REINFORCED COMPONENT FOR CELL CULTIVATION BIOREACTOR

Abstract

The present invention relates to a bioprocess bag 118 comprising a bag wall defining an enclosed volume for holding biomaterials. The bag wall comprises at least one inlet port 142 and at least one outlet port 146. The bioprocess bag 118 also comprises a tube structure 400 comprising a first opened-end proximate the bag wall and a second distal end, the tube extending into the enclosed volume, and the tube structure 400 comprising a reinforced portion 402 proximate the first opened-end.

Claims

1. A bioprocess bag comprising: a bag wall defining an enclosed volume for holding biomaterials, the bag wall comprising at least one inlet port and at least one outlet port; and a tube structure comprising a first opened-end proximate the bag wall and a second distal end, the tube extending into the enclosed volume, and the tube structure comprising a reinforced portion proximate the first opened-end.

2. The bioprocess bag of claim 1, wherein the second distal end is a closed-end, and the tube is adapted to accept a probe for measuring one or more properties of the biomaterials.

3. The bioprocess bag of claim 2, wherein the probe comprises a thermocouple or resistance temperature detector (RTD).

4. The bioprocess bag of claim 1, wherein the tube structure comprises a first opened-end proximate the bag wall and a second distal end extending into the enclosed volume, the reinforced portion proximate the first opened-end.

5. The bioprocess bag of claim 1, wherein the tube structure is adapted to accept a sparging wand.

6. The bioprocess bag of claim 1, wherein the reinforced portion comprises a ribbed structure.

7. The bioprocess bag of claim 6, wherein the ribbed structure comprises a pattern of sections that are raised relative to the tube outer surface, and the raised sections contacting each other when the tube structure is bent.

8. The bioprocess bag of claim 7, wherein the contact of the raised sections prevents crimping of the tube structure.

9. The bioprocess bag of claim 1, wherein the tube structure comprises a predominantly cylindrical inner wall, and a notch extending at least a portion of the length of the inner wall.

10. The bioprocess bag of claim 9, wherein the notch defines a channel that allows air to flow out when a probe is inserted into the tube structure.

11. The bioprocess bag of claim 1, wherein the bag wall comprises one or more of: an impeller, a heater, and/or a gas outlet.

12. A reinforced probe housing, the probe housing comprising; a tip portion having a first outer diameter and a first inner diameter defining a thickness, the inner diameter adapted to accept a probe, the probe housing having a closed-end proximate the tip portion; a reinforced portion sharing the same inner diameter as the tip portion, wherein the outside diameter of the reinforced portion includes raised sections that provide reinforcement through contact with one another when the probe housing is bent, the probe housing having an opened-end proximate the reinforced portion, the opened-end adapted to accept the probe.

13. The probe housing of claim 12, wherein the probe comprises a thermocouple or resistance temperature detector (RTD).

14. The probe housing of claim 12, wherein the reinforced portion comprises a ribbed structure.

15. The probe housing of claim 12, wherein the ribbed structure comprises a pattern of sections that are raised relative to the tube outer surface, and the raised sections contacting each other when a tube structure is bent.

16. The probe housing of claim 15, wherein contact of the raised sections during a bend prevents crimping of the tube structure.

17. The probe housing of claim 12, wherein a tube structure comprises a predominantly cylindrical inner wall, and a notch that extends at least a portion of the length of the inner wall.

18. The probe housing of claim 17, wherein the notch defines a channel that allows air to flow out when a probe is inserted into the tube structure.

19. A bioprocess bag comprising: a bag wall defining an enclosed volume for holding biomaterials, the bag wall comprising at least one inlet port and at least one outlet port; and a tube structure comprising a first opened-end proximate the bag wall and a second closed-end distal to the bag wall, the tube extending into the enclosed volume, the tube structure comprising a predominantly cylindrical inner wall and a notch that extends at least a portion of the length of the inner wall, wherein the notch defines a channel that allows air to flow out when a probe is inserted into the tube structure.

20. The bioprocess bag of claim 19, wherein the tube structure comprises a reinforced portion proximate the first opened-end.

21. The bioprocess bag of claim 19, comprising a ribbed structure having a pattern of sections that are raised relative to the tube outer surface, and the raised sections contacting each other when the tube structure is bent.

22. The bioprocess bag of claim 19, wherein the bag wall comprises one or more of an impeller, a heater, and/or a gas outlet.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1 shows an example of a prior art disposable large-scale bioreactor system.

[0021] FIG. 2 shows an example of a prior art disposable bioreactor bag.

[0022] FIG. 3 shows an example of another prior art disposable bioreactor bag.

[0023] FIG. 4 shows a thermowell tube with a thermowell probe inserted therein according to an aspect of the invention.

[0024] FIG. 5 shows a close-up perspective view of a thermowell tube according to an aspect of the invention.

[0025] FIG. 6 shows the thermowell tube according to an aspect of the invention that is bent.

[0026] FIG. 7 shows a cross section of a portion of a thermowell tube according to an aspect of the invention.

DETAILED DESCRIPTION

[0027] The present inventors have found that several of the internal structures of a bioreactor or fermenter bag are susceptible to damage or perceived damage as a result of sterilization and packaging, and further damage to these elements can occur during shipping, setup, or use. The sterilization of the bag with gamma irradiation can in some cases exacerbate the problem by fusing adjacent pieces of material or freezing the material into bent shape. With respect to parts that are internal to the bag, these problems are sometimes compounded by the inability to inspect internal portions of the bag given the need to maintain sterility and not compromise the bag structure. The perception of damage to an internal part may result in the entire bag being deemed unsuitable for use. The tube structure maybe adapted to accept a probe, such as a thermocouple or resistance temperature detector (RTD), or a sparging wand. Alternatively, or in addition, the tube structure may be adapted for introducing or withdrawing material from the bioprocess bag.

[0028] Those internal bioreactor bag structures most susceptible to this kind of damage or perceived damage are tubular structures. These tubular structures internal to the bag may become bent, crimped, folded at some point in the supply chain.

[0029] One particular structure that is susceptible to damage is the thermowell tube found in existing bioreactor bags. One example of such a thermowell is described in U.S. Pat. No. 6,599,012 entitled “Thermowell Adapter,” which is incorporated by reference for its disclosure of thermowell structures. The thermowell tube is a piece of straight tubing made from plastic material that allows insertion of a thermowell into a bioreactor bag without breaching the seal of the bag. Often the thermowell is made from a molded plastic or rubber material. A rigid insert is used to prevent tubing from collapsing and self-sealing internally during gamma irradiation. In some cases, the rigid support breaks and can puncture the tubing. Without the support, the tubing kinks and can seal during gamma irradiation. When the temperature sensor 405 is inserted it can puncture the tubing.

[0030] In one embodiment shown in FIG. 4, a thermowell tube 400 includes a tip portion 401 and a reinforced portion 402. The tip portion 401 may have a length on the order of approximately 1 inch (2.54 cm), although the tip 401 may be longer or shorter depending on the needs of the user. The tip portion of the thermowell tube 400 is generally thinner than the reinforced portion 402 and is designed to allow enhanced heat flow from the interior portion of the bioreactor (not shown) to the thermowell distal tip 401 when it is inserted into the thermowell tube 400 as shown in FIG. 4. The reinforced portion 402 is defined by rib portions 402a that are spaced apart by separating portions 402b, in a spaced interval. The reinforced portion 402 provides greater structural stability for the thermowell tube 400.

[0031] The thermowell tube 400 may also comprise an optional base portion 403 that attaches to a thermowell flange 404, which may be used to form a seal with the bioreactor bag (not shown). Alternatively, the thermowell tube can be directly molded into the bioreactor bag. The base portion provide additional structural support for the thermowell when the thermowell is inserted into the thermowell tube 400.

[0032] FIG. 5 shows a close-up perspective view of the thermowell tube 400. The tip portion 401 of the thermowell tube 400 has a shape that maximizes the thermal exposure of the thermowell (not show) when inserted into the thermowell tube 400. The rib portions 402a are preferably present in a cylindrical configuration and are spaced apart by separating portions 402b, which may have the same geometry as the tip portion. In one aspect, the rib portion 402a are designed to have a length 406 and the separating portions 402b are designed to have a length 407. In a cylindrical configuration, the rib portions project outwardly to a height 408 that is defined by the difference in outer diameter of the rib portion 402a and the outer diameter of the separating portions 402b. The thermowell tube 400 has an inside diameter 409 that is adapted to closely match the outer diameter of the thermowell probe (not shown).

[0033] The reinforced portion 402 may be defined by several geometries in order to accomplish one or more objective of the invention. For example, in one variation, the height 408 of the rib portion 402a may progressively increase in a continuous or stepwise fashion in a direction from the tip portion 401 to the base portion 403. In some cases, the progressive increase in height 408 may result in a more continuous transition from the outer diameter of the tip portion 401 to the base portion 403. Other various reinforcement geometries are within the scope of the invention.

[0034] FIG. 6 shows the thermowell tube having a tip 401 and base 404 connected to a flange 404 that is being bent to illustrate the operation of the reinforced portion according to an aspect of the invention. The rib portions 402a toward the interior of the bend 410 may be configured to come into contact with each other to resist further deformation of the thermowell tube 400. In a preferred aspect, the contact between the rib portions 402a reinforces the entire structure when the tube is bent. This reinforcement protects the internal conduit 409 of the thermowell tube from collapse, crimping or other deformation. In this aspect, the length 407 of the spaced portion 402b between adjacent rib portions 402a is increased toward the exterior of the bend 411.

[0035] FIG. 7 shows a cutout of the thermowell tube 400 showing the details of the inner diameter of the thermowell tube 400 according to an optional aspect of the invention. The thermowell tube 400 as discussed above has an interior diameter 409 that accommodates a cylindrical thermowell probe (not shown). In this aspect, the interior wall of the thermowell tube 400 is provided with a notch 413, wherein the inner diameter is increased to 412 for a length 414. The notch forms an internal channel which will allow air passage during insertion and removal of the sensor. The notch 413 allows air to escape from the interior of the thermowell tube 400 as the thermowell probe is inserted into the thermowell tube 400. It will be appreciated that the exact geometry of the notch can be varied in order to achieve one or more objectives of the invention. Also, the notch may be designed to run the entire length of the inner diameter of the thermowell cavity from the edge of the thermowell 400, or the edge of the optional thermowell base 403, all the way to the end of the thermowell tip 401. Alternatively, the notch may run over a defined portion of the interior diameter of the thermowell tube 400. In one aspect the notch 413 runs past the reinforced portion and terminates at some point in the tip portion 401. Alternatively, the notch 413 runs to the edge of the reinforced portion 402. In yet another aspect, the notch terminates at a point within the reinforced portion 402.

[0036] It should be appreciated that reinforced portion 402 described above with respect to a thermowell tube 400 may be applied to any other structure within a bioreactor or fermenter bag. The ribbing structure on the tubing can be applied to other applications on the single-use bioreactor bag where there is potential for the tubing to be kinked and shut down fluid flow. These areas include any internal tubing for fluid transfer, such as the internal sparge tubing or internal dip tubes that deliver fluid directly into the bulk process fluid. This can be used on the top of the bioreactor for the exhaust filter lines as these typical need to be bent in order to be contained and supported within the heaters while still providing a drain path for condensate back to the reactor. Any addition line that is supported and draped over a rigid bar could benefit from a small section of the ribbed tubing where the it is bent. This may prevent fattening of the tube which can cause flow restrictions and high-pressure events. As with the thermowell tube, these portions may be molded directly into the bag or attached to the bag using a flange as was shown with the thermowell above.

[0037] It should be appreciated that the reinforced tubing structure of the present invention will be particularly useful when added to a single use bioreactor. The ribbing along the tubing, e.g., a molded thermowell tube 400, prevents kinking and self-sealing due to gamma irradiation. When used with a thermowell probe, the temperature sensor portion of the probe is in the ˜1 inch (˜2.54 cm) section at the thermowell tube tip 401 and the thermowell tubing 400 will have a thin wall section to promote fast heat transfer response. An internal channel, or notch 413, will allow air passage during insertion and removal of temperature sensor 405.

[0038] The reinforced tubular structures of the present invention, and particularly the reinforced thermowell tube, may be applied to any disposable bioprocess bag, and particularly those system made of flexible material such as plastics. Any of the disposable bags shown in FIGS. 1-3 may be modified to include internal tubular structures that are reinforced using embodiments of the present invention. In addition, any of the bags shown may be modified to include a reinforced thermowell tube in accordance with aspects of this invention.

[0039] Other embodiments and uses of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. All references cited herein, including all referenced patents and patent applications, are specifically and entirely hereby incorporated herein by reference where permissible. It is intended that the specification and examples be considered exemplary only, with the true scope and spirit of the invention indicated by the following claims.