DEVICE AND METHOD FOR REPEATEDLY MODIFYING THE COMPOSITION OF A FLUID

Abstract

A device and a method for repeatedly modifying the composition of a fluid. The device includes a first module (19) modifying the composition of the fluid, a second module (21) modifying the composition of the fluid and a dwell module (20) with an inlet (8) and an outlet (10). The first module is connected in a fluid-conducting manner to the dwell module inlet and the dwell module outlet is connected in a fluid-conducting manner to the second module. Either the first or the second module is a filter unit, or the first module is a first filter unit and the second module is a second filter unit. The filter unit(s) include(s) at least one first filter medium (4, 14) delimiting a supply channel (2, 12) and a retentate channel (1, 11) and at least one second filter medium (5, 15) delimiting the retentate channel and a permeate channel (3, 13).

Claims

1. A device for repeatedly modifying a composition of a fluid, comprising: a first module for modifying the composition of the fluid, a second module for modifying the composition of the fluid and a dwell module with an inlet and an outlet, wherein the first module is connected in a fluid-conducting manner to the inlet of the dwell module and the outlet of the dwell module is connected in a fluid-conducting manner to the second module, wherein: the first module or the second module is a filter unit, or the first module is a first filter unit and the second module is a second filter unit, wherein the filter unit has or the first and the second filter units each respectively have: at least one supply channel, at least one first filter medium, at least one retentate channel, at least one second filter medium, and at least one permeate channel, arranged so that the first filter medium delimits the supply channel and the retentate channel from one another, and the second filter medium delimits the retentate channel and the permeate channel from one another, wherein the supply channel is connected in a fluid-conducting manner to at least one inlet for a supply medium, wherein the retentate channel is connected in a fluid-conducting manner to at least one inlet for the fluid and to at least one outlet for the fluid, and wherein the permeate channel is connected in a fluid-conducting manner to at least one outlet for a permeate.

2. The device as claimed in claim 1, wherein the first module is the first filter unit and the second module is the second filter unit.

3. The device as claimed in claim 1, wherein the first module or second module is a static mixer.

4. The device as claimed in claim 3, wherein the first module is the static mixer and the second module is the filter unit.

5. The device as claimed in claim 1, wherein the first module is the filter unit and the second module is a further filter.

6. The device as claimed in claim 5, wherein the further filter comprises a single filter medium and/or is selected from the group consisting essentially of: a sterile filter; a dead-end filter; a filter consisting essentially of a supply channel, a single filter medium and a retentate channel; and a filter consisting essentially of a retentate channel, a single filter medium and a permeate channel.

7. The device as claimed in claim 1, wherein the first module comprises a membrane adsorber or a chromatography module, and the second module is the filter unit.

8. The device as claimed in claim 7, wherein the membrane adsorber is laden with a product and comprises an outlet controlled by a valve.

9. A method for repeatedly modifying a composition of a fluid, comprising: (a) providing the device as claimed in claim 1; (b) feeding the fluid into the first module; and (c) conducting the fluid out of the second module, wherein said step (b) and/or said step (c) comprise/comprises the following steps: feeding the supply medium into the inlet for the supply medium; (ii) feeding the fluid into the inlet for the fluid; (iii) conducting the fluid out through the outlet for the fluid; and (iv) conducting the permeate out through the outlet for the permeate.

10. The method as claimed in claim 9, wherein the fluid which is fed into the first module contains at least one product.

11. The method as claimed in claim 10, wherein the fluid which is fed into the first module additionally contains at least one contaminant.

12. The method as claimed in claim 9, wherein a pH value of the fluid is reduced and/or increased in the first module, and wherein, in the second module, the pH value of the fluid is increased and/or reduced.

13. The method as claimed in claim 12, wherein the pH value of the fluid is reduced in the first module and wherein the pH value of the fluid is increased in the second module.

14. The method as claimed in claim 9, wherein a dwell time of the fluid in the dwell module is from 1 minute to 24 hours.

15. The method as claimed in claim 9, wherein the first module is the first filter unit and the second module is the second filter unit, wherein said step (b) comprises the following steps: (b-i) feeding the supply medium into the inlet of the first filter unit for the supply medium; (b-ii) feeding the fluid into the inlet of the first filter unit for the fluid; (b-iii) conducting the fluid out of the first filter unit through the outlet of the first filter unit for the fluid; and (b-iv) conducting the permeate out of the first filter unit through the outlet of the first filter unit for the permeate, and step (c) comprises the following steps: (c-i) feeding the supply medium into the inlet of the second filter unit for the supply medium; (c-ii) feeding the fluid into the inlet of the second filter unit for the fluid; (c-iii) conducting the fluid out of the second filter unit through the outlet of the second filter unit for the fluid; and (c-iv) conducting the permeate out of the second filter unit through the outlet of the second filter unit for the permeate.

16. The method as claimed in claim 9, configured for virus inactivation.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0069] FIGS. 1 and 2 show exemplary embodiments of the device according to the invention and additionally illustrate embodiments of the method according to the invention. FIG. 1 shows an embodiment configured to adjust a pH value of a fluid, while FIG. 2 shows an embodiment configured for virus inactivation of a fluid that contains monoclonal antibodies and for removing contaminants; and

[0070] FIG. 3 shows results of a representative example performed in accordance with the invention.

DETAILED DESCRIPTION

[0071] FIG. 1 shows an exemplary embodiment of the device according to the invention and/or of the method according to the invention. The device of this embodiment is suitable, for example, for adjusting the pH value of a fluid. The device has three modules: a first module (left) which transitions directly into a dwell module (center), which in turn transitions directly into a second module (right).

[0072] In a first aspect, the present invention relates to a device for repeatedly modifying the composition of a fluid, comprising a first module (19) for modifying the composition of the fluid, a second module (21) for modifying the composition of the fluid and a dwell module (20) with an inlet (8) and an outlet (10). The first module (19) is connected in a fluid-conducting manner to the inlet (8) of the dwell module (20) and the outlet (10) of the dwell module (20) is connected in a fluid-conducting manner to the second module (21). The first module (19) or the second module (21) is a filter unit or the first module (19) is a first filter unit and the second module (21) is a second filter unit. The filter unit and/or filter units each has at least one supply channel (2, 12), at least one first filter medium (4, 14), at least one retentate channel (1, 11), at least one second filter medium (5, 15) and at least one permeate channel (3, 13), arranged so that the first filter medium (4, 14) delimits the supply channel (2, 12) and the retentate channel (1, 11) from one another and the second filter medium (5, 15) delimits the retentate channel (1, 11) and the permeate channel (3, 13) from one another, the supply channel (2, 12) is connected in a fluid-conducting manner to at least one inlet (6, 16, 24, 27) for a supply medium, the retentate channel (1, 11) is connected in a fluid-conducting manner to at least one inlet (7, 10, 23) for the fluid and to at least one outlet (8, 17, 23) for the fluid, and the permeate channel (3, 13) is connected in a fluid-conducting manner to at least one outlet (9, 18, 25, 28) for a permeate.

[0073] As shown in FIG. 1, each of the first and second modules is a filter unit. Each of the filter units has a retentate channel (1, 11), a supply channel (2, 12), a permeate channel (3, 13), a first filter medium (4, 14) and a second filter medium (5, 15). The first filter medium (4, 14) separates the supply channel (2, 12) from the retentate channel (1, 11) and the second filter medium (5, 15) separates the retentate channel (1, 11) from the permeate channel (3, 13).

[0074] By way of the inlet (7, 10) of the retentate channel (1, 11) of the filter unit of the first module (first filter unit) and/or of the filter unit of the second module (second filter unit), the fluid is fed to the first and/or the second module. A supply medium is fed in by way of the inlet (6, 16) of the supply channel (2, 12). The supply medium passes through the first filter medium (4, 14) and is thus brought into contact with the fluid in the retentate channel (1, 11). According to the invention, the same supply medium can be fed into the first and second filter units, whereby supply media with different compositions are preferably used. By way of the supply channel (2, 12), a fluid is fed in, which changes the composition of the fluid in the retentate, e.g. its pH value. In the case of the virus inactivation, an acidic aqueous solution, for example, a solution of citric acid in water, can be fed in as the first supply medium by way of the inlet (6) of the supply channel of the first filter unit, in order to bring about a reduction in the pH value of the fluid in the retentate channel (1). A buffer solution (e.g. an aqueous phosphate buffer) or a basic aqueous solution can be fed in as the second supply medium by way of the inlet (16) of the supply channel of the second filter unit, so that the pH value of the fluid in the retentate channel (11) of the second filter unit is increased.

[0075] The properties of the second filter medium (5, 15) can be selected so that only particular components of the fluid pass through the second filter medium (5, 15) in order thereby to achieve a desired separation effect. In particular, if the fluid contains one or more antibodies as the product, an ultrafiltration membrane with a pore size from 2 to 100 nm can be used as the second filter medium (5, 15) so that the antibody/antibodies remain in the fluid and do not pass into the permeate channel (3, 13). Furthermore, by using an ultrafiltration membrane with a pore size from 2 to 100 nm as the second filter medium (5, 15), a vaccine contained in the fluid as the product can be held back by the ultrafiltration membrane. Constituents of the fluid which are able to pass through the second filter medium (5, 15) (e.g. contaminants) pass through the second filter medium (5, 15) at least partially or completely and are conducted away by way of the permeate channel (3, 13) and its outlet (9, 18) as the permeate. Thereby, in addition to a repeated modification of the composition of the fluid, contaminants can be separated out.

[0076] By way of the outlet (8) of the retentate channel (1) of the first filter unit and/or the inlet (8) of the dwell module, the fluid is fed from the first module to the dwell module. The dwell module has a plurality of deflector plates which define a fluid path through which the fluid flows. Through the design of the fluid path (path length, flow velocity of the fluid and the face area of the path), the dwell time of the fluid in the dwell module can be adjusted. Thus, for example, in the case of the virus inactivation during this dwell time, the viruses are subjected to the adjusted properties of the fluid (for example, a low pH value) in the first module, so that a complete inactivation of the viruses can be ensured. The fluid leaves the dwell module by way of its outlet (10) and/or the inlet (10) of the retentate channel of the second filter unit.

[0077] FIG. 2 shows a further exemplary embodiment of the device according to the invention and/or of the method according to the invention. The embodiment shown in FIG. 2 is also suitable for the virus inactivation and, in particular, for virus inactivation of a fluid which contains monoclonal antibodies, while simultaneously removing contaminants from the fluid (by way of the permeate).

[0078] In this embodiment, the fluid is introduced, by the use of a pressure gradient, into the retentate channel and simultaneously, by the use of a pressure gradient between the retentate channel and the permeate channel, a filtration takes place in the permeate channel. The pressure gradient can be controlled, for example, by a valve on the outlet of the retentate channel of the first module (19) and/or the first filter unit (19) and/or by a valve on the outlet of the retentate channel of the second module (21) and/or of the second filter unit (21) and/or by a valve on the outlet of the dwell module (20).

[0079] The fluid can be introduced from a chromatography step possibly arranged upstream, with the aid of a pump (not shown in FIG. 2) into the inlet (23) of the retentate channel of the first filter unit (19). Through the selection of a suitable separating boundary of the second filter medium of the filter units (19, 21), a product/target molecule contained in the fluid (e.g. a monoclonal antibody) can be retained without passing through the second filter medium.

[0080] By way of the inlet (24) of the supply channel, a supply medium (for example, an aqueous citric acid solution) is introduced into the supply channel and thereby by way of the first filter medium into the retentate channel. The quantity fed in is controlled by use of the pH value measured by a pH sensor (26). The pH value can be reduced, for example, from 7 to 3.5.

[0081] At the same time, in this preferred embodiment, by use of a pressure gradient between the retentate channel and the permeate channel, a filtration takes place in the permeate channel. The volumetric flow rate at the outlet (25) of the permeate channel is the same size in the exemplary embodiment as the volumetric flow rate of the quantity of supply medium fed to the supply channel. Thus, the concentration of the constituents remaining in the fluid, and the volume of the fluid, remain constant.

[0082] Preferably, an ultrafilter with a pore size in the region from 2 to 100 nm is used as the second filter medium. The first and the second filter medium do not have to have the same pore size and/or material properties. Preferably, the transmembrane pressure between the retentate channel and the permeate channel is from 0.1 to 1.5 bar. The transmembrane pressure between the supply channel and the retentate channel is preferably from 0.01 to 0.4 bar.

[0083] In the exemplary embodiment shown in FIG. 2, the dwell module is connected directly to the first module/the first filter unit. In the dwell module of this exemplary embodiment, by use of the arrangement of deflector films (22) and spacers (e.g. textile materials; not shown in FIG. 2) in stacks, a channel is formed. This channel forms a fluid path. In accordance with common flat filter constructions which are known to persons skilled in the art, the stacks can be combined, for example, by pressing, overmolding or injection molding.

[0084] In the second module of the embodiment shown in FIG. 2, similarly to the first module, for example a phosphate-buffered salt solution with a pH value of 7 is introduced by way of the inlet (27) of the supply channel into the supply channel and thereby by way of the first filter medium into the retentate channel. The quantity fed in can be adjusted on the basis of the pH value. The pH value can be measured with a sensor (29). The pH value can be increased, for example, from 3.5 to a value of 7.

[0085] With the aid of a pressure sensor (30) and a valve (31), the filtration pressure and the output volumetric flow rate can be adjusted.

[0086] In the exemplary embodiment shown in FIG. 2, in the case of a (perfusion) process with a batch volume of 501, the area of the filter medium of the first and the second module can each be 1.5 m.sup.2 and the overall channel length (fluid path length) of the dwell module can be 2 m, provided that a continuous volumetric flow rate of approximately 35 ml/min for a total duration of 24 h is assumed for the (perfusion) process. The dwell time of the fluid in the dwell module at a pH value of 3.5 would be approximately 42 minutes in this case.

REFERENCE SIGNS

[0087] 1, 11 Retentate channel

[0088] 2, 12 Supply channel

[0089] 3, 13 Permeate channel

[0090] 4, 14 First filter medium

[0091] 5, 15 Second filter medium

[0092] 6, 16, 24, 27 Inlet for supply medium

[0093] 7, 10, 23 Inlet of the retentate channel for the fluid

[0094] 8 Inlet of the dwell module

[0095] 8, 17, 32 Outlet for the fluid

[0096] 9, 18, 25, 28 Outlet for the permeate

[0097] 10 Outlet of the dwell module

[0098] 19 First module

[0099] 20 Dwell module

[0100] 21 Second module

[0101] 22 Deflector films

[0102] 26, 29 pH sensor

[0103] 30 Pressure sensor

[0104] 31 Valve

[0105] The present invention is explained further with the following reference example, but is not limited thereto.

Representative Example

[0106] The following starting materials were provided.

Feed liquid (fluid): 20 g/l bovine serum albumin (BSA) in 0.1 M citrate buffer with a pH value of 3.5
Supply liquid: 0.1 M citrate buffer with a pH value of 2

[0107] Aim: the rebuffering (buffer exchange) of the feed liquid and a pH value reduction from pH 3.5 to pH 2.5 with the aid of supply liquid and an incubation in a dwell module.

[0108] As the first module, a first filter unit with first and second filter media of the ultrafine membrane type made from polyethersulfone with a MWCO (molecular weight cut-off) of 10 kDa was used. The total membrane area of the first filter medium was 0.027 m.sup.2. A textile material for thorough mixing of the retentate was introduced into the retentate channel of the first filter unit.

[0109] In order to monitor the process, the transmembrane pressure (TMP) was measured. Furthermore, the protein concentration of the retentate at the retentate outlet was measured to determine when the concentration of BSA in the retentate corresponded to that in the feed liquid and the process was in a state of equilibrium. Furthermore, the pH value of the retentate at the retentate outlet was measured to determine when the pH value of the retentate corresponded to the target setpoint of pH 2.5 and the process was in a state of equilibrium. The volumetric flow rates of the feed liquid, the supply liquid and the retentate were 6 ml/min, 6.5 ml/min and 6 ml/min, respectively.

[0110] FIG. 3 shows that an equilibrium state was reached for all the parameters TMP, pH and protein concentration. The required pH value of 2.5 in the retentate was achieved. Due to the textile material in the retentate channel, the retentate was optimally mixed.

[0111] The retentate was subsequently fed into a dwell module consisting of 50 successive channels as shown schematically in FIG. 2. The channels were each subdivided by a deflector film. The height, breadth and length of each channel were respectively approximately 0.41 mm, 30 mm and 150 mm. This resulted in a total length of the fluid path defined by the dwell module of approximately 7500 mm. The dwell time of the fluid in the dwell module was determined by measuring the time from the entry of the liquid into the inlet until the emergence of the liquid from the outlet. With an inlet volumetric flow rate into the dwell module of 6 ml/min, a dwell time of 15.5 min was measured.