CROSSFLOW FILTRATION UNIT FOR CONTINUOUS DIAFILTRATION

Abstract

A crossflow filtration unit for continuous diafiltration of a feed fluid for obtaining a retentate and a permeate, a corresponding method for diafiltration and the use of the crossflow filtration unit are provided. The crossflow filtration unit includes a diafiltration channel, a flat first filter material, a retentate channel, a flat second filter material, and a permeate collection channel, arranged such that the flat first filter material delimits the diafiltration channel and the retentate channel from one another, and the flat second filter material delimits the retentate channel and the permeate collection channel from one another. The diafiltration channel is fluidly connected to at least one inlet for the diafiltration medium, the retentate channel is fluidly connected to at least one inlet for the feed fluid and to at least one outlet for the retentate. The permeate collection channel is fluidly connected to at least one outlet for the permeate.

Claims

1. A crossflow filtration unit for continuous diafiltration of a feed fluid for obtaining a retentate and a permeate, at least comprising: a diafiltration channel, a flat first filter material, a retentate channel, a flat second filter material, and a permeate collection channel, arranged such that the flat first filter material delimits the diafiltration channel and the retentate channel from one another, and the flat second filter material delimits the retentate channel and the permeate collection channel from one another, wherein the flat first filter material and the flat second filter material have a respective pore size or a respective molecular weight cut-off; the diafiltration channel is connected in a fluid conducting manner to at least one inlet for the diafiltration medium; the retentate channel is connected in a fluid conducting manner to at least one inlet for the feed fluid and to at least one outlet for the retentate; and the permeate collection channel is connected in a fluid conducting manner to at least one outlet for the permeate, and wherein the pore size or the molecular weight cut-off of the flat first filter material is at least as large as the pore size or the molecular weight cut-off of the flat second filter material.

2. The crossflow filtration unit, as claimed in claim 1, wherein the flat first filter material is a first filtration membrane; and/or the flat second filter material is a second filtration membrane.

3. The crossflow filtration unit, as claimed in claim 2, wherein the first filtration membrane is a microfiltration membrane or an ultrafiltration membrane, and/or the second filtration membrane is an ultrafiltration membrane.

4. The crossflow filtration unit, as claimed in claim 1, wherein the crossflow filtration unit comprises a plurality of stacked arrays each including a respective diafiltration channel, a respective flat first filter material, a respective retentate channel, a respective flat second filter material, a respective permeate collection channel, a respective flat second filter material, a respective retentate channel and a respective flat first filter material, such that the stacked arrays are combined to form a filter cassette.

5. The crossflow filtration unit, as claimed in claim 1, wherein a free volume of the diafiltration channel and/or the retentate channel decreases in a flow direction from the inlet for the feed fluid to the outlet for the retentate.

6. The crossflow filtration unit, as claimed in claim 5, wherein a plurality of layers of textile materials are arranged one above another in the retentate channel such that the free volume of the retentate channel decreases in the flow direction.

7. A method for diafiltration of a feed fluid for obtaining a retentate and a permeate comprising: providing a crossflow filtration unit, wherein the crossflow filtration unit comprises: a diafiltration channel, a flat first filter material, a retentate channel, a flat second filter material, and a permeate collection channel, wherein the flat first filter material and the flat second filter material have a respective pore size or a respective molecular weight cut-off; the unit is arranged such that the flat first filter material delimits the diafiltration channel and the retentate channel from one another, and the flat second filter material delimits the retentate channel and the permeate collection channel from one another; the diafiltration channel is connected in a fluid conducting manner to at least one inlet for the diafiltration medium; the retentate channel is connected in a fluid conducting manner to at least one inlet for the feed fluid and to at least one outlet for the retentate; and the permeate collection channel is connected in a fluid conducting manner to at least one outlet for the permeate, feeding a diafiltration medium into the inlet for the diafiltration medium; feeding the feed fluid into the inlet for the feed fluid; discharging the retentate from the outlet for the retentate; and discharging the permeate from the outlet for the permeate.

8. The method for diafiltration, as claimed in claim 7, wherein the diafiltration medium and the feed fluid are continuously supplied.

9. The method for diafiltration, as claimed in claim 7, wherein a plurality of crossflow filtration units are provided, each connected in series such that the outlet for the retentate of the respective upstream crossflow filtration unit is connected in a fluid conducting manner to the inlet for the feed fluid of a downstream crossflow filtration unit, wherein the feed fluid is fed into the inlet for the feed fluid of that crossflow filtration unit, which is not preceded by any other crossflow filtration unit, and wherein the retentate is discharged from the outlet for the retentate of that crossflow filtration unit, which is not followed by any other crossflow filtration unit.

10. The method for diafiltration, as claimed in claim 7, wherein the retentate, during discharging the retentate, is recycled at least partially into the inlet for the feed fluid.

11. The method for diafiltration, as claimed in claim 7, further comprising: separating a fluid into a pre-retentate and a pre-permeate, wherein the feed fluid comprises the pre-retentate or the pre-permeate.

12. The method for diafiltration, as claimed in claim 7, further comprising concentrating and/or modifying the ion composition of a protein solution with the crossflow diafiltration unit.

13. The method for diafiltration, as claimed in claim 7, further comprising performing continuous diafiltration within a chemical or biological process, wherein the continuous diafiltration is preceded by at least one conditioning step for the feed fluid and/or is followed by at least one post-conditioning step for the retentate.

14. The method for diafiltration, as claimed in claim 7, wherein the flat first filter material is a first filtration membrane; and/or the flat second filter material is a second filtration membrane.

15. The method for diafiltration, as claimed in claim 14, wherein the first filtration membrane is a microfiltration membrane or an ultrafiltration membrane, and/or the second filtration membrane is an ultrafiltration membrane.

16. The method for diafiltration, as claimed in claim 7, wherein the crossflow filtration unit comprises a plurality of stacked arrays each including a respective diafiltration channel, a respective flat first filter material, a respective retentate channel, a respective flat second filter material, a respective permeate collection channel, a respective flat second filter material, a respective retentate channel and a respective flat first filter material, such that the stacked arrays are combined to form a filter cassette.

17. The method for diafiltration, as claimed in claim 7, wherein a free volume of the diafiltration channel and/or the retentate channel decreases in a flow direction from the inlet for the feed fluid to the outlet for the retentate.

18. The method for diafiltration, as claimed in claim 17, wherein a plurality of layers of textile materials are arranged one above another in the retentate channel such that the free volume of the retentate channel decreases in the flow direction.

19. The method for diafiltration, as claimed in claim 7, wherein the pore size or the molecular weight cut-off of the flat first filter material is at least as large as the pore size or the molecular weight cut-off of the flat second filter material.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0100] FIG. 1 shows an example structure of a crossflow diafiltration unit according to embodiments provided herein.

[0101] FIG. 2 is a schematic of an example diafiltration process carried out with a crossflow diafiltration unit according to embodiments provided herein.

[0102] FIG. 3 is a schematic of an example diafiltration process using three diafiltration cassettes connected in series according to embodiments provided herein.

[0103] FIG. 4 is a schematic of an example diafiltration process using a crossflow diafiltration unit, wherein the feed fluid/the retentate is/are oscillated in the retentate channel according to embodiments provided herein.

[0104] FIGS. 5A-5C show various examples of processes using a crossflow diafiltration unit, according to the embodiments provided herein. FIG. 5A shows a crossflow diafiltration unit with a bioreactor and a cell separation unit positioned upstream and a chromatography unit/a chromatography step positioned downstream of the crossflow diafiltration unit. The embodiment shown in FIG. 5B shows a crossflow diafiltration unit preceded by a chromatography step and followed by a chromatography step, and the embodiment shown in FIG. 5C shows a crossflow diafiltration unit positioned before a final filtration step.

DETAILED DESCRIPTION

[0105] FIG. 1 shows a possible structure of a crossflow diafiltration unit (1) according to aspects of the invention 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 streams of diafiltration medium (3), feed fluid (5), retentate (7) and permeate (2) are illustrated by arrows. The diafiltration channel, the retentate channel and the permeate collection channel are kept open by spacers (8) for the respective media.

[0106] FIG. 2 shows in schematic form an example of how the diafiltration process according to aspects of the present invention is carried out with a crossflow diafiltration unit that is designed as a diafiltration cassette (1). In this case the feed fluid (5) is supplied by a pump (14) at the inlet for the feed fluid. In front of the inlet for the diafiltration medium and after the outlet for the retentate, the pressure of the diafiltration medium (3) or the retentate (7) is measured by manometers (16). The respective composition of the retentate (7) and the permeate (2) is monitored by a measuring device, for example, a conductometer (19). The volume flow rate of the retentate (7) is controlled by a throttle valve (17).

[0107] FIG. 3 shows in schematic form an example of how the diafiltration process according to aspects of the present invention is carried out, wherein three diafiltration cassettes (1) are connected in series. Upstream there is a step of separating a fluid into a pre-retentate and a pre-permeate using a conventional crossflow filtration cassette (11). The feed fluid (5) is supplied with a pump (14). The diafiltration medium (3) is fed to the three diafiltration cassettes (1) with a pump (12). The pre-retentate from the respective upstream filtration unit is fed through a channel (10) to the respective downstream filtration unit as a feed fluid. In front of the inlet for the diafiltration medium and after the outlet for the retentate, the pressure of the diafiltration medium (3) or the retentate (7) is measured by manometers (16). The composition of the retentate (7) is monitored by a measuring device, for example, a conductometer (19). The volume flow rate of the retentate (7) is controlled by a throttle valve (17). The permeate (2) from all of the modules (11, 1) is discharged through the collection line (20).

[0108] FIG. 4 shows in schematic form an example of how the diafiltration process according to aspects of the present invention is carried out as well as a crossflow diafiltration unit of the present invention, wherein the feed fluid/the retentate (5) is/are oscillated in the retentate channel. The feed fluid (5) is introduced with a pump (14) into a reservoir (30a) and subsequently into the retentate channel. Thereafter, the feed fluid/the retentate (5) passes/pass through a second device for generating oscillation or a second reservoir (30b). The diafiltration medium (3) is introduced with a pump (12) into the diafiltration channel. The illustrated crossflow diafiltration unit has two devices for generating oscillation, with the first device comprising a first reservoir (30a) and the second device comprising a second reservoir (30b) that is different from said first one. The reservoir (30a) is connected in a fluid conducting manner to the inlet for the feed fluid (5). The reservoir (30b) is connected in a fluid conducting manner to the outlet for the retentate (7). Each reservoir is separated into two halves by an elastic and fluid impermeable membrane. The first half of the first reservoir (30a) (shown with non-hatched region in FIG. 4) is connected to a pressure source through a valve controller. The second half of the first reservoir (30a) (shown with hatched region in FIG. 4) is connected in a fluid conducting manner to the inlet for the feed fluid. The second reservoir (30b) is separated into two halves by an elastic and fluid impermeable membrane. The first half of the second reservoir (30b) (shown with non-hatched region in FIG. 4) is connected to a pressure source through a valve controller. The second half of the second reservoir (30b) (shown with a hatched region in FIG. 4) is connected in a fluid conducting manner to the outlet for the retentate. By controlling or regulating the pressure level of the compressed air (opposing application of compressed air on the respective first half of 30a and 30b) an oscillating motion of the feed fluid/the retentate is generated in the retentate channel. Part of the retentate is continuously discharged, in order to ensure a continuous process.

[0109] FIG. 5 shows examples of various sections A to C of the process schematics for carrying out a method for producing biopharmaceuticals, wherein each of the processes comprises the provision of at least one crossflow diafiltration unit (1) of the present invention. The dashed square brackets and the preceding or following arrows indicate that further process steps can be upstream or downstream.

[0110] The embodiment, shown in FIG. 5A, comprises a crossflow diafiltration unit (1) of the invention, wherein a bioreactor (41) and a cell separation unit (42) are located upstream. Downstream of the crossflow diafiltration unit (1) there is a chromatography unit/a chromatography step (44). The flow of the product solution from the bioreactor (1) is illustrated by arrows.

[0111] The embodiment, shown in FIG. 5B, comprises a crossflow diafiltration unit (1) of the invention between two chromatography steps (44). That means that the diafiltration is preceded by a chromatography step and followed by a chromatography step.

[0112] The embodiment, shown in FIG. 5C, comprises a crossflow diafiltration unit (1) of the invention before a final filtration step (45).

[0113] The process steps, shown in FIGS. 5A to 5C, can be expanded, as desired, to include additional process steps or can be combined, as desired. In this context the crossflow filtration of the invention is used preferably for filtration, diafiltration, concentration and/or modification of the composition of a solution.

LIST OF REFERENCE NUMERALS

[0114] 1 crossflow diafiltration unit/diafiltration cassette [0115] 2 permeate [0116] 3 diafiltration medium [0117] 4 first filter material [0118] 5 feed fluid [0119] 6 second filter material [0120] 7 retentate [0121] 8 spacer [0122] 10 channel for reversing the feed fluid [0123] 11 standard crossflow cassette [0124] 12 diafiltration pump [0125] 14 feed fluid pump [0126] 16 manometer [0127] 17 throttle valve [0128] 19 conductometer [0129] 20 collection line [0130] 30a, [0131] 30b reservoir [0132] 41 bioreactor [0133] 42 cell separation [0134] 44 chromatography [0135] 45 filtration step/filter