Cross flow filtration unit for continuous infiltration

Abstract

The invention relates to a cross flow filtration unit for continuous diafiltration. A cross-flow filtration unit for continuous diafiltration of a feed fluid to obtain a retentate and a permeate, a corresponding method for diafiltration, and the use of the cross-flow filtration unit.

Description

[0001] This application is a divisional application of the Chinese application with application number 201780018349.X, filing date April 5, 2017, and title “Cross-flow filtration unit for continuous diafiltration”. Technical Field

[0002] The present invention relates to a cross-flow filtration unit for the continuous diafiltration of a feed fluid to obtain a retentate and a permeate, a corresponding diafiltration method and the use of the cross-flow filtration unit. Background Art

[0003] In cross-flow filtration, which may also be referred to as cross-flow filtration or tangential flow filtration, the feed fluid to be filtered ("feed") flows tangentially across the surface of a filter material, typically a membrane, and as it flows past, separates the feed into its various component retentate (concentrate) and permeate (filtrate).

[0004] The retentate flows over the surface of the filter material and can be removed after a single pass ("single-pass" mode), but it can also be fed back into the circuit so that it flows repeatedly over the membrane surface. The permeate flows perpendicularly to the surface through the membrane and is then discharged. The target substance to be recovered may be contained in the permeate (permeate) and / or the retentate (retentate).

[0005] Cross-flow filtration units are typically used in the form of filter cartridges, as described, for example, in DE-PS 34 41 249. A filter cartridge comprises a plurality of adjacent cross-flow filtration elements (filter cells), which typically consist of a repeating array of retentate slits for the feed fluid to be filtered or the retentate, a flat membrane layer, and permeate collecting slits. The permeate collecting slits of one filter cell are separated from the retentate slits of the next filter cell by a further flat membrane layer. Each retentate slit is fluidically connected to an inlet for the feed fluid to be filtered and to an outlet for the retentate; and each permeate collecting slit is fluidically connected to an outlet for the permeate.

[0006] By conventional filtration, the feed fluid is separated into a retentate and a permeate. In diafiltration, this separation is combined with a step of adding a diafiltration medium to the feed fluid / retentate. This step makes it possible, for example, to free a common solution of the target substance and one or more additional substances from the other substances. For example, by diafiltration of a protein solution, buffer exchange or desalination can be achieved, optionally in combination with a concentrate.

[0007] A distinction is made between two basic types of diafiltration; variable volume diafiltration (sometimes referred to in the art as "discontinuous" diafiltration) and constant volume diafiltration (sometimes referred to in the art as "continuous" diafiltration).

[0008] In variable volume diafiltration, the filtration step and the step of adding the diafiltration medium are performed alternately. Therefore, during this alternating process, the volume of the retentate fluctuates, which is why the term "discontinuous diafiltration" is derived. In constant volume diafiltration, the volume of the retentate remains constant because both filtration and addition of the diafiltration medium are performed continuously. However, the addition of the feed fluid is discontinuous and usually only occurs at the beginning of the process. Therefore, both variable volume diafiltration and constant volume diafiltration are discontinuous processes. In a discontinuous diafiltration process, a specified volume of feed fluid must be completely subjected to a process run before a new process run can be started (a "batch" process). For reasons of cost-effectiveness and efficiency, a continuous process in which a material flow can be continuously supplied and discharged is preferred over a discontinuous process. Therefore, there is a need for a continuous diafiltration process. Summary of the Invention

[0009] Therefore, an object of the present invention is to provide a cross-flow filtration unit suitable for continuous diafiltration.

[0010] This object is achieved by the embodiments characterized in the claims.

[0011] In particular, the present invention relates to a cross-flow filtration unit for continuous diafiltration of a feed fluid to obtain a retentate and a permeate, the cross-flow filtration unit comprising at least a diafiltration slot, a first planar filter material, a retentate slot, a second planar filter material, and a permeate collecting slot, the slots and materials being arranged in such a way that the first planar filter material delimits the diafiltration slot and the retentate slot from one another, and the second planar filter material delimits the retentate slot and the permeate collecting slot from one another, wherein the diafiltration slot is fluidically connected to at least one inlet for the diafiltration medium, the retentate slot is fluidically connected to at least one inlet for the feed fluid and to at least one outlet for the retentate, and the permeate collecting slot is fluidically connected to at least one outlet for the permeate, and wherein the pore size or molecular weight cut-off of the first planar filter material is at least as large as the pore size or molecular weight cut-off of the second planar filter material. The pore size or molecular weight cut-off of the first planar filter material is preferably larger than the pore size or molecular weight cut-off of the second planar filter material.

[0012] The flat first filter material preferably has a molecular weight cutoff (MWCO) in the range of 30 kDa to 1,500 kDa. The flat second filter material preferably has a MWCO in the range of 5 kDa to 1,500 kDa. The MWCO can be determined according to ASTM E1343-90 ("Standard Test Method for Estimation of Molecular Weight Cutoff of Flat Sheet Ultrafiltration Membranes").

[0013] The pore size of the flat first filter material is preferably 0.01 to 50 μm, preferably 0.01 to 0.5 μm. The flat second filter material preferably has a pore size of less than 0.01 μm. The pore size, also known as "maximum pore size" or "dp," and in English, "maximum pore size," can be determined according to the American standard ASTM F316-03 Test Method A ("Standard Test Method for Pore Size Characteristics of Membrane Filters by Bubble Point and Mean Flow Pore Test").

[0014] The basic methods used to characterize the membranes are described in the paper "Structure Formation of Cellulose Ester Membranes" by Melanie Sossna, University of Hannover, Germany, 2006, page 10, section 2.5, especially in Tables 2-4.

[0015] According to the prior art (discontinuous diafiltration), diafiltration medium is introduced between serially connected cross-flow filtration units; alternatively, the feed fluid is diluted with diafiltration medium and then subjected to cross-flow filtration in combination with prior or subsequent concentration. However, the cross-flow filtration unit of the present invention makes it possible to introduce a defined amount of diafiltration medium into the retentate slits by applying appropriate pressure to achieve optimal diafiltration. For example, according to the present invention, the volume of diafiltration medium can be 0.1 to 15 times the volume of the feed fluid. Preferably, the diafiltration medium is introduced into the retentate slits in such a way that the entire available surface area of the flat first filter material is covered by the diafiltration medium. The cross-flow filtration unit of the present invention makes it possible to achieve improved diafiltration results compared to discontinuous diafiltration. Furthermore, the present invention reduces both the time required for the process and the amount of equipment required.

[0016] In continuous diafiltration, both the feed fluid and the diafiltration medium are added continuously, thus making it unnecessary to interrupt the process.As a result, the cross-flow filtration unit of the present invention makes it possible to run the process in an efficient and economical manner.

[0017] Through the improved cross-flow filtration unit of the present invention, fluids such as liquids, emulsions, suspensions, beverages such as beer, wine, juice, water, milk and whey, beer wort, industrial wastewater, and solutions in the pharmaceutical, medical, cosmetic, chemical, biotechnology, genetic engineering, environmental protection, and laboratory sectors can be used as feed fluids and can be diafiltered. They can be used for the recovery of valuable materials; separation of substances, such as the separation of macromolecules and biomolecules; for the depyrogenation and sterilization of solutions; for the separation of pollutants from fluids; for the (diafiltration) filtration and concentration of biological solutions; for the separation of microorganisms such as bacteria, yeast, viruses, and cellular components; and for the desalination of protein solutions and other biological media.

[0018] The cross-flow filtration unit of the present invention can be used particularly advantageously for filtration, diafiltration, concentration (reduction of solvent or water content) and / or modification (eg desalting or buffer exchange) of ionic components of solutions, preferably protein solutions.

[0019] With respect to the fluid present in the retentate slit, the terms "feed fluid" and "retentate" can be used synonymously.

[0020] The term "flat" means that the respective filter material lies essentially in a single plane. Preferably, all filter materials lie in planes that are more or less substantially parallel to each other.

[0021] According to a preferred embodiment of the present invention, the flat first filter material is a first filter membrane. The flat second filter material is preferably a second filter membrane. Particularly preferably, the flat first filter material is the first filter membrane and the flat second filter material is the second filter membrane.

[0022] In particular, porous membranes within the ultrafiltration and microfiltration ranges are suitable as the first filter material. Ultrafiltration membranes can also be advantageously used as the second filter material. This configuration allows for the introduction of a specific amount of diafiltration medium into the retentate slit by appropriate pressure to achieve optimal diafiltration. When pressure is applied, the entire available area of the flat first filter material is covered with the diafiltration medium.

[0023] Ultrafiltration membranes are characterized by a pore size of less than 0.01 μm or a molecular weight cut-off in the molecular weight range of approximately 5 to 1,500 kDa, while microfiltration membranes exhibit a pore size in the range of 0.01 to 50 μm, preferably 0.01 to 0.5 μm, or a molecular weight cut-off of 30 to 1,500 kDa. The filtration membranes can be composed, for example, of polyvinylidene fluoride, cellulose and its derivatives, polyethersulfone or polysulfone, with cross-linked cellulose hydrate being particularly preferred.

[0024] The feed fluid inlet is preferably installed in the first edge region of the cross-flow filtration unit, and the retentate outlet is installed in the second edge region of the cross-flow filtration unit, facing the first edge region. This arrangement ensures a generally uniform retentate flow direction from the feed fluid inlet (as a starting point) to the retentate outlet (as a terminal point). As a result, the retentate flow direction extends generally parallel to the flow path along the flat filter material, i.e., with essentially no deflection, ensuring a stable and reliable retentate flow through the cross-flow filtration unit. Furthermore, the generally linear flow path, free of deflections, loops, etc., minimizes pressure drop within the filtration unit and any adverse effects of nonlinear flow on target substances contained in the feed fluid. For the reasons described above, it is also preferred to install the filtration medium inlet in the first edge region of the cross-flow filtration unit. However, the filtration medium inlet may also be installed in the second, third, and / or fourth edge regions.

[0025] According to a preferred embodiment of the present invention, the permeate outlet is arranged in the second edge region of the cross-flow filter element. Particularly preferably, at least one permeate outlet is arranged in both the first and second edge regions of the cross-flow filter element. In another embodiment of the present invention, the permeate outlet is alternatively or additionally arranged in the third and / or fourth edge regions of the cross-flow filter element. In a plan view of the cross-flow filter element viewed from the percolation slot side, the third edge region is located to the left in the direction of flow. Accordingly, the fourth edge region is located to the right, and therefore opposite the third edge region. This arrangement of the outlets not only achieves particularly high permeation performance but also offers design advantages.

[0026] The first edge region preferably comprises the outer third of the length of the filter element, opposite to the direction of flow. Correspondingly, the second edge region comprises the outer third of the length of the filter element, along the direction of flow. The same applies to the third and fourth edge regions. It is advantageous to keep the first to fourth edge regions as small as possible. Therefore, it is particularly preferred that the edge region comprises the outer 20%, even more preferably the outer 10%, and most preferably the outer 3%.

[0027] In principle, there are no particular restrictions on the arrangement of the inlet and outlet. For example, the inlet and outlet can be arranged so that the feed fluid enters the retentate slit in the direction of flow and leaves the retentate slit in the direction of flow. Correspondingly, the permeate outlet can be arranged so that the permeate leaves the permeate collection slit in the direction of flow, and / or the inlet of the filtration medium can be arranged so that it enters the filtration slit in the direction of flow. However, preferably, the inlet and outlet are arranged so that the filtration medium enters the filtration slit perpendicular to the direction of flow, and the feed fluid then enters the retentate slit perpendicular to the direction of flow and leaves the retentate slit perpendicular to the direction of flow. This arrangement of the inlet and outlet facilitates the arrangement of multiple filter units according to the present invention to form a filter cartridge.

[0028] Preferably, the cross-flow filtration unit comprises a plurality of inlets for the feed fluid, a plurality of outlets for the retentate and a plurality of outlets for the permeate.

[0029] In a preferred embodiment, the free volume (the space available for the filtration medium / retentate, dead volume, or void volume) of the diafiltration slits and / or the retentate slits decreases in the direction of flow from the feed fluid inlet to the retentate outlet. Due to the reduced volume and flatness of the filter material, the cross-flow filtration unit exhibits low pressure losses and a substantially undeflected flow path for the diafiltration medium and retentate. This allows, among other things, an increase in the output per unit area of the cross-flow diafiltration unit and allows the cross-flow diafiltration unit to be operated in "single-pass" mode (where only a single retentate passage occurs without recirculation).

[0030] In another preferred embodiment of the invention, the reduction of the free volume in the flow direction is achieved by reducing the width of the filtration slit and / or the width of the retentate slit in the flow direction. The width extends along the flat first filter material and perpendicular to the flow direction. It is particularly preferred that the width of the entire cross-flow filter unit decreases in the flow direction. The retentate slit or, more specifically, the cross-flow filter unit is preferably trapezoidal in a plan view along the normal to the plane in which the flat first filter material is located. The filtration slit and / or the retentate slit or, more specifically, the basic trapezoidal shape of the cross-flow filter unit can have unequal sides, for example can be right-angled, and preferably form equal sides.

[0031] According to one embodiment, the height of the filtration slots and / or the retentate slots, or more specifically, the cross-flow filtration unit, can decrease in the direction of flow. For example, the filtration slots and / or the retentate slots can be wedge-shaped. The height of the filtration slots and / or the retentate slots, or more specifically, the cross-flow filtration unit, can be perpendicular to the flat first filter material and perpendicular to the direction of flow.

[0032] There are no particular restrictions on the width, length, and height of the cross-flow filtration unit. The length is parallel to the flow direction and extends along the flat first filter material. Preferably, the cross-flow filtration unit is at least 50 mm long, preferably at least 150 mm, more preferably 500 mm, and most preferably 750 mm or longer. Such a length can be achieved, for example, by connecting multiple cross-flow filtration units in series, such as at least two, at least three, or at least four. This greater length allows for particularly high efficiency.

[0033] In a preferred embodiment of the invention, the free volume of the permeate collecting slit varies in the direction of flow. Particularly preferably, the free volume of the permeate collecting slit decreases in the direction of flow. This makes it possible, for example, to maintain the outer dimensions of the filter cartridge.

[0034] The explanations regarding the configuration of the retentate slit apply correspondingly to the permeate collecting slit, and vice versa.

[0035] "Free volume reduction in the flow direction" means the existence of: a cross-sectional area A1, through which the filtration medium or the retentate can flow, and which cross-sectional area A1 is located in a plane having a normal parallel to the flow direction; and a corresponding cross-sectional area A2, which is parallel to A1 and is farther from the inlet of the filtration medium or the feed fluid than A1, wherein the surface area A1 through which the filtration medium or the retentate can flow is greater than A2; and there are no correspondingly defined planes A1' and A2' where the surface area of A1' is smaller than the surface area of A2'.

[0036] The reduction in free volume can be continuous (for all A1 and A2, A1 ≥ A2) or continuous (for all A1 and A2, A1 > A2). The volume reduction can also be discontinuous. This means that there is at least one discontinuous decrease or break in the cross-sectional area along the flow direction.

[0037] Depending on the filtration task, the variation of the free volume of the retentate slit in the flow direction is preferably in the range of 20:1 to 1.2:1, preferably in the range of 10:1. In this case, the "variation of the free volume of the retentate slit in the flow direction" refers to the ratio of the cross-sectional area A1 at the inlet of the feed fluid to the cross-sectional area A2 at the outlet of the retentate.

[0038] In one embodiment of the invention, the thickness of the permeate slit and / or the thickness of the retentate slit and optionally also the thickness of the permeate collecting slit decreases in the direction of flow.

[0039] The diafiltration slits, retentate slits and permeate collecting slits are usually kept open by gaskets for the corresponding media. In a preferred embodiment of the invention, flat gaskets are installed in the diafiltration slits and / or retentate slits of the cross-flow filtration unit in such a way that the free volume of the retentate slits decreases in the direction of flow.

[0040] Suitable gaskets for cross-flow filtration units are known in the prior art and can be used in the filtration slits, retentate slits, and / or permeate collection slits of the cross-flow filtration units of the present invention. According to the present invention, the gaskets are preferably modified such that their volume in the direction of flow increases, thereby reducing the free volume available for the filtration medium or retentate. Preferred gaskets can be textile materials, such as woven fabrics, knitted fabrics, nonwoven fabrics, or extruded webs, of organic or non-organic material.

[0041] The gasket can advantageously be a non-planar plate. A non-planar plate can be a plate having at least one non-planar major surface. The major surface of the plate is the opposing surface with the largest surface area. The at least one non-planar major surface can have unevenness in the form of a corrugated or serrated surface. Furthermore, the uneven surface can have protruding elements such as cones (truncated cones of cones), pyramids (truncated pyramids of pyramids), knobs, or other geometric shapes. The non-planar plate can also be a corrugated sheet with a corrugated or serrated shape, wherein the corrugations or serrations preferably extend parallel to the flow direction. Suitable materials for the non-planar plate are the same as those listed below for the gasket in the form of an open grid matrix.

[0042] According to a preferred embodiment, the gasket is made up of open-pore mesh matrix or extruded net. Such gaskets are known in the prior art and have been described in the publication of, for example, German patent application DE 100 22 259 A1. As mentioned above, the gasket of the present invention is preferably modified so that their volume increases in the flow direction so that the volume reduction that can be used for the free volume of filtration medium or retentate is realized. In principle, traditional gaskets also can be installed in the cross-flow filter unit of the present invention, for example, in all slits with the width that reduces in the flow direction of permeate collection slit and / or filtration slit or filter unit of having. As mentioned above, for example, can realize the width that reduces by the trapezoidal structure of slit or more specifically cross-flow filter unit.

[0043] In one embodiment, the mesh width of the open-cell matrix or extruded mesh can decrease in the direction of flow to achieve a reduction in free volume along the direction of flow. For example, the mesh count is 5 / cm to 15 / cm at the inlet of the filtration medium or the inlet of the feed fluid; 10 / cm to 30 / cm between the inlet of the filtration medium or the inlet of the feed fluid and the outlet of the retentate; and 20 / cm to 40 / cm at the outlet of the retentate.

[0044] Alternatively or additionally, the open-cell matrix or extruded web can be composed of intersecting longitudinal and transverse threads; and the number and / or thickness of the longitudinal and / or transverse threads can increase in the direction of flow. The open-cell matrix is preferably composed of an organic polymer, such as polypropylene, polyethylene, polyester, polyvinyl chloride, or polyvinylidene fluoride, or blends thereof. Furthermore, the open-cell matrix can be composed of fibers of different polymer types.

[0045] In another preferred embodiment of the present invention, multiple layers of textile material are arranged one above the other in the retentate slit such that the free volume decreases in the direction of flow. This can be achieved, for example, by initially placing the multiple layers of textile material one above the other in an offset manner in the direction of flow. The superimposed layers preferably extend all the way to the second edge region. As a result, the textile material in the retentate slit utilizes an increasing volume in the direction of flow, resulting in a decrease in the free volume in the direction of flow. The textile material, such as a woven fabric, knitted fabric, nonwoven fabric, or extruded web, can be composed of organic or non-organic materials.

[0046] The embodiments shown here for achieving a free volume reduction of the percolation slot or retentate slot can be combined in any desired manner.

[0047] According to the present invention, the retentate slit is bounded by a flat first filter material and a flat second filter material. The filtration slit is bounded by at least one flat first filter material. The permeate collection slit is bounded by at least one flat second filter material. Adjacent to the retentate slit are the filtration slit and the permeate collection slit. A preferred cross-flow filtration unit of the present invention comprises a plurality of stacked arrays consisting of a filtration slit, a flat first filter material, a retentate slit, a flat second filter material, a permeate collection slit, a flat second filter material, a retentate slit, and a flat first filter material, preferably sealed by another filtration slit, so that the stacked arrays are combined to form a filter cartridge. Suitable embodiments for filter cartridges are known in the art. Preferably, each filtration slit in these arrays is bounded by two retentate slits on either side by a corresponding filter material corresponding to the first filter material. Correspondingly, preferably, each permeate collection slit in these arrays is bounded by two retentate slits on either side by a corresponding filter material corresponding to the second filter material. The first filter material and the second filter material may each be different from one another. That is, substantially different first filter materials and different second filter materials can be used. Preferably, similar first filter materials and / or similar second filter materials are used.

[0048] According to a preferred embodiment, the flat first and second filter materials independently have a substantially uniform thickness, preferably between 50 μm and 10,000 μm, more preferably between 150 μm and 1,000 μm. If the flat boundary of the filtration slot by the flat first filter material and the flat boundary of the filtration slot and / or the flat boundary of the retentate slot by the first and second filter materials do not extend parallel to one another, the free volume of the filtration slot and / or the retentate slot can be designed to be wedge-shaped, such that the free volume decreases in the direction of flow. It is particularly preferred that the filtration slot, the retentate slot, and the permeate collecting slot are delimited on both sides by substantially parallel surfaces.

[0049] The shape of the cross-flow filtration unit is not subject to any particular restrictions. The cross-flow filtration unit can be, for example, a rectangular parallelepiped or a cylindrical shape.

[0050] In another aspect, the present invention relates to a method for diafiltration of a feed fluid to obtain a retentate and a permeate, the method comprising the steps of: (A) providing a cross-flow filtration unit according to the present invention; (B) feeding a diafiltration medium to an inlet for the diafiltration medium; (C) feeding a feed fluid to an inlet for the feed fluid; (D) discharging the retentate from an outlet for the retentate; and (E) Discharging the permeate from the outlet for the permeate.

[0051] The explanations regarding the cross-flow filtration unit and the diafiltration method are applicable interchangeably.

[0052] Step (A) preferably provides the cross-flow filtration unit described above, comprising a plurality of stacked arrays consisting of percolation slits, a flat first filter material, a retentate slit, a flat second filter material, a permeate collection slit, a flat second filter material, a retentate slit, and a flat first filter material, such that the stacked arrays are combined to form a filter cartridge.

[0053] The diafiltration medium used is not subject to any particular restrictions. In principle, any fluid is suitable, preferably water and saline solutions. Aqueous buffer solutions are particularly preferred as diafiltration media.

[0054] Preferably, the volume flow rate of the supplied diafiltration medium is 0.1 to 15 times the volume flow rate of the supplied feed fluid.The volume flow rate of the discharged retentate is preferably 0.05 to 10 times the volume flow rate of the supplied feed fluid.

[0055] In a preferred embodiment of the method, the diafiltration medium is supplied at a pressure of 0.1 to 4 bar. More preferably, the diafiltration medium is supplied at a pressure greater than the retentate outlet pressure.

[0056] Preferably, the method of the present invention is carried out continuously, i.e., with constant / continuous addition of diafiltration medium and feed fluid, thereby providing a particularly efficient and economical filtration method. According to the present invention, "continuous diafiltration" refers to a diafiltration method in which both the diafiltration medium and the feed fluid are added continuously.

[0057] In a preferred embodiment of this method, in step (A), a plurality of independent crossflow filtration units according to the present invention are provided and connected in series, such that the retentate outlet of the respective upstream crossflow filtration unit is fluidically connected to the feed fluid inlet of the downstream crossflow filtration unit. Furthermore, in this embodiment, in step (C), the feed fluid is fed into the feed fluid inlet of the crossflow filtration unit preceding any other crossflow filtration unit (the first crossflow filtration unit), and in step (D), the retentate is discharged from the retentate outlet of the crossflow filtration unit following any other crossflow filtration unit (the last crossflow filtration unit). In this manner, the retentate / feed fluid passes through the series-connected crossflow filtration units from the first crossflow filtration unit to the last crossflow filtration unit. Preferably, 2 to 10, and more preferably 2 to 5, crossflow filtration units are connected in series. In this embodiment, the diafiltration medium is fed separately to each crossflow filtration unit connected in series. Although different types of diafiltration media may be used, it is preferred that the same diafiltration media is fed into each cross-flow filtration unit.Preferably, each of the series-connected cross-flow filtration units is in the form of a filter cartridge, as described above.

[0058] In a preferred embodiment of the method, a plurality of independent cross-flow filtration units according to the invention are provided and connected in parallel in step (A). Parallel connection and series connection can be combined with one another.

[0059] In a further preferred embodiment of the method, the retentate discharged in step (D) is at least partially fed back to the inlet for the feed fluid. Due to the recirculation process, improved process results can be achieved even when a single pass through the cross-flow filtration unit is insufficient. In this case, the addition of diafiltration fluid and the removal of permeate occur without recirculation. If multiple cross-flow filtration units are connected in series, in principle, any retentate stream can be fed back to each inlet for the feed fluid. Preferably, in this case, the retentate of each individual cross-flow filtration unit is fed back to the inlet for the feed fluid of the same cross-flow filtration unit.

[0060] According to another preferred embodiment of the method according to the present invention, the feed fluid or retentate in the retentate slit is caused to oscillate. As a result, the flow motion in the retentate slit is superimposed on the oscillations (oscillations). This can be achieved by at least one device for generating oscillations that can be mounted at the feed fluid inlet and / or the retentate outlet. This oscillation-generating device causes the retentate to move back and forth in the retentate slit. This means that the retentate begins an oscillatory motion substantially parallel to the planar first filter material. Preferably, the oscillations are generated by an oscillation-generating device mounted at the feed fluid inlet and another oscillation-generating device mounted at the retentate outlet. According to the present invention, a suitable oscillation-generating device is, for example, a piston pump. The device for generating oscillations preferably includes a reservoir divided into two halves by an elastic membrane and, optionally, a pressure source. The reservoir is a reservoir (storage) for the feed fluid or retentate. The first half of the reservoir is connected to a pressure source, such as a compressed air source or a pump, via a valve controller. The second half of the reservoir is fluidically connected to the feed fluid inlet or retentate outlet of the filtration device. In the second half, a flushing or drain valve is also preferably present. Due to the opposite (alternating) pressurization of each of the first halves of the two reservoirs (e.g., with compressed air), the retentate flow is able to move back and forth (initiate oscillation). As described above, the reservoirs can be either a separate part of the system (not an integral part of the cross-flow filtration unit) or integrated into the housing of the cross-flow filtration unit as an integral part thereof.

[0061] The cross-flow filtration device of the present invention preferably has at least one (preferably two) means for generating oscillations in the feed fluid or retentate in the retentate slit. According to the present invention, the means for generating oscillations preferably comprises a reservoir having a pressure source. Particularly preferably, the cross-flow filtration unit of the present invention comprises a first reservoir, optionally having a first pressure source, and a second reservoir, optionally having a second pressure source, wherein the first reservoir is fluidically connected to the feed fluid inlet and the second reservoir is fluidically connected to the retentate outlet, assuming at least one of the first and second pressure sources is present. Preferably, both the first and second reservoirs each have a pressure source. Each reservoir is preferably divided into two halves by an elastic and fluid-impermeable (gas and liquid impermeable) membrane, wherein the first half is connected to the pressure source. The second half of the first reservoir is preferably fluidically connected to the feed fluid inlet. The second half of the second reservoir is preferably fluidically connected to the retentate outlet.

[0062] According to a preferred embodiment, the method of the present invention further comprises a step (C0) of separating the pre-feed fluid into a pre-retentate and a pre-permeate. This upstream step allows the fluid to be first concentrated, for example by filtration or diafiltration, and / or to be (partially) freed of impurities, so that it can then be subjected to subsequent diafiltration using the cross-flow filtration unit of the present invention. If step (C0) is a filtration step or a diafiltration step, then in principle, both the pre-retentate and the pre-permeate can be used as feed fluid, but it is preferred to use the pre-retentate from step (C0).

[0063] Advantageously, step (C0) is performed using a cross-flow filtration unit (C0 unit) to separate the pre-feed fluid into a pre-retentate and a pre-permeate. Such cross-flow filtration units are known in the prior art. In this case, the C0 unit can be upstream of the first cross-flow filtration unit, as described above for the serial connection of cross-flow filtration units according to the present invention.

[0064] It is particularly advantageous to have a cross-flow filtration unit as a CO unit, comprising a pre-retentate slit, a flat filter material, and a pre-permeate collecting slit arranged such that the flat filter material delimits the pre-retentate slit and the pre-permeate collecting slit, wherein the pre-retentate slit is fluidically connected to at least one inlet for a pre-feed fluid and to at least one outlet for the pre-retentate; and the pre-permeate collecting slit is fluidically connected to at least one outlet for the pre-permeate; the inlet for the pre-feed fluid is arranged in a first edge region of the cross-flow filtration unit; and the outlet for the pre-retentate is arranged in a second edge region of the cross-flow filtration unit, the second edge region being opposite the first edge region; and preferably, the free volume of the pre-retentate slit decreases in the direction of flow from the inlet for the pre-feed fluid to the outlet for the pre-retentate. Due to the reduction in free volume in the direction of flow, a CO unit with low pressure loss and high surface area utilization can be provided.

[0065] The explanations regarding the cross-flow filtration unit of the present invention for diafiltration, particularly regarding its retentate slit and permeate collection slit, apply accordingly to the design of the CO unit, and particularly to the design of the pre-retentate slit and pre-permeate collection slit. The flat filter material of the CO unit can be a microfiltration membrane, preferably an ultrafiltration membrane. Like the cross-flow filtration unit of the present invention, the CO unit can be expanded into a filter cartridge.

[0066] Preferably, the method of the present invention is performed under the following conditions: P DF ≥ P 渗余物 ; x = V DF / V 进料 , preferably x ≥ 1, more preferably 3 to 10; and k = V 进料 / V 渗余物 , preferably k ≥ 1; in P DF The pressure at which the filtration medium is added, P 渗余物 is the retentate outlet pressure, i.e., the pressure at which the retentate leaves the diafiltration apparatus; V 渗余物 is the volume flow rate of the retentate; V DF is the volume flow rate of the filtration medium; V 进料 is the volume flow rate of the feed fluid; x is the so-called DF ratio; and k is the so-called concentration factor.

[0067] The method of the present invention is particularly suitable for filtering, diafiltration, concentrating and / or modifying ionic components of protein solutions or combinations thereof.

[0068] The methods of the present invention may be part of a broader procedure. For example, the diafiltration process may be performed after pretreatment and / or before posttreatment. Examples of suitable pretreatments or posttreatments include reacting the educts to form products by biological or chemical means, thermal and mechanical separation methods, and chemical analysis methods.

[0069] In another aspect, the present invention relates to an apparatus for performing a chemical or biological process, comprising the cross-flow diafiltration unit described above. Such an apparatus may comprise, for example, a bioreactor, a unit for cell separation, a unit for diafiltration using the cross-flow diafiltration unit of the present invention, and a unit for chromatography. Suitable chemical and biological processes are, for example, the production of vaccines or biopharmaceuticals.

[0070] Furthermore, the present invention relates to the use of a cross-flow filtration unit for continuous diafiltration in chemical or biological processes, wherein the continuous diafiltration step is preceded by at least one conditioning step for the feed fluid and / or followed by at least one post-conditioning step for the retentate. Suitable conditioning and post-conditioning steps are, for example, reactions in bioreactors, optionally followed by cell separation, chromatography, filtration, concentration and dilution (cf. Figure 4 ).

[0071] The present invention is explained by the following examples, but the present invention is not limited thereto. DETAILED DESCRIPTION

[0072] Example 1

[0073] A solution of albumin and NaCl (5.2% by weight albumin in a 0.9% by weight aqueous NaCl solution) was diafiltered. The albumin concentration was determined photometrically at a wavelength of 280 nm. The starting solution had a conductivity of 14 mS. Demineralized water was used as the diafiltration medium.

[0074] The diafiltration unit is designed as a filter cartridge in which 13 arrays consisting of diafiltration slots, a flat first filter material, a retentate slot, a flat second filter material, a permeate collecting slot, a flat second filter material, a retentate slot and a flat first filter material are stacked on top of each other and supplemented with further diafiltration slots. ® A 30 kDa polyethersulfone membrane from Sartorius Stedim Biotech was used as the flat second filter material. The DF ratio (volume of diafiltration medium / volume of feed fluid) was approximately 5.5:1.

[0075] The pump and valve settings were not readjusted for the duration of the test. The diafiltration unit operated stably. The low conductivity of the retentate of 2.2 mS indicated that excellent diafiltration performance was achieved.

[0076] The results of the above example are shown in Table 1 below. Table 1 P 进料 The pressure at which the feed fluid is added P 渗余物 Retentate outlet pressure P DF The pressure at which the filtration medium is added V 进料 Volume flow rate of feed fluid V 渗余物 Volume flow rate of retentate V 渗透物 Volume flow rate of permeate C 蛋白质 Albumin concentration (weight percentage) x DF ratio (diafiltration medium volume / feed fluid volume) LF 渗透物 Conductivity of the permeate LF 渗余物 Conductivity of the retentate T temperature

[0077] Example 2

[0078] Diafiltration was performed on a solution of approximately 22 g / L albumin (1 g / L corresponds to 0.1% by weight) in 10 mM KPi buffer (10 mmol / L potassium dihydrogen phosphate and 10 mmol / L potassium hydrogen phosphate) and 0.9% by weight NaCl. Albumin concentration was determined photometrically at a wavelength of 280 nm. The conductivity of the starting solution was 15.9 mS. The diafiltration medium (DF) used was a 10 mM KPi solution with a conductivity of 2.05 mS.

[0079] The diafiltration units used were designed as filter cartridges, each having an array of eight stacked on top of each other consisting of a diafiltration slit, a flat first filter material, a retentate slit, a flat second filter material, a permeate collecting slit, a flat second filter material, a retentate slit and a flat first filter material, supplemented by further diafiltration slits. ® The flat second filter material was a 30 kDa Hydrosart membrane from Sartorius Stedim Biotech. ® The membrane serves as a flat first filter material.

[0080] In this example, three of the above-mentioned diafiltration units are connected in series via a deflection plate for the feed fluid, so that the feed fluid passes through all three filter cartridges in series. Conversely, the diafiltration fluid enters all three diafiltration units in parallel.

[0081] The total filter area of all three flat second filter materials is 0.2 m 2 The DF ratio (diafiltration medium volume / feed fluid volume) was about 4.5:1.

[0082] The results of the above example are shown in Table 2 below.

[0083] The pump and valve settings were not readjusted for the duration of the test period.

[0084] The diafiltration unit was run continuously and steadily for 2 hours.

[0085] The efficiency of the percolation is calculated from the reduction in conductivity (LF) in the feed stream and is referred to in the table as "clearance". The clearance percentage is calculated according to the following formula: Clearance = 100 - ((LF 渗余物 - LF DF ) / (LF 进料 - LF DF ) * 100) Where LF is the conductivity of each medium.

[0086] The clearance values calculated in this way were compared with theoretically achievable values.

[0087] Theoretically achievable clearance calculations were performed according to the following formula: Theoretically achievable clearance = 100 - ((1 / e) n 100) Where e is the Euler number, n represents the DF ratio

[0088] Example 2 shows that using the device according to the invention a very efficient continuous diafiltration can be achieved, which is able to achieve a theoretical (maximum possible) clearance value of 99%.

[0089] In this regard, it must be noted that, when, according to the known prior art, the diafiltration solution mentioned in the example is diluted 4.5 times and the protein solution is subsequently concentrated to the original volume, only a clearance value of 78% can be achieved. Even if it is added continuously in 5 separate steps, each of which is subsequently concentrated to the starting volume, a clearance value of only 96% will result. Even this value is still significantly lower than the clearance of 99% that can be achieved according to the present invention. Table 2 P 进料 The pressure at which the feed fluid (feed) is added P 渗余物 Retentate outlet pressure P DF The pressure at which the filtration medium is added V 进料 Volume flow rate of feed fluid V 渗余物 Volume flow rate of retentate V 渗透物 Volume flow rate of permeate C 蛋白质 Albumin concentration (g / L) x DF ratio (diafiltration medium volume / feed fluid volume) LF 渗余物 Conductivity of the retentate Removal rate is the percentage of conductivity reduction (100% = maximum possible conductivity reduction) Theoretical removal rate is the percentage of the maximum possible conductivity reduction T temperature BRIEF DESCRIPTION OF THE DRAWINGS

[0090] Figure 1A possible structure of a cross-flow filtration unit (1) according to the invention is shown, with a flat second filter material in the form of an ultrafiltration membrane (6) and a flat first filter material in the form of a microfiltration membrane (4), wherein the arrows indicate the flow streams of the diafiltration medium (3), the feed fluid (5), the retentate (7) and the permeate (2). The diafiltration slits, the retentate slits and the permeate slits are kept open by gaskets (8) for the respective media.

[0091] Figure 2 Schematic diagram showing an example of how the diafiltration process according to the invention can be carried out by means of a cross-flow diafiltration unit designed as a diafiltration cartridge (1). In this case, the feed fluid (5) is supplied by a pump (14) at the inlet for the feed fluid. The pressure of the diafiltration medium (3) or the retentate (7) is measured by a pressure gauge (16) before the inlet for the diafiltration medium and after the outlet for the retentate. The respective components of the retentate (7) and the permeate (2) are monitored by a measuring device, for example a conductivity meter (19). The volume flow rate of the retentate (7) is controlled by a throttle valve (17).

[0092] Figure 3 A schematic diagram showing an example of how the diafiltration process according to the invention can be carried out, wherein three diafiltration cartridges (1) are connected in series. Upstream, there is a step of separating the fluid into a pre-retentate and a pre-permeate by means of a conventional cross-flow filter cartridge (11). The feed fluid (5) is supplied via a pump (14). The diafiltration medium (3) is fed to the three diafiltration cartridges (1) via a pump (12). The pre-retentate from the respective upstream filter unit is fed as feed fluid via a channel (10) to the respective downstream filter unit. The pressure of the diafiltration medium (3) or the retentate (7) is measured by a pressure gauge (16) before the inlet for the diafiltration medium and after the outlet for the retentate. The composition of the retentate (7) is monitored by a measuring device, such as a conductivity meter (19). The volume flow rate of the retentate (7) is controlled by a throttle valve (17). The permeate (2) from all modules (11, 1) is discharged via a collecting line (20).

[0093] Figure 4Schematic diagram showing an example of how the diafiltration process of the invention is carried out and of a cross-flow diafiltration unit of the invention, wherein a feed fluid / retentate (5) oscillates in a retentate slit. The feed fluid (5) is introduced into a reservoir (30a) by means of a pump (14) and subsequently into a retentate slit. Thereafter, the feed fluid / retentate (5) passes through a second device for generating oscillations or a second reservoir (30b). The diafiltration medium (3) is introduced into the diafiltration slit by means of a pump (12). The cross-flow diafiltration unit shown has two devices for generating oscillations, wherein the first device comprises a first reservoir (30a) and the second device comprises a second reservoir (30b) different from the first reservoir. The reservoir (30a) is connected in a fluid-conducting manner to an inlet of the feed fluid (5). The reservoir (30b) is connected in a fluid-conducting manner to an outlet of the retentate (7). Each reservoir is divided into two halves by an elastic and fluid-impermeable membrane. The first half ( Figure 4 The second half of the first reservoir (30a) (shown as a non-shaded area) is connected to a pressure source through a valve controller. Figure 4 The second reservoir (30b) is connected to the inlet of the feed fluid in a fluid-conducting manner. The second reservoir (30b) is divided into two halves by an elastic and fluid-impermeable membrane. The first half of the second reservoir (30b) Figure 4 The second half of the second reservoir (30b) is connected to the pressure source through a valve controller. Figure 4 The retentate slit (shown as a shaded area) is fluidically connected to the retentate outlet. By controlling or adjusting the compressed air pressure level (compressed air is applied in opposite directions to the respective first halves of 30a and 30b), an oscillating motion of the feed fluid / retentate is generated in the retentate slit. Portions of the retentate are continuously discharged to ensure a continuous process.

[0094] FIG5 shows an example of individual parts A to C of a process diagram for carrying out a method for producing a biopharmaceutical, wherein each process comprises providing at least one cross-flow diafiltration unit ( 1 ) according to the invention. The dashed square brackets and the arrows before or after indicate that further processing steps can be upstream or downstream.

[0095] Figure 5A The embodiment shown in FIG comprises a cross-flow diafiltration unit ( 1 ) according to the invention, wherein a bioreactor ( 41 ) and a cell separation unit ( 42 ) are located upstream. Downstream of the cross-flow diafiltration unit ( 1 ) is a chromatography unit / chromatography step ( 44 ). The flow of the product solution from the bioreactor ( 1 ) is indicated by arrows.

[0096] Figure 5BThe embodiment shown in comprises a cross-flow diafiltration unit (1) according to the invention between two chromatography steps (44). This means that the diafiltration is preceded by the chromatography step and then by the chromatography step.

[0097] Figure 5C The embodiment shown in comprises a cross-flow diafiltration unit (1) according to the invention prior to a final filtration step (45).

[0098] Figures 5A to 5C The process steps shown can be expanded as required to include additional process steps or can be combined as required.In this context, the cross-flow filtration of the present invention is preferably used for filtering, diafiltration, concentrating and / or modifying components of a solution.

[0099] Reference Signs List

[0100] 1 Cross-flow filtration unit / filtration cartridge

[0101] 2. Permeate

[0102] 3 Filtration medium

[0103] 4First filter material

[0104] 5 Feed fluid

[0105] 6. Second filter material

[0106] 7 Retentate

[0107] 8 gaskets

[0108] 10 Channel for reversing the feed fluid

[0109] 11 standard cross flow filter cartridges

[0110] 12 percolation pumps

[0111] 14 Feed fluid pump

[0112] 16 pressure gauges

[0113] 17 throttle valve

[0114] 19 Conductivity meter

[0115] 20 collection pipeline

[0116] 30a,

[0117] 30b liquid reservoir

[0118] 41 Bioreactor

[0119] 42 Cell separation

[0120] 44 Chromatographic analysis

[0121] 45 filtration steps / filters

Claims

1. A method for diafiltration of a feed fluid (5) to obtain a retentate (7) and a permeate (2), comprising the steps of: (A) Providing a plurality of cross-flow filtration units (1), each of the cross-flow filtration units comprising at least a plurality of stacked arrays consisting of: Percolation slits, a flat first filter material (4), Retentate slit, a flat second filter material (6), Permeate collection slit, a flat second filter material (6), retentate slit, and a flat first filter material (4) such that the stacked array is combined to form a filter cartridge, The stacked array is arranged such that the flat first filter material (4) delimits the permeate slit and the retentate slit from one another, and the flat second filter material (6) delimits the retentate slit and the permeate collecting slit from one another, in The diafiltration slit is fluidically connected to at least one inlet for the diafiltration medium (3); the retentate slit is fluidically connected to at least one inlet for the feed fluid (5) and to at least one outlet for the retentate (7); and the permeate collecting slit is fluidically connected to at least one outlet for the permeate (2), and wherein the pore size or molecular weight cut-off of the flat first filter material (4) is at least as large as the pore size or molecular weight cut-off of the flat second filter material (6); (B) feeding diafiltration medium (3) to said inlet for said diafiltration medium (3); (C) feeding the feed fluid (5) to the inlet for the feed fluid (5); (D) discharging the retentate (7) from the outlet for the retentate (7); and (E) discharging the permeate (2) from the outlet for the permeate (2), in, The method is performed under the following constraints: P DF ≥ P 渗余物 ; x = V DF / V 进料 , x ≥ 1, and k = V 进料 / V 渗余物 ,k≥1; in P DF is the pressure of the diafiltration medium added in step (B), P 渗余物 is the retentate outlet pressure, i.e., the pressure at which the retentate leaves the diafiltration apparatus in step (D); V 渗余物 is the volume flow rate of the retentate; V DF is the volume flow rate of the filtration medium; V 进料 is the volume flow rate of the feed fluid, and wherein the permeate slit, the retentate slit and the permeate collecting slit are held open by gaskets for the respective media, wherein the plurality of cross-flow filtration units (1) are connected in series such that the outlet for the retentate (7) of the respective upstream cross-flow filtration unit (1) is connected in a fluid-conducting manner to the inlet for the feed fluid (5) of the downstream cross-flow filtration unit (1), and In step (C), the feed fluid (5) is fed into the inlet for the feed fluid (5) of the cross-flow filtration unit (1) which is not preceded by any other cross-flow filtration unit (1), and In step (D), the retentate (7) is discharged from the outlet for the retentate (7) of the cross-flow filtration unit (1) that is not followed by any other cross-flow filtration unit (1), The feed fluid is passed through the plurality of cross-flow filtration units in series, while the diafiltration medium (3) enters all of the cross-flow diafiltration units in parallel, and the permeate (2) from all of the cross-flow diafiltration units in the plurality of cross-flow filtration units exiting the at least one outlet for the permeate (2) is discharged through a collection line (20), and The diafiltration medium is supplied at a pressure of 0.1 to 4 bar and at a pressure greater than the retentate outlet pressure.

2. The method for diafiltration according to claim 1, wherein The flat first filter material (4) of the cross-flow filter unit (1) is a first filter membrane; and / or the flat second filter material (6) is a second filter membrane.

3. The method for diafiltration according to claim 2, wherein The first filter membrane of the cross-flow filtration unit (1) is a microfiltration membrane or an ultrafiltration membrane, and / or the second filter membrane of the cross-flow filtration unit (1) is an ultrafiltration membrane.

4. The method for diafiltration according to claim 1, wherein The first filter material has a molecular weight cut-off (MWCO) in the range of 30 kDa to 1,500 kDa, and / or the second filter material has a molecular weight cut-off in the range of 5 kDa to 1,500 kDa.

5. The method for diafiltration according to claim 1, wherein The pore size (maximum pore diameter) of the first filter material is 0.01 to 50 μm, preferably 0.01 to 0.5 μm, and / or the second filter material has a pore size of less than 0.01 μm.

6. The method for diafiltration according to any one of claims 1 to 5, wherein The volume of the diafiltration medium is 0.1 to 15 times the volume of the feed fluid.

7. The method for diafiltration according to any one of claims 1 to 5, wherein The filtration medium is introduced into the retentate slit in such a way that the entire available surface area of the flat first filter material is covered by the filtration medium.

8. The method for diafiltration according to any one of claims 2 to 5, wherein The filter membrane is composed of polyvinylidene fluoride, cellulose and its derivatives, polyethersulfone or polysulfone, preferably cross-linked cellulose hydrate.

9. The method for diafiltration according to any one of claims 1 to 5, wherein The flat first and second filter materials independently of one another have a substantially uniform thickness, which is preferably from 50 μm to 10,000 μm, more preferably from 150 μm to 1,000 μm.

10. The method for diafiltration according to any one of claims 1 to 5, wherein The diafiltration medium is fed separately to each of the cross-flow filtration units connected in series.

11. A method for diafiltration according to any one of claims 1 to 5, wherein The feed fluid or the retentate begins to oscillate in the retentate slot.

12. A method for diafiltration according to any one of claims 1 to 11, wherein The free volume of the filtration slot and / or the retentate slot of the cross-flow filtration unit (1) decreases in the flow direction from the inlet for the feed fluid (5) to the outlet for the retentate (7).

13. The method for diafiltration according to claim 12, wherein Multiple layers of textile material are arranged on top of each other in the retentate slit of the cross-flow filter unit (1) such that the free volume of the retentate slit decreases in the flow direction.

14. A method for diafiltration according to any one of claims 1 to 13, wherein The diafiltration medium (3) and the feed fluid (5) are supplied continuously.

15. A method for diafiltration according to any one of claims 1 to 14, wherein The retentate (7) discharged in step (D) is at least partially recycled into the inlet for the feed fluid (5).

16. The method for diafiltration according to any one of claims 1 to 15, further comprising the steps of: (C0) separating a fluid into a pre-retentate and a pre-permeate, wherein the pre-retentate or the pre-permeate is used as the feed fluid (5).

17. A method for diafiltration according to any one of claims 1 to 16, wherein The ionic components of the solution are filtered, diafiltered, concentrated and / or modified by the method.

18. A method for diafiltration according to any one of claims 1 to 17, wherein The diafiltration process is performed after pretreatment and / or before posttreatment.

19. A method for diafiltration according to any one of claims 1 to 18, wherein X is 3 to 10.

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