WO2016193100A1

WO2016193100A1 - Method and filtration device for producing a concentrated product solution

Info

Publication number: WO2016193100A1
Application number: PCT/EP2016/061809
Authority: WO
Inventors: Martin Leuthold; Matthias Grabosch; Ulrich Grummert
Original assignee: Sartorius Stedim Biotech Gmbh
Priority date: 2015-05-29
Filing date: 2016-05-25
Publication date: 2016-12-08
Also published as: DE102015108501A1

Abstract

The invention relates to a method for producing a concentrated product solution via a tangential flow filtration, in which the following steps are carried out: a) providing a filtration device with a filtration module, in which a retentate space is separated from a permeate space by a filter medium, b) flowing the product solution to be concentrated across the filter medium on the retentate side, c) removing the retentate from the retentate space via a retentate discharge, d) removing the permeate from the permeate space via a permeate discharge. The method is characterized in that a solution of increased colligative properties is introduced into the permeate space, the osmotic pressure of which solution is higher than the osmotic pressure of the product solution in the retentate space. The invention further relates to a filtration device for producing a concentrated product solution via a tangential flow filtration with a filtration module, in which a retentate space is separated from a permeate space by a filter medium, wherein the filtration module has a feed supply to the retentate space and a retentate discharge from the retentate space, and wherein the filtration module has a permeate space discharge from the permeate space. The device is characterized in that a solution of increased colligative properties is introduced into the permeate space, the osmotic pressure of which solution is higher than the osmotic pressure of the product solution to be introduced into the retentate space.

Description

Method and filtration device for producing a concentrated

product solution

description

Field of the invention

The invention relates to a method for producing a concentrated product solution by tangential flow filtration, in which the following steps are carried out:

a) providing a filtration device with a filtration module, wherein a

Retentatraum is separated from a Permeatraum by a filter medium, b) overflow of the filter medium on the retentate side with the product solution to be concentrated,

c) removing the retentate from the retentate space via a retentate effluent, d) discharging the permeate from the permeate space via a permeate effluent.

The invention further relates to a filtration device for producing a

concentrated product solution by a tangential flow filtration with a

Filtration module in which a retentate from a permeate through a

Filter medium is separated, wherein the filtration module feed flow to the

Retentate and a retentate effluent from the retentate, and wherein the filtration module has a Permeatraumabfluss from the permeate space.

State of the art

For applications in pharmaceutical therapy, it is often necessary

To provide active ingredient-containing solutions in a high concentration. For example, highly concentrated protein formulations are needed in cancer therapy or in the treatment of immunodeficiency. For example, immunoglobulin in high drug concentrations is used for subcutaneous injection. Among other things, the advantages of subcutaneous administration include the possibility of self-administration, the development of drug depots and the reduction of the risk of infection compared with intravenous administration. The omission of outpatient or inpatient visits by subcutaneous injection generally leads to a better quality of life in patients.

One widely used method of producing concentrated protein solutions on an industrial scale is tangential flow filtration. The medium to be filtered ("feed") is conveyed tangentially over the filter medium in order to prevent the formation of a cover layer

Filtration resistance lead and slow down the filtration or bring to a standstill. Concentration is the target molecule during the

Tangential flow filtration retained ("retentate"), wherein the solvent and, for example, smaller components of the feed pass through the filter medium ("permeate").

Decisive for the retention of the target molecule is the separation limit of the filter medium. The filtration rate (permeate flow per area and time through the membrane = "flux") depends not only on the filter medium and properties of the protein solution but primarily on the overflow velocity and the pressure gradient between

Permeate and Retentatseite from.

Despite suppression of the surface layer formation, well-known limitations in the high concentration (> 200 g / L) of proteins by means of tangential flow filtration are one

Concentration polarization or gel layer formation on the filter medium, but also the high flow resistance of the protein solution within the filtration module due to the high viscosities. These lead to a reduction in the filtration performance and ultimately bring the concentration process to a standstill.

Reducing the negative effects of influencing the feed, for example, reducing the viscosity of additives such as salts or increasing the temperature are limited. Thus, additives in the form of salts in high

Concentrations lead to incompatibilities, reduced shelf life or lowering the potency of the product. Likewise, temperature increases lead to Decreasing the viscosity sustained to damage the product, especially in proteins.

WO 2001 / 085316A1 and WO 2013 / 086498A1 disclose filter modules for

Tangential flow filtration (cross-flow filtration) known. Flat filter modules consist of a variety of stacked filter media. These filter media are separated from one another by spacers which at the same time function as a feed or retentate or permeate channel. The design of the spacers significantly influences the properties of the flat filter modules with regard to

Flow properties and cover layer formation on the filter medium

(Concentration polarization or gel layer formation).

From US Pat. No. 8,580,933 B2 it is known to set the operating parameters during the

To adjust concentration. Depending on the retentate properties (type of molecule, concentration, viscosity) pressure difference and overflow rate are varied.

The disadvantage here is the more complex control of the process and the need to know the retentate properties over the time course of the process.

WO 2010/1 1 1378 A1 discloses a method and a device for producing highly concentrated product solution by means of tangential flow filtration in combination with evaporation. Along the permeate side of the porous filter medium, a gas stream is passed to obtain a more concentrated solution. The solution to be concentrated is circulated on the retentate side. Evaporation can increase the achievable concentration.

The disadvantage here is that the evaporation processes are very slow. In order to achieve acceptable process times, the filtration area must be increased. However, this leads to higher costs and a poorer yield.

task

It is the object of the present invention to provide a method and a filtration device which has a higher filtration performance even at high concentrations enables and thus enables the production of highly concentrated product solutions, for example highly concentrated protein solutions. The process times should be relatively short and damage to the highly concentrated product solution should be avoided.

Presentation of the invention

This object is achieved with respect to the method in conjunction with the features of the preamble of claim 1, characterized in that in the Permeatraum a solution of increased Kolligativitat is introduced, whose osmotic pressure is higher than the osmotic pressure of the product solution in the retentate.

Surprisingly, it has been shown that by an additional solution with increased colligativity in the permeate space limitations with respect to the achievable

Final concentrations of the product solutions to be concentrated can be reduced, so that higher final concentrations can be achieved in a shorter time without, for example, increase the filtration area. Damage to the highly concentrated product solution can also be avoided.

A solution with increased or high colligativity is understood as meaning a solution having a high particle number of dissolved components which increase the osmotic pressure.

For concentration, the target molecule of the product solution to be concentrated is retained during the tangential flow filtration ("retentate"), the solvent and, for example, smaller constituents of the feed, that is to say the concentrate to be concentrated

Product solution that pass filter medium as permeate. Decisive for the

Retention of the target molecule is the separation limit of the filter medium. The

Filtration rate (permeate flow per area and time through the membrane = "flux") depends not only on the filter medium and the properties of the product solution but primarily on the overflow velocity and the pressure gradient between permeate and

Retentate side off.

Preferred embodiments are subject of the dependent claims. According to a preferred embodiment of the invention, the product solution to be concentrated (feed) is fed batchwise or continuously to a retentate tank. The product solution to be filtered, ie in the present case the product solution to be concentrated, can be supplied to the retentate tank from a separate storage or feed container. In principle, however, it is also possible to supply the product solution to be filtered directly from the storage or feed container to the retentate space of the filter module and to concentrate the retentate

Collect product solution in a retentate tank.

According to another preferred embodiment of the invention, the retentate is recirculated between the retentate space and the retentate tank by means of a pump.

According to a preferred embodiment of the invention, the solution of increased colligativity is supplied via an additional (in addition to the inflow via the filter medium) Permeatraumzufluss the permeate space and discharged together with the permeate via the Permeatabfluss. In principle, a one-time delivery of the solution with increased colligativity is possible. The permeate side can be designed such that no further supply of ion-containing solution is necessary by a single filling. In addition to the one-time feed, batch-wise feeding of the solution with increased colligativity is also possible in principle.

The inventive method can be independent of the

Filtrationsmodulbauweise (such as flat filter or hollow fiber or

Wrap modules).

According to a further preferred embodiment of the invention, the solution of increased colligativity is fed continuously to the permeate space via the additional permeate space inflow.

According to a preferred embodiment of the invention, the solution of increased colligativity and the permeate are fed to a collection container. The solution of increased colligativity and the permeate can be between the permeate space and the

Collection tank to be recirculated via a pump. In a further embodiment, instead of pumps, gravity or containers pressurized with compressed air can be used to ensure an overflow of the filter medium.

According to a further preferred embodiment of the invention retentate and permeatseitig a pressure measurement and pressure control or alternatively a

Pressure measurement and a pressure control performed.

According to a preferred embodiment of the invention, a highly concentrated protein solution is prepared as the product solution.

According to a preferred embodiment of the invention, an ion-containing solution is fed to the permeate space as a solution of increased colligativity.

The ion-containing solution may in particular comprise sodium, potassium, ammonium, magnesium, chloride, sulfate, phosphate or carbonate ions. Preferably, a sodium chloride solution is added as the ion-containing solution.

The term "ion-containing solution" describes the colligative property (high colligativity) of a solution and can generally be understood as a solution with a defined (high) osmotic pressure or as a solution with a defined (high) mole fraction of dissolved components Salt solutions that have a particularly high osmotic pressure by the dissociation in ions according to the van 't Hoff law see.

Furthermore, it has been shown that the recovery of protein from the

Tangentialflussfiltrationsvorrichtung after completion of the filtration process can be improved by the inventive method. In a known manner, the product remaining in the device can be flushed out with the aid of a liquid after completion of the tangential flow filtration. This minimizes product loss. To minimize dilution of the pre-concentrated product, it is advantageous to rinse the filtration device with as little liquid as possible. It is possible to fill the permeate side with buffer after concentration and over a longer Period to obtain a solution of the concentrated product (cover layer).

Subsequently, the protein is flushed out with buffer.

The application of the device and the method according to the invention has shown that by filling the permeate side with an ion-containing solution with high

osmotic pressure an osmotic pressure gradient is generated from the permeate side to the retentate side, whereby the cover layer or the gel layer is dissolved more effectively. As a result, the recovery of the proteins from the top layer was significantly improved in comparison with the prior art rinse.

The object is achieved with respect to the filtration device in conjunction with the features of the preamble of claim 12, characterized in that in the permeate a solution of increased Kolligativitat is introduced, the osmotic pressure is higher than the osmotic pressure of the product to be introduced into the retentate solution.

Surprisingly, it has been shown that a filtration device whose permeate space has an additional solution with increased colligativity can reduce limitations with regard to the more achievable final concentrations of the product solution to be concentrated, so that higher final concentrations can be achieved in a shorter time without, for example, increasing the filtration area , Damage to the highly concentrated product solution can also be avoided with such a device.

According to a preferred embodiment of the invention, the filtration module has an additional (in addition to the inflow through the filter medium) Permeatraumzufluss in the Permeatraum on the solution with increased Kolligavität in the permeate space can be introduced.

According to a preferred embodiment of the invention, in each case one pump is arranged in the feed inflow to the retentate space and in the permeate space inflow to the permeate space. In principle, it is also possible to use gravitation or containers pressurized with compressed air instead of pumps in order to ensure an overflow of the filter medium. In the feed inflow and in the permeate inflow or in the Permeatraumabfluss pressure sensors can be arranged, which are like the pumps connected to a control or regulating unit.

According to a further preferred embodiment of the invention, the filtration module is designed as a flat filter module or a hollow fiber module or a spiral winding module.

The filter medium has at least one microporous ultrafiltration membrane with a nominal degree of separation (NMWOC: nominal molecular weight cut-off) of 1 kDa to 1000 kDa and a thickness of between 25 and 300 μηη. In this case, for example, a microporous polymer membrane with pore sizes of 0.01 to 10 μηη can be used.

The following experiments were carried out:

Exemplary embodiment 1 "Concentration of bovine serum albumin":

Bovine serum albumin (fraction V lyophilized, Kraeber) was concentrated by the method according to the invention. The achieved final concentration or process performance was compared with a standard method with different ion concentrations in the feed.

Bovine serum albumin was dissolved in phosphate buffer (buffer components

Potassium hydrogen phosphate and dipotassium hydrogen phosphate) having a molarity of 10 mM and a pH of 7.2.

For the experiments with increased ion content or salt content, the feed solution (bovine serum albumin in buffer) was added in accordance with sodium chloride (NaCl).

The concentration was determined by absorption measurement at 280 nm using a UV-VIS photometer. The calculation of the concentration from the measured extinction was carried out according to the Lambert-Beer law. The extinction coefficient for bovine serum albumin was determined to be 0.63 l / (g ^* cm).

For all experiments, tangential flow flat filter cartridges with a filtration area of 0.02 m ^{2 were} used. Membranes of the type were installed in the flat filter cassettes Hydrosart® (cellulose-based ultrafiltration membrane, Sartorius Stedim Biotech GmbH) with a cut-off of 30 kDa. For tangential flow filtration, the Sartoflow Slice 200 Bench-Top Laboratory System (Tandem 10982 Peristaltic Pump, Sartocon Slice 200 Cassette Holder, Laboratory Scale Talent TE 4100, Sartorius Stedim Biotech GmbH) was used. The permeate circulation was realized via the pump of a second Sartoflow Slice 200 bench-top laboratory system.

Before carrying out the concentration experiments according to the method of the invention, experiments were carried out to determine a transmembrane pressure suitable for the concentration range at different protein concentrations (100 g / l, 175 g / l, 250 g / l) and pressure differences (P _F -P _R ).

It was found that a transmembrane pressure of 1, 5 bar for the

Concentration range up to 250 g / l is best. For higher

Transmembrandrücke no significantly higher filtration performance was achieved.

For a comparison of the concentration according to the invention, protein solutions were first concentrated in the standard tangential flow method.

Standard methods here denote concentration without additional ionic solution on the permeate side. Concentrations were carried out at different ion content in the feed. Over the control of the feed pump became a constant

Inlet pressure of 2.7 bar set. The transmembrane pressure was regulated according to the preliminary tests to 1, 5 bar. The retentate tank was charged with 300 ml of feed solution (100 g / l). During the concentration was feed solution with a

Concentration of 100 g / l fed continuously. The level of 300 ml in

Retentate tank was retained. At a permeate flux of <2.1 l / (m ^{2 *} h), the concentration was scavenged.

Figure 1 shows the final concentrations achieved in the standard tangential flow method when the concentration is stopped. Increasing the salt concentration of the feed solution increased the achievable final concentration in the retentate. However, as mentioned above, it has the disadvantage that the increased salt concentration in the retentate (and thus in the product) can have a negative effect on durability, effect and stability. In the exemplary embodiment, the conductivity is for

Bovine serum albumin in phosphate buffer and 150 mM NaCl 14.4 mS / cm, for 1 M NaCl 69.9 mS / cm. For comparison: the conductivity of bovine serum albumin in 10 mM

Phosphate buffer without addition of sodium chloride was 2.5 mS / cm. Depending on the salt content or product, it would be necessary to desalinate after concentration by means of a further step. Another Diafiltration is for example at a high

Protein concentration is not possible.

For the concentration experiments by the method according to the invention was

Protein solution initially also concentrated in the standard tangential flow method. A constant inlet pressure of 2.7 bar was set via the control of the feed pump. The transmembrane pressure was regulated to 1, 5 bar according to the optimization experiments. Sub-step of the flux 15 l / (m ^{2 *} h), the permeate circulation was started. It was added according to the volume in the permeate tank, the concentrated salt solution to a specific salt concentration to start the Adjust permeate circulation. For permeate circulation, a constant flow of 60 mL / min was set. At a permeate flux <2.1 l / (m ^{2 *} h), the concentration was also scavenged to allow comparison of the power for concentration.

10mM KPi 10mM KPi 150mM 10mM KPi 1M NaCl 10mM KPi 2.5M

NaCl NaCl

Buffer permeate

Figure 2

Figure 2 shows the final concentrations achieved by the method according to the invention when discontinuing the concentration. By the circulation of the ion-containing solution on the permeate side, the final concentration in the exemplary embodiment could be increased by up to 27%. During the concentration pass through the

Concentration gradient in the embodiment also salt ions from the permeate to the retentate side. However, the amount is elevated compared to the concentration

Salt concentration in the feed solution significantly lower. Depending on the concentration selected, the final retentate conductivity was 4.5 mS / cm for 150 mM NaCl, 14.5 mS / cm for 1 M NaCl, and 19.3 mS / cm for 2.5 M NaCl.

For the concentration of protein according to the method of the invention, various salt solutions were circulated on the permeate side at a starting concentration of 500 mM. Process parameters and sequence were selected as before.

10mM KPi 10mM KPi 500mM 10mM KPi 500mM 10mM KPi 500mM

MgCl 2 Na citrate (NH 4) 2 SO 4

Buffer permeate

Figure 3

Figure 3 shows the increase of the final concentration at the termination criterion

(Permeatfluss <2.1 l / (m ^{2 *} h)) when using other salt solutions for

Permeatzirkulation.

EMBODIMENT 2 "Concentration of Bovine Serum Albumin After

Process according to the invention with increased transmembrane pressure and different flat filter cartridge "

In Embodiment 2, a flat filter cartridge with other spacers was used to concentrate bovine serum albumin. Concentration was carried out as in Working Example 1 with the following differences: The volume of the retentate tank was 70 ml. The transmembrane pressure was set to 2.4 bar.

During concentration without salt circulation, a final concentration of 324 g / l was achieved. Concentration with salt circulation (1 M sodium chloride) reached a final concentration of 518 g / L. The final conductivity of the pension yield was 15.7 mS / cm in permeate circulation.

Further features and advantages of the invention will become apparent from the following specific description and the drawings. Brief description of the drawings

Show it

Figure 1: a side view in section of a trained as a flat filter module

Filter module,

Figure 2: a schematic representation of a filtration device with a

Recirculation between a retentate tank and a retentate space of a filtration module and with a recirculation between one

Collection tank and a permeate space of the filtration module and

Figure 3: a schematic representation of a filtration device with a

Reservoir for a product solution to be concentrated and with a collection tank for permeate and solution of increased colligativity.

DESCRIPTION OF PREFERRED EMBODIMENTS

A filtration device 1 consists essentially of a filtration module 2 with a feed inlet 3, a retentate outlet 4 and a permeate drainage 5.

According to the embodiment of FIG. 1, the filtration module 2 is designed as a flat filter module, in which a retentate space 6 is separated from a permeate space 7 by a filter medium 8. The retentate 6 is connected on the one hand to the feed flow 3 and on the other hand to the retentate 4 flow. The permeate space 7 is filled with a solution 10 with increased colligativity. The solution 10 with the increased colligativity can be introduced into the permeate space 7 via the permeate space inflow 9. The osmotic pressure of the solution 10 with increased colligativity is higher than the osmotic pressure of a to be introduced into the retentate 6 via the feed flow 3

Product solution 1 1, which should be highly concentrated. Concentrated retentate 12 of the product solution 11 is removed via the retentate effluent 4. Permeate 13 passing through the filter medium 8 is discharged via the permeate space drain 5 together with the solution 10. According to FIG. 1, the filter medium 8 is thus supplied via the feed flow 3 through the retentate space 6, which forms a retentate channel, due to a pressure difference P between the pressure P _{F of} the feed flow 3 and the pressure P _{R of} the retentate effluent 4 (P = P _F -PR ) overflowed. Depending on the size of the molecule, ultrafiltration membranes (eg, from) are particularly suitable as the filter medium 8 for the concentration of proteins

Polyethersulfone or regenerated cellulose) with deposition rates of 1 - 1000 kDa.

Due to a pressure difference, the transmembrane pressure TMP, on both sides of the filter medium 8, namely the mean pressure in the retentate 6 (P _F - PR) / 2 and the pressure P _P in the permeate 7 results from a transmembrane pressure TMP = (P + P _R ) / 2 - P _P , whereby a portion of the product solution 1 1 is filtered as permeate 13 through the filter medium 8. The non-filtered portion of the product solution 1 1 (Feed) leaves the filtration module 2 via the retentate 4 as retentate 12. The product solution 1 1, for example, an ion-containing solution (eg sodium chloride solution), can be continuously supplied via the Permeatraumzufluss 9. Depending on the inventive design, the retentate 12 of the filter medium 8 via the retentate 6 as well as the permeate 13 with the solution 10 via the filtration medium 8 in the permeate 7 is both leaving the filtration unit 2 once over currents as well as recirculated. Furthermore, the permeate space 7 can be designed such that no further supply of the solution 10 is necessary by a single filling with the solution 10. The inventive method can be independent of the formation of the filtration module 2 as Flachfilter-, hollow fiber, or winding module perform.

According to the embodiment of Figure 2 is the filtration module 2 a

Retentattank 14 upstream with the product solution to be concentrated 1 1. Of the

Retentattank 14 is connected via a pump 15 to the feed inlet 3 of the filtration module 2. Between the feed inlet 3 and the pump 15, a pressure sensor 16 is arranged. The retentate 4 of the filtration module 2 is a first

Rezirkulationsleitung 17 connected to the retentate tank 14. In the first

Recirculation line is a first valve 23 ordered. The filtration module 2 is a collecting container 18 downstream. The permeate space 7 of the filtration module 2 is connected to its permeate space drain 5 via a collecting line 19 with the collecting container 18. The collecting container 18 is connected via a second recirculation line 20 with the Permeatraumzufluss 9 of the filter module 2. In the second Recirculation line 20, a pump 21 is arranged. Between the pump 21 and the Permeatraumzufluss 9, a pressure sensor 22 is arranged. In the second

Recirculation line 20, a second valve 24 is arranged.

The product solution to be concentrated 1 1 (Feed) is located in the retentate tank 14. By the pump 9, the product solution is conveyed into the retentate 6 of the filtration module 2. The retentate 12 is via the first recirculation line 17 in the

Retentattank 14 transported. In the collecting container 18 is the solution 10, which can be transported by the pump 21 in the permeate 7. According to that

Embodiment of Figure 2, both the retentate 12 and the permeate 13 including solution 10 are circulated. About the pump power of the pumps 15, 21, via the control of the valves 23, 24 and the pressure sensors 16, 22, the

corresponding pressure conditions for the Tangentialflussfiltration be controlled by a control or regulating unit, not shown.

According to the embodiment of Figure 3, the filtration device V is formed as a closed system and without recirculation of the retentate 12 '. The product solution 1 1 'to be concentrated is conveyed from a storage container 25 via the pump 15' and the feed inflow 3 'into the retentate space 6' of the filtration module 2 '. The filter medium 8 'separates the retentate space 6' from the permeate space 6 '. The retentate 12 'leaves the filtration module 2' via the retentate effluent 4 'and the valve 26 as a concentrated product solution without circulation. On the permeate side is from the

Sump 18 'the solution 10' with increased colligativity and the permeate 13 'by means of the pump 21' via the circulation line 20 'and the Permeatraumzufluss 9' in the permeate 7 'and together with the permeate 13' via the manifold 19 'in the Collecting container 18 'promoted. The sump 18 'is adapted to receive both the solution 10' and the permeate 13 '. About the valve 26, the

Pressure sensors 16 ', 22' and the pumps 15 ', 21', the transmembrane pressure TMP can be controlled or regulated.

Of course, the embodiments discussed in the specific description and shown in the figures represent only illustrative embodiments of the present invention. A broad range of possible variations will be apparent to those skilled in the art in light of the disclosure herein. LIST OF REFERENCE NUMBERS

1, V filtration device

2, 2 'filtration module

3, 3 'feed flow

4, 4 'Retentate

5.5 'permeate effluent

6, 6 'Retentate space

7, 7 'permeate space

8, 8 'filter medium

9, 9 'Permeatraumzufluss

10, 10 'solution with increased coll

1 1, 1 1 'product solution

12, 12 'retentate of 1 1

13, 13 'permeate

14 Retentate tank

15, 15 'pump

16, 16 'pressure sensor

17 first recirculation line

18, 18 'sump

19, 19 'manifold

20, 20 'second recirculation line

21, 21 'pump

22, 22 'pressure sensor

23 first valve of 17

24 second valve of 20

25 storage containers

26 valve

Claims

claims

1. A process for producing a concentrated product solution (1 1, 1 1 ') by a Tangentialflussfiltration, wherein the following steps are carried out:

a) providing a filtration device (1, 1 ') with a

Filtration module (2, 2 '), in which a retentate space (6, 6') is separated from a permeate space (7, 7 ') by a filter medium (8, 8'),

b) overflowing the filter medium (8, 8 ') on the retentate side with the

to be concentrated product solution (1 1, 1 1 '),

c) removing the retentate (12, 12 ') from the retentate space (6, 6') via a retentate effluent (4, 4 '),

d) discharging the permeate from the permeate space (7, 7 ') via a

Permeate discharge (5, 5 '),

characterized,

in that a solution of increased colligativity (10, 10 ') is introduced into the permeate space (7, 7') whose osmotic pressure is higher than the osmotic pressure of the product solution (11, 11 ') in the retentate space (6, 6') ,

2. The method according to claim 1,

characterized,

the product solution (11) is fed to a retentate tank (14) once or batchwise or continuously.

3. The method according to claim 2,

characterized,

the retentate (12) is recirculated between the retentate space (6) and the retentate tank (14) by means of a pump (15).

4. The method according to any one of claims 1 to 3,

characterized,

in that the solution of increased colligativity (10, 10 ') is fed via a permeate space inlet (9, 9') to the permeate space (7, 7 ') and removed together with the permeate (13, 13') via the permeate space outlet (5, 5 ') becomes.

5. The method according to any one of claims 1 to 4,

characterized,

in that the solution of increased colligativity (10, 10 ') and the permeate (13, 13') are fed to a collecting container (18, 18 ').

6. The method according to claim 4 or 5,

characterized,

the solution of increased colligativity (10, 10 ') is fed continuously to the permeate space (7, 7').

7. The method according to claim 4 or 5,

characterized,

in that the solution of increased colligativity (10, 10 ') and the permeate (13, 13') between the permeate space (7, 7 ') and the collecting container (18, 18') are recirculated via a pump (21, 21 ').

8. The method according to any one of claims 1 to 7,

characterized,

that retentate and permeatseitig a pressure measurement and pressure control or alternatively a pressure measurement and pressure control are performed.

9. The method according to any one of claims 1 to 8,

characterized,

that as product solution (1 1, 1 1 ') a highly concentrated protein solution is produced.

10. The method according to any one of claims 1 to 9,

characterized,

in that an ion-containing solution is fed to the permeate space (7, 7 ') as a solution of increased colligativity (10, 10').

1 1. A method according to claim 10,

characterized,

that a sodium chloride solution is supplied as the ion-containing solution.

12. filtration device (1, 1 ') for producing a concentrated

Product solution (1 1, 1 1 ') by a Tangentialflussfiltration with a

Filtration module (2, 2 '), in which a Retentatraum (6, 6') of a

Permeate space (7, 7 ') is separated by a filter medium (8, 8'), wherein the

Filtration module (2, 2 ') has a feed flow (3, 3') to the retentate (6, 6 ') and a Retentatabfluss (4, 4') from the retentate (6, 6 '), and wherein the filtration module (2 , 2 ') has a permeate discharge (5, 5') from the permeate space (7, 7 '),

characterized,

in that a solution of increased colligativity (10, 10 ') is introduced into the permeate space (7, 7') whose osmotic pressure is higher than the osmotic pressure of the product solution (11, 11) to be introduced into the retentate space (6, 6 ') ').

13. Filtration device according to claim 12,

characterized,

in that the filtration module (2, 2 ') has an additional permeate space inflow (9, 9') into the permeate space (7, 7 ') through which the solution with increased colligativity (10, 10') into the permeate space (7, 7 ') ) can be introduced.

14. Filtration device according to claim 13,

characterized,

in that a respective pump (21, 21 ') is arranged in the feed inflow (3, 3') to the retentate space (6, 6 ') and in the permeate space inflow (9, 9') to the permeate space (7, 7 ').

15. Filtration device according to one of claims 12 to 14,

characterized,

the filtration module (2, 2 ') is a flat filter module or a hollow fiber module or a spiral winding module.

16. Filtration device according to one of claims 12 to 14,

characterized,

in that the filter medium (8) has at least one microporous ultrafiltration membrane with a nominal separation efficiency of 1 kDa to 1000 kDa and a thickness

between 25 to 300 μηη has.