Filter holding device

Abstract

A filter holding device (1; 41; 75; 81) is arranged to dispose at least one filter (7; 43a, 43b; 85) inside a flexible bag (3; 71), and the filter holding device includes attachment means (19a-d, 21a-d; 79; 83) for attaching the filter holding device to the inner surface of the flexible bag such that at least one filter held by the filter holding device is arranged at a distance from the inner surface of the flexible bag.

Description

Technical Field

[0001] The present invention relates to a filter holding device arranged to dispose at least one filter inside a flexible bag. Background Art

[0002] The bioprocessing industry has traditionally used stainless steel systems and piping in the manufacturing process for fermentation and cell culture. These devices are designed to be sterilized by steam and reused. However, cleaning and sterilization are costly and labor-intensive operations. In addition, the installation cost of these traditional systems with the required piping and instruments is typically prohibitively high. Moreover, these systems are typically designed for specific processes and cannot be easily reconfigured for new applications. These limitations have led to the new approach of using plastics, single-use disposable bags and piping taking decades to replace the usual stainless steel tanks.

[0003] Specifically, bioreactors traditionally made of stainless steel have been replaced in many applications by disposable bags that are shaken to provide the required aeration and mixing for cell culture. These single-use bags are typically provided as sterile units and eliminate the costly and time-consuming steps of cleaning and resterilization. The bags are designed to maintain a sterile environment during operation, thus minimizing the risk of contamination.

[0004] A successful disposable bioreactor system uses a shaking table on which a bioreactor bag is placed. The bioreactor bag is partially filled with a liquid nutrient medium and the desired cells. The table shakes the bag, providing continuous movement to the cells in the bag and also providing efficient gas exchange from the turbulent air-liquid surface. The bag typically has at least one gas supply tube for introducing air, carbon dioxide, nitrogen or oxygen, and at least one exhaust tube to allow removal of the exhaled gas. Nutrients can be added through other tubes.

[0005] During cultivation, cells produce waste products such as metabolites, ammonium ions and lactate, which are inhibitory to the cells. This effect is particularly problematic in cultures at high cell density, which is required for cost-effective production of biopharmaceuticals such as therapeutic proteins or viral antigens. One way to reduce the concentration of inhibitory metabolites is to use perfusion culture, in which the culture medium is flowed out through a filter by hydraulic flow, the filter retaining the cells but allowing the metabolites to pass through the filter. The said protein can then be recovered from the filtrate and fresh culture medium is continuously supplied to the bioreactor to replenish the lost liquid. The perfusion filter can typically be installed inside (or outside) the bioreactor.

[0006] One way to provide a perfusion filter for a single - use bioreactor is to provide a perfusion filter for a device that includes a sieve and a connector having a tube for attaching and withdrawing the filtrate (usually waste), and only floating the device with the filter and the sieve within the bioreactor. However, there are some drawbacks associated with this when shaking the bioreactor. One problem is that the usually fragile filter diaphragm can be damaged by the sieve when the sieve and the filter are forced into the bioreactor wall by the shaking motion. Another problem is associated with the clogging and fouling of the filter.

[0007] Another way to provide a perfusion filter is described in US 9017997. In it, a perfusion filter is attached to the bottom of a bioreactor bag. The problem associated with this is that the filter attached to the bottom of the bag is likely to be easily clogged and fouled. Summary of the Invention

[0008] An object of the present invention is to provide a filter holding device for a flexible bag.

[0009] Another object of the present invention is to provide an improved perfusion filter system for a flexible bag.

[0010] This is achieved in a filter holding device that is arranged to dispose at least one filter inside a flexible bag, the filter holding device including attachment means for attaching the filter holding device to the inner surface of the flexible bag such that at least one filter held by the filter holding device is disposed at a distance from the inner surface of the flexible bag.

[0011] Another object of the present invention is to provide a bioreactor that includes a perfusion filter.

[0012] This is achieved in a bioreactor that includes the filter holding device described above, wherein the filter holding device is attached to the inner surface of the flexible bag by its attachment means such that at least one filter held by the filter holding device is disposed at a distance from the inner surface of the flexible bag.

[0013] Another object of the present invention is to provide a method of disposing a filter on a flexible bag.

[0014] The method includes the following steps:

[0015] - Disposing at least one filter on the filter holding device described above;

[0016] - Attaching the filter holding device to the inner surface of the flexible bag such that at least one filter held by the filter holding device is disposed at a distance from the inner surface of the flexible bag;

[0017] - Attaching a tube to a port provided in the filter holding device for withdrawing the filtrate.

[0018] Thus, the filter is arranged at a distance from the inner surface of the flexible bag, and the liquid arranged in the flexible bag is allowed to flow between the filter and the flexible bag. Thus, cross-flow filtration is achieved, also known as TFF, and the filter can be used for a longer time because the filter has fewer problems of clogging and fouling.

[0019] In one embodiment of the invention, the filter holding device comprises two flow deflector regions which are arranged on opposite sides of the filter holding device, and the flow deflector regions are angled with respect to the rest of the filter holding device such that when the filter holding device is arranged in the flexible bag, the flow deflector regions point away from the surface of the flexible bag to which the filter holding device is attached. Thus, the flow between the filter and the inner surface of the flexible bag is increased.

[0020] Further embodiments are described in the dependent claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 A cross-sectional side view of a filter holding device according to one embodiment of the invention, arranged in a flexible bag, is schematically shown.

[0022] Figure 2 A top view of the flexible bag, which has the filter holding device shown in Figure 1 is schematically shown.

[0023] FIG. 3a schematically shows a cross-sectional side view of a filter holding device according to one embodiment of the invention.

[0024] FIG. 3b schematically shows a bottom view of the filter holding device shown in FIG. 3a.

[0025] Figure 4 A filter holding device according to another embodiment of the invention is schematically shown, in which two filters / diaphragms are attached to the same filter holding device.

[0026] FIG. 5a schematically shows a cross-sectional side view of another type of flexible bag, which includes an impeller. A filter holding device according to one embodiment of the invention is attached to the side wall of the flexible bag.

[0027] FIG. 5b schematically shows a top view of the flexible bag shown in FIG. 5a.

[0028] Figure 6 An alternative way of attaching the filter holding device to the inner surface of the flexible bag is schematically shown. DETAILED DESCRIPTION

[0029] Figure 1Schematic cross-sectional side view showing a filter holding device 1 according to an embodiment of the present invention. The filter holding device 1 is arranged in a flexible bag 3.

[0030] The filter holding device 1 is suitably a flat or slightly curved plate. The filter holding device 1 includes some kind of spacing device, which is on one side of the middle part 5 of the filter holding device. This spacing device can be, for example, a rib or a sieve or some other kind of structure. The spacing device is arranged on the side of the filter holding device to which the filter 7 should be attached. In this description, the term filter is used, but it can also be a diaphragm or a bioprocess separation device for retaining or blocking substances. The spacing device in the form of a rib is further shown and described with reference to FIG. 3b. The filter holding device 1 further includes a filter sealing area 9, which is arranged around the spacing device. The filter sealing area 9 is arranged to seal to the periphery of the filter 7 held by the filter holding device. When the filter is sealed to the filter sealing area 9 of the filter holding device, the filter will then cover the spacing device. In one embodiment, the filter can also be sealed to one or more areas of the spacing device to prevent the filter from slackening. In addition, the filter holding device includes a port 11, which is arranged around an opening 13 in the filter holding device 1, and the opening is in fluid communication with the space between the ribs. The port 11 is arranged to be connected to a tube 15 for withdrawing the filtrate (usually waste). The port 11 and the opening 13 are arranged in the middle of the filter holding device 1 and centered inside the filter sealing area 9 in an embodiment of the present invention. However, the port and the opening can also be arranged in another position, but they still need to be arranged inside the filter sealing area 9.

[0031] The flexible bag is shown herein as being disposed in the rocking tray 17. Attachment means are provided for the filter holding device to attach the filter holding device to the inner surface of the flexible bag such that at least one filter held by the filter holding device is disposed at a distance from the inner surface of the flexible bag. In this embodiment of the invention, the attachment means are provided as four openings 19a-d (only 19a and 19b are visible) in the filter holding device and four supports 21a-d received in the openings. Each of the supports 21a-d is attached in a suitable manner to each of the openings 19a-d in the filter holding device, for example by heat sealing or mechanical retention. The supports 21a-d are then attached to the inner surface of the flexible bag, for example by heat sealing or mechanical retention. In this embodiment, the supports 21a-d are shown as being attached to the bottom wall of the flexible bag 3, but they could also be attached to another wall, as will be shown with respect to FIG. 5. Another possibility would be for the supports to be molded together with the filter holding device. The number and their position of the openings and the supports can be varied. The height of the attachment means which are the supports in the embodiment shown herein should be adapted to ensure that there will be an appropriate distance between the filter and the inner surface of the bag to allow fluid flow between the filter and the bag surface and thus to create a cross-flow effect, also known as tangential flow, on the filter. This tangential or cross-flow on the filter will prevent fouling and blockage and will increase the life of the filter. In another embodiment, the attachment means are in the form of sealing two opposite sides of the filter holding device to the inner surface of the flexible bag. In order to provide a passage or channel for fluid transfer between the filter and the bag surface, the filter holding device needs to be bent or curved in some way. In Figure 6 See further details.

[0032] In the embodiment shown in Figure 1 the filter holding device 1 further includes two deflector regions 23a, 23b. These deflector regions 23a, 23b are provided on opposite sides of the filter holding device and outside the filter sealing region 9. The deflector regions 23a, 23b are angled with respect to the remainder of the filter holding device and when the filter holding device is mounted to the flexible bag, the deflector regions point away from the inner surface of the flexible bag to which the filter holding device is attached. The deflector regions 23a, 23b affect the fluid flow in the flexible bag. The rocking tray moves in a particular pattern such that the fluid inside the flexible bag moves back and forth in a wave-like motion. The deflector regions 23a, 23b will direct the fluid and force more fluid to transfer between the filter and the bag surface to which the filter holding device is attached. Thus, a cross-flow effect is created on the filter which will reduce blockage and fouling.

[0033] Figure 2 A top view of the flexible bag 3 is schematically shown which has the display in Figure 1The filter holding device 1 therein. As can be seen here, in this embodiment, four supports 21a-d are provided, one in each corner of the filter holding device 1.

[0034] Figure 3a schematically shows Figure 1 and 2 a cross-sectional side view of the filter holding device 1 shown in.

[0035] Figure 3b schematically shows a bottom view of the filter holding device 1 shown in Figure 3a. In this view, it can be seen that the filter sealing area 9 encloses the spacing device, which is in the form of ribs 31 here. All the ribs are given the same number. The configuration and number of the ribs can be changed. The function of the ribs is to hold the filter and determine the distance between the filter and the other side of the filter holding device, so that the fluid can be filtered through the filter and drawn out through the opening 13 and the port 11.

[0036] Figure 4 Schematically shows a filter holding device 41 according to another embodiment of the present invention, wherein two filters, namely a first filter 43a and a second filter 43b, are attached to the same filter holding device 41. In this embodiment, the intermediate part 45 of the filter holding device includes a first spacing device (such as a first set of ribs 47a) on one side and a second spacing device (such as a second set of ribs 47b) on the other side, rather than having ribs only on one side as in the previously described embodiment. In this embodiment, two filter sealing areas are also provided, namely a first filter sealing area 49a and a second filter sealing area 49b, one on each side of the filter holding plate. The first filter sealing area 49a surrounds the first spacing device (in this embodiment, the first set of ribs 47a) and the second filter sealing area 49b surrounds the second spacing device (in this embodiment, the second set of ribs 47b). The port 51 is provided at the center of the intermediate part 45 or near the center of the intermediate part 45. The port 51 connects the opening between the ribs to the outlet for the filtrate. In addition, as in the previously described embodiment, a deflector area 53a, 53b is provided at each end of the filter holding device 41. These deflector areas 53a, 53b are angled with respect to the rest of the filter holding device as in the previously described embodiment, and when the filter holding device is installed on the flexible bag, they point away from the bottom surface of the bag (or away from the inner surface of the bag to which the filter holding device is attached, not necessarily the bottom surface). Attachment devices in the form of openings and supports are provided in the same manner as previously described to attach the filter holding device to the flexible bag.

[0037] If more filters are provided in the flexible bag, then these filter holding devices (all shown in Figure 1 -3 and Figure 4in) can be stacked on top of each other.

[0038] Figure 5a schematically shows a cross-sectional side view of another type of flexible bag 71, which includes at least one impeller 73. This type of flexible bag is thus not arranged on a shaking tray. In fact, the contents in the flexible bag are mixed by one or more impellers 73. The flexible bag 71 is typically arranged in a rigid tank 74. According to an embodiment of the present invention, a filter holding device 75 is attached to the inner surface of the side wall 77 of the flexible bag 71. The filter holding device 75 includes an attachment device 79, which is in the form of a support here. The attachment device 79 is attached to the inner surface of the side wall 77 of the flexible bag 71, as described above for the previous embodiment. As for the previously described embodiment, at least one filter held by the filter holding device 75 will thus be arranged at a certain distance from the inner surface of the side wall 77 of the flexible bag 71. Therefore, the liquid arranged in the flexible bag 71 can flow between the filter holding device 75 and the inner surface of the side wall 77 of the flexible bag 71 to which the filter holding device 75 is attached. Therefore, as discussed above, a cross-flow action or a tangential flow action is achieved on the filter.

[0039] Figure 5b schematically shows a top view of the flexible bag 71 shown in Figure 5a. It can be seen here that the filter holding device 75 according to the present invention can be bent so as to conform to the inner surface of the side wall 77 of the flexible bag 71.

[0040] Figure 6 Schematically shows an alternative way of attaching a filter holding device 81 to the inner surface of a flexible bag. The attachment devices 83 of the filter holding device 81 are provided as parts of two opposite sides of the filter holding device 81. The two opposite sides of the filter holding device are thus attached to the inner surface of the flexible bag, and the filter holding device is formed between these two opposite sides such that the filter holding device and thus the attached filter 85 are arranged at a certain distance from the inner surface of the flexible bag. Therefore, fluid is allowed to flow between the filter and the inner surface of the flexible bag in one direction, suitably, in the shaking direction in the embodiment where the flexible bag is arranged in a shaking tray.

[0041] When a filter is arranged in a flexible bag, according to the present invention, the following steps are performed:

[0042] S1: Arrange at least one filter on the filter holding device described above. The filter can be sealed to the filter holding device.

[0043] S3: Attach the filter holding device to the inner surface of the flexible bag such that at least one filter held by the filter holding device is disposed at a distance from the inner surface of the flexible bag. The filter holding device can be attached to the flexible bag by a sealing attachment means (such as a support provided for the filter holding device). The support can be attached to the bottom wall or another wall of the flexible bag as also described above.

[0044] S5: Attach a tube to the port provided in the filter holding device. Through this tube, the filtrate can be withdrawn and removed from the flexible bag.

Claims

1. A filter holding device (1; 41; 75; 81) arranged to dispose at least one filter (7; 43a, 43b; 85) inside a flexible bag (3; 71), the filter holding device comprising attachment means (19a-d, 21a-d; 79; 83) for attaching the filter holding device to the inner surface of the flexible bag, wherein spacing means (31; 47a, 47b) are provided on at least one side of the filter holding device where the at least one filter (7; 43a, 43b; 85) is to be attached and arranged to set the at least one filter held by the filter holding device at a distance from the inner surface of the flexible bag, wherein the filter holding device further comprises at least two flow deflector regions (23a, 23b; 53a, 53b) provided at opposite ends of the filter holding device, the flow deflector regions being angled with respect to the remainder of the filter holding device such that when the filter holding device (1; 41; 75; 81) is disposed in the flexible bag (3; 71), the flow deflector regions point away from the surface of the flexible bag to which the filter holding device is attached; wherein, the filter holding device further comprises: - a filter sealing region (9; 49a, 49b) surrounding the spacing means (31; 47a, 47b) and arranged to seal to the periphery of the filter held by the filter holding device, the filter then covering the spacing means; - a port (11; 51) surrounding an opening (13) in the filter holding device, the port being arranged to connect to a tube for withdrawing filtrate.

2. The filter holding device according to claim 1, characterized in that, the attachment means (19a-d, 21a-d; 79; 83) attach the filter holding device (1; 41; 75; 81) to the inner surface of the flexible bag (3; 71) such that liquid disposed in the flexible bag can flow between the filter holding device and the inner surface to which the filter holding device is attached.

3. The filter holding device according to claim 1, characterized in that, the attachment means is a support or an opening (19a-d) for receiving a support (21a-d) for attaching the filter holding device to the inner wall of the flexible bag.

4. The filter holding device according to claim 3, characterized in that, the opening or support is provided outside the filter sealing region (9; 49a, 49b).

5. The filter holding device (41) according to any one of claims 1 to 4, characterized in that, comprises: - a first spacing means (47a) provided on one side of the filter holding device and a second spacing means (47b) provided on the other side of the filter holding device, - A first filter sealing region (49a) surrounding the first spacing device (47a), which is arranged to seal to the periphery of a first filter (43a) held by the filter holding means, the first filter then covering the first spacing device; - A second filter sealing region (49b) surrounding the second spacing device (47b), which is arranged to seal to the periphery of a second filter (43b) held by the filter holding means, the second filter then covering the second spacing device.

6. A flexible bag comprising the filter holding means according to any one of claims 1 to 5, wherein the filter holding means is attached to the inner surface of the flexible bag (3; 71) by its attachment means (19a-d, 21a-d; 79; 83) such that at least one filter (7; 43a, 43b; 85) held by the filter holding means is arranged at a distance from the inner surface of the flexible bag.

7. A method for arranging a filter (7; 43a, 43b; 85) in a flexible bag (3; 71), the method comprising the steps of: - arranging at least one filter (7; 43a, 43b; 85) in the filter holding means according to any one of claims 1 to 5; - attaching the filter holding means to the inner surface of the flexible bag such that at least one filter held by the filter holding means is arranged at a distance from the inner surface of the flexible bag; - attaching a tube (15) to a port (11; 51) provided in the filter holding means to recover the filtrate.

8. A bioreactor comprising the flexible bag according to claim 6.

9. The bioreactor according to claim 8, characterized in that it is adapted to be agitated by a shaking motion, wherein the flexible bag is placed in a shaking tray (17).

10. The bioreactor according to claim 8, characterized in that it is adapted to be agitated by an impeller, wherein the flexible bag (71) comprises at least one impeller (73).

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