PASSIVE AUTOMATIC ANTIFOAM DELIVERY SYSTEM FOR USE WITH SINGLE-USE BIOREACTORS

Abstract

The aspects of the disclosed embodiments generally relate to an apparatus which allows for the controlled addition of antifoam to the foam present in the headspace of a disposable single-use bioreactor in a reliable manner. The aspects of the disclosed embodiments also generally relate to a method of using such apparatus which allows for the controlled addition of antifoam to the foam present in the headspace of a disposable single-use bioreactor in a reliable manner. The aspects of the disclosed embodiments generally relate to antifoam systems, methods and apparatus, and more particularly, to an antifoam device operably connected to a single use biobag.

Claims

1. A passive automatic antifoam delivery apparatus for use with a single-use bioreactor comprising: a porous object secured in the bioreactor proximally to an exhaust gas port and/or in an exhaust gas line fluidically connected to said exhaust gas port, wherein said porous object is fluidically connected to an antifoam reservoir and arranged to receive antifoam from said antifoam reservoir and to release antifoam when foam from the bioreactor rises to a level wherein it makes contact with the porous object.

2. The passive automatic antifoam delivery apparatus of claim 1 wherein said porous object absorbs antifoam from the antifoam reservoir connected to the bioreactor and the porous object and retains said antifoam substance therein until foam from the bioreactor rises to the level wherein it makes contact with the antifoam absorbed porous object which releases small quantities of an antifoam substance sufficient to neutralize the foam and clear the gas exhaust port.

3. The passive automatic antifoam delivery apparatus according to claim 1, wherein said antifoam reservoir is external to the bioreactor and connected to the porous object via an antifoam port in a wall of the bioreactor.

4. The passive automatic antifoam delivery apparatus according to claim 3, wherein said antifoam port is located in a top wall of the bioreactor.

5. The passive automatic antifoam delivery apparatus according to claim 1 wherein said porous object is located in a headspace of said bioreactor.

6. The passive automatic antifoam delivery apparatus according to claim 1 wherein said porous object is in the shape of a cylindrical wick or a ring.

7. The passive automatic antifoam delivery apparatus according to claim 1 wherein said porous object is of medical grade.

8. The passive automatic antifoam delivery apparatus according to claim 1 wherein said porous object is non-reactive.

9. The passive automatic antifoam delivery apparatus according to claim 1 wherein said porous object is in direct contact with an antifoam reservoir attached to the bag or tubing and the antifoam is introduced into the antifoam reservoir by a user via a sterile syringe fitting or by tube welding of a small container of antifoam.

10. The passive automatic antifoam delivery apparatus according to claim 1, wherein said antifoam is selected from polydimethylsiloxane, block copolymers of polyethylene glycol and polypropylene glycol, polypropylene based polyether dispersions, fatty acid esters, insoluble oils, polydimethylsiloxanes, mineral oil, vegetable oil, and EO/PO based defoamers containing polyethylene glycol and polypropylene glycol copolymers.

11. The passive automatic antifoam delivery apparatus according to claim 1 wherein said porous object comprises open cell porous foams, fibrous mesh or pads or sintered bead foams.

12. The passive automatic antifoam delivery apparatus according to claim 1 wherein said porous object comprises polymeric plastic materials, metals or metal alloys or ceramics.

13. The passive automatic antifoam delivery apparatus according to claim 1 wherein said porous object comprises polymeric plastic materials selected from polyethylene, polypropylene, polyester, polyolefins, polyamides, polyurethane, acrylics, and styrenics.

14. The passive automatic antifoam delivery apparatus according to claim 1 wherein said porous object comprises metals or metal alloys selected from titanium and stainless steel.

15. The passive automatic antifoam delivery apparatus according to claim 1 wherein said porous object comprises ceramics selected from silicon nitride and zirconium dioxide.

16. A porous object in the shape of a cylindrical wick or ring; wherein said porous object is absorbed/wicked with antifoam and retains said antifoam therein until exposed to a mass of foam which causes the release of small quantities of antifoam sufficient to neutralize the foam from the mass.

17. A method of controlling foam formation in a single use bioreactor bag comprising: securing a porous object around or adjacent to the exhaust gas port in the top of a single-use bioreactor bag; absorbing/wicking antifoam onto the porous object; retaining antifoam absorbed/wicked porous object therein until exposed to a mass of foam, and neutralizing foam in a bioreactor by the release of small quantities of antifoam.

18. (canceled)

19. The method according to claim 17, wherein said porous object is in the shape of a cylindrical wick or a ring.

20. The method according to claim 17, wherein said porous object is of a medical grade material.

21. The passive automatic antifoam delivery apparatus of claim 1 further comprising: a bioreactor apparatus.

22. The passive automatic antifoam delivery apparatus of claim 21 wherein the bioreactor apparatus further comprises a single-use flexible bioreactor bag, mounted in a rigid support vessel.

23. The passive automatic antifoam delivery apparatus of claim 21 wherein the bioreactor apparatus further comprises a magnetically driven agitator.

24. The passive automatic antifoam delivery apparatus of claim 21 wherein the bioreactor apparatus, further comprises a sparger.

25. The passive automatic antifoam delivery apparatus of claim 21 wherein the bioreactor apparatus further comprises at least one exhaust gas port and at least one exhaust gas line.

26. The passive automatic antifoam delivery apparatus of claim 25 wherein the bioreactor apparatus further comprises an exhaust filter, fluidically connected to said exhaust gas line.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The accompanying drawings illustrate presently preferred embodiments of the present disclosure, and together with the general description given above and the detailed description given below, serve to explain the principles of the present disclosure. As shown throughout the drawings, like reference numerals designate like or corresponding parts.

[0035] FIG. 1 refers to one embodiment in which the exhaust gas exit tube is connected to a section of the bioreactor bag wall.

[0036] FIG. 2 refers to another embodiment in which the exhaust gas exit tube is connected to a section of the bioreactor bag wall.

[0037] FIG. 3 refers to another embodiment in which the exhaust gas exit tube is connected to a section of the bioreactor bag wall.

[0038] FIG. 4 refers to another embodiment in which the exhaust gas exit tube is connected to a section of the bioreactor bag wall.

[0039] FIG. 5 refers to another embodiment in which the exhaust gas exit tube is connected to a section of the bioreactor bag wall.

[0040] FIG. 6 refers to another embodiment in which the exhaust gas exit tube is connected to a section of the bioreactor bag wall.

DETAILED DESCRIPTION

[0041] The present disclosure is generally directed towards the use of antifoam devices and methods so as to improve the use of bioreactor bags. As will be understood, the various diagrams, flow charts and scenarios described herein are only examples, and there are many other scenarios to which the present disclosure will apply.

[0042] Referring to FIGS. 1, 2 and 7, two embodiments of the passive antifoam system are illustrated. In these Figures the exhaust gas exit tube 1 is shown connected to a section of the bioreactor bag wall 4 via a port fitment 6a which may be heat welded to the bag film 4. The tube can be made of one of many materials commonly used in the pharmaceutical industry such as platinum cured silicone or C-Flex. The tube can be flexible, semi-rigid or rigid. There can be one or more exhaust gas exit tubes attached to a bioreactor bag 11. The other end of each exhaust tube can be connected to a condenser (not shown), an exhaust filter 19 and/or to another bag (not shown). Inside the bioreactor bag headspace 15 located in proximity to the exhaust gas port fitment is shown the porous or fibrous material pad or wick 3 which retains the antifoam. The porous or fibrous material pad or wick 3 can be formed into many different shapes such as the shape of a disc or ring. The antifoam reservoir in these Figures is depicted as a tubular or cylindrical shaped container 2 which is connected to a section of the bioreactor bag wall 4 (e.g. the top wall) via an antifoam port fitment 6b, which may be heat welded to the bag film 4. An aseptic connector 5 is shown at the top of the antifoam reservoir through which the user can fill the reservoir with antifoam, e.g. from a sterile antifoam container 20 (e.g. a syringe, bag or bottle) attached via the aseptic connector. This aseptic connector 5 could be replaced by a simple plug (not shown) if tube welding a sterile bag of antifoam is to be the method of adding antifoam to the reservoir.

[0043] FIG. 3 and FIG. 4 illustrate other embodiments of the passive antifoam system. In these Figures, the exhaust gas exit tube 1 is shown connected to a section of the bioreactor bag wall 4 (e.g. the top wall) via an exhaust gas port fitment 6a which can be heat welded to the bag film 4. The tube can be made of one of many materials commonly used in the pharmaceutical industry such as platinum cured silicone or C-Flex. The tube can be flexible, semi-rigid or rigid. There can be one or more exhaust gas exit tubes attached to a bioreactor bag 11. The other end of the exhaust tube can be connected to a condenser (not shown), an exhaust filter 19 and/or to another bag (not shown). Inside the bioreactor bag headspace 15 located in proximity to the exhaust gas port fitment are one or more porous or fibrous material pads or wicks 3 which retain the antifoam. The porous or fibrous material pads or wicks 3 can be formed into many different shapes such as the shape of a cylinder or tube. The antifoam reservoirs in these Figures are depicted as a tubular or cylindrical shaped container 2 which is connected to a section of the bioreactor bag wall 4 (e.g. the top wall) via an antifoam port fitment 6b heat welded to the bag film 4. An aseptic connector 5 is shown at the top of one of the antifoam reservoirs through which the user can fill the reservoir with antifoam. The aseptic connector 5 could be replaced by a simple tube plug 8 if tube welding a sterile bag of antifoam is to be the method of adding antifoam to the reservoir.

[0044] FIG. 5 and FIG. 6 illustrate other embodiments of the passive antifoam system. In these Figures, the exhaust gas exit tube 1 is shown connected to a section of the bioreactor bag wall 4 via an exhaust gas port fitment 6a which can be heat welded to the bag film 4. The tube can be made of one of many materials commonly used in the pharmaceutical industry such as platinum cured silicone or C-Flex. The tube can be flexible, semi-rigid or rigid. There can be one or more exhaust gas exit tubes attached to a bioreactor bag 11. The other end of each exhaust tube can be connected to a condenser (not shown), an exhaust filter 19 or to another bag (not shown). Inside the bioreactor bag headspace 15 located in proximity to the exhaust gas port fitment are one or more porous or fibrous material pads or wicks 3 which retain the antifoam. The porous or fibrous material pads or wicks 3 can be formed into many different shapes such as the shape of a disc or ring. The antifoam reservoir is in this figure shown to be a bag shaped container 2 which is connected through a section of tubing 7a to a section of the bioreactor bag wall 4 via an antifoam port fitment 6b heat welded to the bag film 4. An aseptic connector 5 is shown at the top of a section of tubing 7b through which the user can fill the reservoir with antifoam. The aseptic connector 5 could be replaced by a simple tube plug (not shown) if tube welding a sterile bag of antifoam is to be the method of adding antifoam to the reservoir.

[0045] FIG. 7 illustrates a bioreactor apparatus 10, incorporating the passive antifoam apparatus/system as disclosed above. The bioreactor apparatus can e.g. include a rigid support vessel 12, inside which a single-use flexible bioreactor bag 11 is located. The bag can have a top wall 4, a side wall 20 and a bottom wall 21 and may e.g. be of a generally cylindrical shape. It may have a volume of e.g. 5-5000 L, such as 10-5000 L or 10-2000 L. The bioreactor apparatus may comprise an agitator 17, which can e.g. be a magnetically driven agitator 17 inside the bag with a magnetic agitator drive unit 18 outside the bag. When in use, the bag is partially filled with liquid (cell culture) 13 up to a liquid level 14, leaving a headspace 15 in the bag above the liquid level. The bag typically comprises a plurality of port fitments, e.g. 6a,6b,22 etc. for transport of fluids through one or more of the bag walls. The bag may also be equipped with a sparger 16 for sparging the cell culture with a gas such as air or oxygen via a sparger port 22. During use of the bioreactor apparatus, foaming may be induced e.g. by sparging and/or agitation and if the foam fills the headspace it may be entrained in the exhaust gas tube 1 and can e.g. cause blockage of the exhaust filter 19. With the passive antifoam apparatus in place, antifoam is transported from antifoam reservoir 2 into the porous object/pad 3 and when the foam contacts the porous object/pad, antifoam is transferred to the foam lamellae and the foam collapses. The transport of the antifoam can e.g. be by gravity flow from the reservoir 2 to the porous object 3 and further by wicking through the porous object. The reservoir can suitably be placed above the porous object during use and the vertical distance from an antifoam liquid level in the reservoir to the porous object can e.g. be at least 5 mm, such as 5 mm-50 cm or 1-20 cm. The vertical distance may be adjusted to provide a desirable extent of gravity flow and wicking. The volume of the reservoir may e.g. be less than 1% of the bag volume, such as 0.01-1% of the bag volume. Thus, the volume of the reservoir may e.g. be 1 mL-50 L, such as 5 mL-1 L. The amount of antifoam released from the porous object in each instance of foam contact can e.g. be less than 1 mL, such as 1 L-1 mL or 1 L-100 L.

[0046] Thus, while there have been shown, described and pointed out, fundamental novel features of the invention as applied to the exemplary embodiments thereof, it will be understood that various omissions and substitutions and changes in the form and details of devices and methods illustrated, and in their operation, may be made by those skilled in the art without departing from the spirit or scope of the invention. Moreover, it is expressly intended that all combinations of those elements and/or method steps, which perform substantially the same function in substantially the same way to achieve the same results, are within the scope of the invention. Moreover, it should be recognized that structures and/or elements and/or method steps shown and/or described in connection with any disclosed form or embodiment of the invention may be incorporated in any other disclosed or described or suggested form or embodiment as a general matter of design choice. It is the intention, therefore, to be limited only as indicated by the scope of the claims appended hereto.