposable device and may further comprise sterile connectors, for example at the inlet 215 and outlet 219, to allow for a sterile connection to the system. Examples of such sterile connectors include ReadyMate™ (Cytiva, formerly GE Healthcare Life Sciences) and Kleenpak™ (Pall). The pre-sterilized device may suitably be double bagged to facilitate entry into a manufacturing clean room.

[0072] In another embodiment, an external holder or clamping mechanism is provided into which the chromatography device 201' is placed to allow further axial locking and / or compression of the end pieces 271a, 271b relative to one another so that the chromatography device 201' can withstand the high fluid pressures and mechanical loads resulting from supporting the chromatography material at a precise thickness without compromising the integrity and / or performance of the device 201'.

[0073] Figures 6a and 6b show a schematic perspective view of a fluid distribution system 207 according to another embodiment of the invention. In this fluid distribution system 207', a parallel groove 255 is provided so that an inlet common rail 256a' and an outlet common rail 256b' are provided from the same side of the distribution device 209a' and the collection device 209b' (as opposed to the previously described embodiment shown in Figures 1 to 5, in which the common rails 256a, 256b are provided on a first side 2a of the distribution device 209a, the collection device 209b and the parallel groove 255 is provided on the opposite second side 2b of the distribution device 209a, the collection device 209b). In this embodiment, an insert 291 is required to cover the common rails and provide an opening between the common rails and the parallel groove 255. The insert 291 is separated from the collection device 209b' in Figure 6b.

[0074] FIG. 6c is a perspective schematic diagram of a fluid distribution system 207″ according to yet another embodiment of the invention. In this embodiment, the fluid distribution system 207″ is 3D printed and the inlet and outlet common rails 256a″, 256b″ are not provided on either side of the distribution device 209a″, collection device 209b″, but instead are provided as internal grooves inside the distribution device 209a″, collection device 209b″. Fluid passages are also provided between the inlet and outlet common rails 256a″, 256b″ and in each of the parallel grooves 255.

[0075] 3D printing is one example of a possible production method for all embodiments, all details of which are explained above. Injection molding is another possible production method for some of the embodiments. In another embodiment, a combination of parts prepared by 3D printing, injection molding or machining can be assembled to result in a device according to the invention.

[0076] In some embodiments, as a means of fluidic connection between the distribution device 209a and the collection device 209b at the first and second corners, a portion of the inlet fluid channel 217 of each of the cassettes 205 can comprise an elastomeric conduit sandwiched between a portion of the distribution device 209a and a portion of the collection device 209b at the first corner 261a, and a portion of the outlet fluid channel 221 of each of the cassettes 205 can comprise an elastomeric conduit sandwiched between a portion of the distribution device 209a and a portion of the collection device 209b at the second corner 261b, said elastomeric conduit fluidly connecting the distribution device 209a and the collection device 209b over a range of separation distances between the distribution device 209a and the collection device 209b.

[0077] At least two states of operation of each cassette can be promoted by combining the elastomeric portions (conduits) of the inlet fluid channel 217, the outlet fluid channel 221 and the elastomeric seal 281. For example, 1) a relaxed state that provides a fluid connection between the dispensing device 209a and the collecting device 209b due to low operating pressures and mechanical loads that preserve the material properties of the rubbery seal by eliminating the compression set effect to extend the useful life, and 2) a compressed state that provides a fluid connection between the dispensing device 209a and the collecting device 209b due to high operating pressures and mechanical loads to achieve the desired thickness of the chromatographic material unit 203 can be promoted. [Explanation of symbols]

[0078] 41 Adsorption membrane 43 Spacer layer 45a top spacer layer 45b bottom spacer layer 201 Chromatography Devices 201´ Chromatography Device 203 Chromatography Materials Unit 205 Cassette 207 Fluid Distribution Systems 207´ Fluid Distribution System 207″ Fluid Distribution System 209a Distribution Devices 209a´ Distribution Device 209a″ Distribution Device 209b Collection Device 209b´ Collection device 209b″ Collection Device 215 Entrance 215´ Entrance 217 Inlet Fluid Channel 219 Exit 219´ Exit 221 Outlet Fluid Channel 251a distribution plate 251b Collection Board 253a Entrance side 253b Exit surface 255 Parallel groove 256a Inlet common rail 256a´ Inlet common rail 256a″ inlet common rail 256b Exit common rail 256b´ Exit common rail 256b″ exit common rail 257a First End 257b Second End 258a First end 258b Second End 261a First corner 261b 2nd corner 271a First end plate, end piece 271b Second end plate, end piece 273 Locking member 281 Elastomer Seals 291 Insert

Claims

1. at least one chromatographic material unit (203) comprising a convection-based chromatographic material, the at least one chromatographic material unit (203) being substantially rectangular having a length (L) and a width (W); at least one fluid distribution system (207, 207', 207'') configured to distribute fluids into and from said at least one chromatographic material unit (203), said fluid distribution system (207, 207', 207'') comprising a distribution device (209a, 209a', 209a'') and a collection device (209b, 209b', 209b'') sandwiching said chromatographic material unit (203); - an entrance (215); at least one inlet fluid channel (217) connecting said inlet (215) to the respective chromatographic material unit (203) via said fluid distribution system (207, 207', 207''); - an exit (219); at least one outlet fluid channel (221) connecting said outlet (219) to each chromatographic material unit (203) via said fluid distribution system (207, 207', 207''); In a chromatographic device (201, 201') comprising the distribution device (209a, 209a', 209a") comprises a plurality of parallel grooves (255) for distributing fluid passing through the chromatographic material unit (203), the plurality of parallel grooves (255) being fluidly connected to the inlet (215) via an inlet common rail (256a, 256a', 256a") of the distribution device (209a, 209a', 209a"); the collection device (209b, 209b', 209b") comprises a plurality of parallel grooves (255) for collecting fluid passing through the chromatographic material unit (203), the plurality of parallel grooves (255) being fluidly connected to the outlet (219) via an outlet common rail (256b, 256b', 256b") of the collection device (209b, 209b', 209b"); the parallel grooves are distributed over substantially the entire length (L) of the chromatographic material unit (203) from a first end (257a) to a second end (257b) of the parallel grooves and over substantially the entire width (W) of the chromatographic material unit (203); A chromatography device (201, 201'), characterized in that the inlet common rail (256a) and the outlet common rail (256b) are fluid channels arranged in a direction substantially perpendicular to the direction of the parallel grooves (255), and the inlet common rail (256a) and the outlet common rail (256b) are fluidically connected to a first end (257a) of each of the parallel grooves (255).

2. 2. The chromatography device of claim 1, wherein the distribution device (209a) comprises a distribution plate (251a) arranged in contact with an inlet face (253a) of the chromatographic material unit (203), the distribution plate (251a) having the parallel grooves (255) for distributing a fluid supply provided from the inlet (215) of the chromatography device (201) to the chromatographic material unit (203), and the collection device (209b) comprises a collection plate (251b) arranged in contact with an outlet face (253b) of the chromatographic material unit (203), the collection plate (251b) having the parallel grooves (255) for collecting fluid from the chromatographic material unit (203).

3. 3. A chromatography device according to claim 1 or 2, characterized in that each of the parallel grooves (255) has a cross-sectional area that decreases from the first end (257a) to the second end (257b).

4. The inlet common rail (256a) and the outlet common rail (256b) are provided across substantially the entire width (W) of the chromatographic material unit (203) from a first end (258a) to a second end (258b) of the inlet common rail (256a) and the outlet common rail (256b), and the inlet fluid channel (217) is connected to the inlet common rail (256a) and the outlet common rail (256b) such that fluid is supplied to the distribution device (209a) from a first corner (261a) of the fluid distribution system (207).

4. The chromatography device of claim 1, wherein the outlet fluid channel (221) is connected to the first end (258a) of the outlet common rail (256a), the second corner (261b) being diagonally opposite the first corner (261a) such that fluid is collected from a second corner (261b) of the fluid distribution system (207) into the collection device (209b).

5. 5. A chromatography device according to claim 1, characterized in that the inlet common rail (256a) and the outlet common rail (256b) are provided along opposite edges of the chromatographic material unit (203).

6. 6. A chromatography device according to claim 1, wherein the inlet common rail (256a) has a cross-sectional area that decreases from a first end (258a) to a second end (258b) of the inlet common rail (256a).

7. 7. A chromatography device according to claim 1, characterized in that the combined total area of ​​the wall surfaces between the parallel grooves (255) of the distribution device (209a) / collection device (209b) facing the chromatographic material unit (203) is more than twice the combined total area of ​​the parallel grooves facing the chromatographic material unit (203).

8. 8. A chromatographic device according to claim 1, wherein each of the parallel grooves (255) has a width of less than 1.5 mm and is spaced apart by more than 2 mm.

9. 9. A chromatography device according to claim 1, characterized in that the holdup of the chromatography device (201) is less than 1.5 times the volume of the membrane of the chromatographic material unit (203).

10. Chromatography device according to any one of claims 1 to 9, characterized in that the outlet common rail (256b) has a larger fluid capacity than the inlet common rail (256a).

11. 11. A chromatography device according to any one of claims 1 to 10, characterized in that the chromatography device (201, 201') comprises at least one cassette (205), each cassette (205) comprising a fluid distribution system (207) and a chromatographic material unit (203).

12. 12. The chromatography device of claim 11, wherein the chromatography device (201') comprises at least two cassettes (205), the at least two cassettes (205) being stacked together, each of the cassettes (205) being fluidically connected to the inlet common rail (256a) provided on the cassette (205) and comprising a portion of the inlet fluid channel (217) that can be fluidically connected to the inlet (215) of the chromatography device (201'), and each of the cassettes (205) being fluidically connected to the outlet common rail (256b) provided on the cassette (205) and comprising a portion of the outlet fluid channel (221) that can be fluidically connected to the outlet (219) of the chromatography device (201').

13. The chromatography device of claim 12, further comprising a first end plate (271a) and a second end plate (271b) sandwiching the at least two cassettes (205) therebetween, and a locking member (273) configured to lock the first end plate (271a) and the second end plate (271b) to each other.

14. 14. The chromatography device according to claim 1, further comprising an elastomeric seal (281) provided on the outer periphery of the chromatographic material unit (203) surrounding the parallel groove (255) to seal against the distribution device (209a) and the collection device (209b).

15. Chromatographic device according to any one of the preceding claims, characterized in that each chromatographic material unit (203) comprises at least one adsorptive membrane.

16. 16. The chromatographic device of claim 15, wherein the adsorbent membrane is a polymer nanofiber membrane.

17. 17. A chromatography device according to claim 1, characterized in that each chromatographic material unit (203) comprises at least one adsorption membrane (41) sandwiched between at least one top spacer layer (45a) and at least one bottom spacer layer (45b), or at least two adsorption membranes (41) stacked on top of each other with a space between them using a spacer layer (43), sandwiched between at least one top spacer layer (45a) and at least one bottom spacer layer (45b).

18. A chromatography device as described in claim 12, wherein a portion of the inlet fluid channel (217) is fluidly connected to the inlet (215) of the chromatography device (201') via one or more other cassettes (205) of the chromatography device (201'), and a portion of the outlet fluid channel (221) may be fluidly connected to the outlet (219) of the chromatography device (201') via one or more other cassettes (205) of the chromatography device (201').

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