Flexible stirring system suitable for disposable biological reaction bag and use method of flexible stirring system

Abstract

The invention relates to the technical field of cell bioreactors, in particular to a flexible stirring system suitable for a disposable biological reaction bag and a using method of the flexible stirring system. The flexible shaft is an axially hollow flexible sleeve, a paddle is mounted on the flexible shaft, the flexible shaft penetrates through the reaction bag, two ends of the flexible shaft are respectively connected with the reaction bag, and the flexible shaft can rotate in the reaction bag; the rigid shaft is inserted into the flexible shaft, the rigid shaft is used for inputting stirring power and is separated from the interior of the reaction bag through the flexible shaft, and when the rigid shaft rotates, the flexible shaft and the paddles are driven to rotate synchronously.

Description

Technical Field

[0001] The invention relates to the technical field of cell bioreactors, and in particular to a flexible stirring system suitable for a disposable bioreactor bag and a use method thereof. Background Art

[0002] Thanks to the development of biotechnology, people can use engineered cells to commercially produce drugs such as antibodies and vaccines. The production process requires the use of bioreactors to culture cells and to grow them to a larger volume through step-by-step amplification.

[0003] Among the traditional bioreactors used for large-scale production, stainless steel stirred bioreactors are the most widely used, and the scale-up process is relatively mature. It is usually a stainless steel tank with a specially designed diameter-to-height ratio, equipped with a vertical stirring paddle inside. The form of the paddle can be specially designed according to the cell type. At the same time, the tank is equipped with various sensors such as pH sensors, temperature sensors, and oxygen concentration sensors, which cooperate with the control system to automatically adjust the process parameters during the culture process. In order to avoid contamination by miscellaneous bacteria during cell culture, traditional stainless steel bioreactors are often equipped with online cleaning and online sterilization systems. This makes the overall verification of the production line and sterilization before batch culture complicated.

[0004] The disposable bioreactor that has emerged in recent years uses a reusable stainless steel tank with a pre-irradiated and sterilized disposable culture bag. It can start culture without online cleaning and sterilization, making production line verification simple and production line configuration flexible.

[0005] The disposable bioreactors currently used in the market include bottom stirring type, straight shaft stirring type, shaker type, etc. Among them, the overall structure of the straight shaft stirring type reactor is most similar to the traditional stainless steel reactor structure, making the development and transfer of cell culture processes simpler and widely used. The straight shaft stirring type disposable bioreactor bags currently on the market use a rigid plastic stirring shaft that runs through the bag body to achieve liquid mixing by a motor through magnetic coupling. When using this stirring system, there are the following practical problems: 1. The agitator shaft is made of rigid plastic, which has low mechanical strength and may break during transportation. Specially designed packaging must be used to reduce the risk. At the same time, since the rigid agitator shaft cannot be compressed, the packaging volume will be large, and the transportation and storage costs will be high.

[0006] 2. Because disposable reaction bags are sterilized by irradiation in advance, large-volume packaging significantly increases irradiation costs. At the same time, due to the size restrictions of the irradiation boxes of irradiation manufacturers, it will be difficult to find matching irradiation manufacturers for large-volume reaction bags. This will restrict the production line construction and capacity expansion of reaction bags, and also make it extremely difficult to further increase the culture volume of such reaction bags.

[0007] 3. The current stirring shaft is connected to the drive device through magnetic coupling, and the mechanical strength of the plastic stirring shaft is low, so the stirring system cannot transmit large torque. This limits the upper limit of the stirring speed of the reaction bag. This makes the reaction bag unsuitable for high-speed processes such as bacterial culture.

[0008] 4. With the development of biotechnology, technologies such as perfusion culture and continuous flow culture are becoming more mature. This will increase the demand for the use of reaction bags. This will pose an increasing challenge to the long-term use of plastic stirring shafts.

[0009] 5. Disposable reaction bags often use disposable fiber optic electrodes. Such electrodes need to be kept away from air during irradiation sterilization. When using a rigid plastic stirring shaft, it is difficult to evacuate the bag, so a special device is required to protect the fiber optic electrode, which increases the cost.

[0010] The information disclosed in this background technology section is only intended to deepen the understanding of the overall background technology of the present invention, and should not be regarded as acknowledging or suggesting in any form that the information constitutes the prior art already known to those skilled in the art. Summary of the invention

[0011] The object of the present invention is to provide a flexible stirring system suitable for a disposable bioreactor bag to solve the technical problems existing in the prior art.

[0012] In order to achieve the above object, the present invention adopts the following technical solutions: The present invention provides a flexible stirring system suitable for a disposable biological reaction bag, comprising: a flexible shaft and a rigid shaft; the flexible shaft is an axially hollow flexible sleeve, a paddle is installed on the flexible shaft, the flexible shaft passes through the reaction bag, the two ends of the flexible shaft are respectively connected to the reaction bag, and the flexible shaft can rotate inside the reaction bag; the rigid shaft is inserted into the flexible shaft, the rigid shaft is used to input stirring power and is separated from the inside of the reaction bag by the flexible shaft, and when the rigid shaft rotates, it drives the flexible shaft and the paddle to rotate synchronously.

[0013] Preferably, the rigid shaft is connected to a driving device to provide the power required for stirring and mixing.

[0014] Preferably, the rigid shaft has an axial telescopic function.

[0015] Preferably, a coupling structure is provided between the rigid shaft and the blades fixed on the flexible sleeve, so that the blades, the rigid shaft and the flexible shaft rotate synchronously.

[0016] Preferably, at least one sliding seal is installed between the flexible shaft and the reaction bag; The stator portion of the sliding seal is fixedly connected to the reaction bag; The movable part of the sliding seal is fixedly connected to the flexible shaft; The rigid shaft can be installed in the sliding seal and the flexible shaft, and drive the flexible shaft to rotate.

[0017] Preferably, both ends of the flexible shaft are connected to the reaction bag via sliding seals.

[0018] Preferably, one end of the flexible shaft is connected to the reaction bag via a sliding seal, and the other end of the flexible shaft is sealed and connected to a bearing inside the bag body.

[0019] Preferably, the flexible shaft is made of a flexible material with biological safety.

[0020] Preferably, the flexible shaft is made of a silicone tube or a flexible bellows.

[0021] Preferably, the flexible shaft and the blades are connected by a cable tie or by welding.

[0022] The present invention also provides a method for using a flexible stirring system suitable for a disposable biological reaction bag, which comprises: after the reaction bag leaves the factory, the reaction bag and a flexible shaft integrated therewith are packaged, transported, and irradiated in a vacuum and foldable manner (during the packaging, transportation, and irradiation of the reaction bag using this system after leaving the factory, the paddle rotating shaft can be perpendicular to the flexible shaft, and when in use, the paddle is inserted into the rigid shaft so that the flexible shaft and the paddle are coaxial); after the reaction bag arrives at the use site, one end of the rigid shaft is inserted into the flexible shaft of the reaction bag, and the other end is connected to a driving device on the reactor, and the rigid shaft drives the flexible shaft and the paddle to rotate synchronously when rotating.

[0023] By adopting the above technical solution, the present invention has the following beneficial effects: The present invention adopts a flexible stirring system design, which can effectively solve the above problems, increase the reliability of equipment operation, and significantly reduce various costs during the use of the reaction bag, including packaging, transportation, irradiation, storage and other costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0025] Figure 1 A schematic diagram of a flexible stirring system applicable to a disposable bioreactor bag provided in an embodiment of the present invention; Figure 2 A schematic diagram of a flexible shaft provided in an embodiment of the present invention having its bottom blocked and connected to a bearing; Figure 3 A schematic diagram of a shaft seal provided in an embodiment of the present invention; Figure 4 A schematic diagram of the structure of a telescopic shaft provided in an embodiment of the present invention; Figure 5 A schematic diagram of a limiting groove in a blade provided in an embodiment of the present invention; Icon: 1-rigid shaft; 2-bag body; 3-flexible shaft; 4-blade; 5-plug; 6-rigid plastic part; 7-shaft seal. DETAILED DESCRIPTION

[0026] The technical solution of the present invention will be described clearly and completely below in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0027] The specific implementation of the present invention is described in detail below in conjunction with the accompanying drawings. It should be understood that the specific implementation described here is only used to illustrate and explain the present invention, and is not used to limit the present invention.

[0028] Combination Figures 1 to 5 As shown, this embodiment provides a flexible stirring system suitable for a disposable biological reaction bag, which includes: a flexible shaft 3 and a rigid shaft 1; the flexible shaft 3 is an axially hollow flexible sleeve, and a paddle 4 is installed on the flexible shaft 3. The flexible shaft 3 passes through the reaction bag, and the two ends of the flexible shaft 3 are respectively connected to the reaction bag, and the flexible shaft 3 can rotate inside the reaction bag; the rigid shaft 1 is inserted into the flexible shaft 3, and the rigid shaft 1 is used to input stirring power and is separated from the interior of the reaction bag by the flexible shaft 3. When the rigid shaft 1 rotates, it drives the flexible shaft 3 and the paddle 4 to rotate synchronously.

[0029] In this embodiment, the flexible shaft 3 is composed of blades 4 and a flexible sleeve, and can be bent and folded. The form and number of the blades 4 can be selected according to the culture process.

[0030] Preferably, the flexible sleeve can be a mature flexible tube on the market, such as a silicone tube. At the same time, a flexible corrugated tube can also be used to further compress the packaging volume of the reaction bag before use.

[0031] Preferably, the connection between the flexible sleeve and the blade 4 can be tightened by using a plurality of cable ties, so as to ensure the connection strength and the sealing performance at the same time.

[0032] Both ends of the flexible shaft 3 are connected to the reaction bag, and when in use, the rigid shaft 1 is inserted into or passes through the flexible shaft 3. The connection at both ends can reduce the shaking of the stirring paddle during stirring, which is conducive to maintaining the stability of the flow field, enhancing the stability of the cell culture process, and reducing the difficulty of scaling up the culture process.

[0033] When the stirring shaft rotates, the stirring shaft and the reaction bag have relative motion. Therefore, in the connection mode between the flexible shaft 3 and the bag body 2, at least one end adopts a component with a sliding sealing function. The stator part of the component is connected to the bag body 2. Preferably, a stator made of plastic material can be selected and directly welded to the bag body 2. The mover part is connected to the flexible sleeve and can be tightened with a cable tie. There is a seal between the mover and the stator that can realize a dynamic sealing function.

[0034] Preferably, the structure of the sliding seal assembly can adopt the mature shaft seal 7 structure on the market. Figure 3 The outer shell is made of plastic that can be welded with the bag body 2, so as to be convenient for connection with the bag body 2.

[0035] The sliding seal components can be respectively installed at both ends of the flexible shaft 3 and connected to the bag body 2. When in use, the rigid shaft 1 passes through the two sliding seal components and the inside of the flexible shaft 3 to achieve transmission.

[0036] It is also possible to set a sliding seal assembly only at one end of the flexible shaft 3, and the other end is blocked and connected to a bearing fixed on the bag body 2. At this time, when the stirring shaft is working, both ends are still fixed ends, and it is not easy for the stirring shaft to shake.

[0037] The flexible shaft 3 needs to be inserted into the rigid shaft 1 when in use, and at least one end of the rigid shaft 1 is connected to a driving device on the reactor, such as a motor, as a power input mechanism for the stirring system.

[0038] The rigid shaft 1 may be provided with a mechanism coupled with the stirring blade 4, so that the rigid shaft 1 can drive the flexible shaft 3 to rotate together, while limiting the axial displacement of the blade 4 during the stirring process.

[0039] Preferably, a pin may be provided on the rigid shaft 1 , and a limiting groove may be provided in the blade 4 .

[0040] The flexible shaft 3 isolates the rigid shaft 1 from the internal space of the reaction bag, preventing the rigid shaft 1 from bringing pollutants into the reaction bag. Therefore, the rigid shaft 1 can be reused, and a non-plastic material with better rigidity can be used.

[0041] Since the rigid shaft 1 can be made of non-plastic material and can be directly mechanically coupled to the drive motor, the entire stirring system can transmit a greater torque after the rigid shaft 1 is inserted. This makes it easier to use the disposable bioreactor bag using the stirring system of the present invention in a more complex culture process, such as microbial culture with higher speed requirements and perfusion culture that requires long-term use.

[0042] In order to facilitate the insertion of the rigid shaft 1, the rigid shaft 1 itself can be designed as a multi-stage telescopic structure in the axial direction. There are many public schemes for this structure. In a preferred scheme, the rigid shaft 1 can be designed as a two-stage sleeve, with a slide groove processed on the outer sleeve and a pin installed at one end of the inner shaft. The pin can move up and down in the slide groove, so that the shaft has a telescopic function, but will not produce relative rotation.

[0043] The advantage of the present invention is that the stirring system in the reaction bag is flexible, and the rigid shaft 1 is inserted only when in use. Therefore, after the reaction bag is manufactured, it can be evacuated and folded. There is no risk of the stirring paddle breaking during transportation of the reaction bag. At the same time, the packaging volume is greatly reduced, which can reduce transportation and storage costs.

[0044] In addition, due to the significant reduction in packaging volume, the irradiation cost can be greatly reduced. At the same time, the size of the irradiation box is no longer a restriction on the further increase of the volume of the reaction bag 2. The matching irradiation supplier is no longer a difficult point to consider when setting up the production line. At the same time, after vacuuming, the impact of irradiation on the disposable fiber optic electrode is reduced, and the protection required for the fiber optic electrode becomes easier.

[0045] Finally, since the rigid shaft 1 inserted during use can be made of a material with much higher strength than plastic, such as stainless steel, during the use of the reaction bag, a greater torque can be transmitted, the maximum stirring speed can be increased, and the stirring system can continue to work longer. This further expands the culture process applicable to the reaction bag.

[0046] The following is combined with Figure 1Specifically explained: This embodiment provides a flexible stirring system suitable for disposable bioreactor bags, which includes: a flexible shaft 3 and a rigid shaft 1; the flexible shaft 3 adopts a corrugated tube and is connected to two paddles 4 by cable ties. The top of the flexible shaft 3 is connected to the mover of the shaft seal 7, and the stator of the shaft seal 7 is made of plastic and welded to the reaction bag. The bottom of the flexible shaft 3 is sealed with a plug 5, and the plug 5 has a hexagonal groove that can be driven by the rigid shaft 1. A rigid plastic part 6 is welded to the bottom of the bag, and the bottom of the plastic part can be docked and fixed with the reactor. A ceramic bearing is inlaid inside the plastic part, and the bearing is connected to the plug 5 at the bottom of the flexible shaft 3, so that the flexible shaft 3 can rotate in the bag. The flexible stirring shaft composed of the flexible shaft 3 sleeve, paddles 4, bearings, rigid connectors, and shaft seal 7 is a closed system.

[0047] The rigid shaft 1 is composed of a shaft and a sleeve, a slide groove is designed on the sleeve, and a pin passing through the sleeve slide groove is fixed on the shaft. Therefore, the shaft and the sleeve have axial telescopic function without affecting the transmission of torque. The rigid shaft 1 is installed with a pin at the height corresponding to the blade 4, and there is a vertical groove inside the blade 4, so that the shaft can pass through the blade 4 when inserted. At the same time, a horizontal limit groove is processed inside the blade 4. When the pin on the rigid shaft 1 is stuck in the horizontal groove of the blade 4, the blade 4 can be limited. The upper end of the rigid shaft 1 is connected to the motor on the reactor to transmit power and drive the entire stirring system to stir.

[0048] When the disposable reaction bag uses this stirring system, after the reaction bag is produced, the stirring shaft integrated with the bag is flexible, so the bag can be vacuumed and folded. The packaging volume is greatly reduced. The reduction in packaging volume reduces transportation, storage, and irradiation costs. In particular, the irradiation cost can be greatly reduced, and it makes it easier to irradiate and sterilize large-volume disposable reaction bags.

[0049] At the same time, the reduction of air in the bag reduces the impact of irradiation on the disposable fiber optic electrode.

[0050] In addition, the flexible paddle does not require special protection during transportation and there is no risk of a broken shaft.

[0051] After the bag arrives at the site of use, the rigid shaft 1 is inserted and connected to the drive device on the reactor. Since the rigid shaft 1 has a large transmission torque, the maximum speed can be increased and the single service life can be extended. The reaction bags using this system can be used in more severe process environments.

[0052] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A flexible stirring system suitable for disposable bioreactor bags, characterized in that: include: A flexible shaft and a rigid shaft; the flexible shaft is an axially hollow flexible sleeve, a paddle is installed on the flexible shaft, the flexible shaft passes through the reaction bag, both ends of the flexible shaft are connected to the reaction bag respectively, and the flexible shaft can rotate inside the reaction bag; The rigid shaft is inserted into the flexible shaft, and the rigid shaft is used to input stirring power and is separated from the interior of the reaction bag by the flexible shaft. When the rigid shaft rotates, it drives the flexible shaft and the blades to rotate synchronously.

2. The flexible stirring system for disposable bioreactor bags according to claim 1, characterized in that: The rigid shaft is connected to a driving device to provide the power required for stirring and mixing.

3. The flexible stirring system for disposable bioreactor bags according to claim 1, characterized in that: The rigid shaft has an axial telescopic function.

4. The flexible stirring system for disposable bioreactor bags according to claim 1, characterized in that: A coupling structure is provided between the rigid shaft and the blade fixed on the flexible sleeve, so that the blade, the rigid shaft and the flexible shaft rotate synchronously.

5. The flexible stirring system for disposable bioreactor bags according to claim 1, characterized in that: At least one sliding seal is installed between the flexible shaft and the reaction bag; The stator portion of the sliding seal is fixedly connected to the reaction bag; The movable part of the sliding seal is fixedly connected to the flexible shaft; The rigid shaft can be installed in the sliding seal and the flexible shaft, and drive the flexible shaft to rotate.

6. The flexible stirring system for disposable bioreactor bags according to claim 5, characterized in that: Both ends of the flexible shaft are connected to the reaction bag through sliding seals.

7. The flexible stirring system for disposable bioreactor bags according to claim 5, characterized in that: One end of the flexible shaft is connected to the reaction bag via a sliding seal, and the other end of the flexible shaft is sealed and connected to a bearing inside the bag body.

8. The flexible stirring system for disposable bioreactor bags according to claim 5, characterized in that: The material of the flexible shaft is a flexible material with biological safety.

9. The flexible stirring system for disposable bioreactor bags according to claim 5, characterized in that: The flexible shaft and the blades are connected by a cable tie or by welding.

10. A method for using a flexible stirring system suitable for a disposable bioreactor bag according to any one of claims 1 to 9, characterized in that: include: After the reaction bag leaves the factory, the reaction bag and the flexible shaft integrated with it are packaged, transported, and irradiated in a vacuum and foldable manner; After the reaction bag arrives at the use site, one end of the rigid shaft is inserted into the flexible shaft of the reaction bag, and the other end is connected to the driving device on the reactor. When the rigid shaft rotates, it drives the flexible shaft and the blades to rotate synchronously.

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