Flexible stirring system suitable for disposable biological reaction bag

Abstract

The utility model relates to the technical field of cell bioreactors, in particular to a flexible stirring system suitable for a disposable biological reaction bag, which comprises a flexible shaft and a rigid shaft, 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 utility model relates to cell biological reactor technical field, especially a flexible stirring system suitable for disposable biological reaction bag. BACKGROUND

[0002] Thanks to the development of biotechnology, people can use the cells of engineering modification to commercialize production such as antibody, vaccine and other drugs. In the production process, biological reactors are needed to culture cells, and the cells are cultured to a larger volume through step-by-step amplification.

[0003] The stainless steel stirring type biological reactor is the most widely used in the traditional biological reactor for large-scale production, and the amplification process is relatively mature. It is usually a stainless steel tank with a special designed diameter-height ratio, which is equipped with a vertical stirring paddle inside. The form of the paddle can be specially designed according to the type of cells. At the same time, the tank is equipped with various sensors such as pH sensor, temperature sensor, oxygen concentration sensor, etc., which cooperate with the control system to automatically adjust the process parameters in the culture process. In order to avoid the contamination of cells in the culture process, the traditional stainless steel biological reactor is often equipped with online cleaning and online sterilization system. This leads to the complexity of the overall validation of the production line and the sterilization before batch culture.

[0004] In recent years, a disposable biological reactor has emerged, which uses a reusable stainless steel tank and a disposable culture bag sterilized by pre-irradiation, and can start culture without online cleaning and online sterilization. This makes the production line validation simple and the production line configuration flexible.

[0005] The disposable biological reactor currently used on the market includes down-stirring type, straight-shaft stirring type and shaking bed type. The overall structure of the straight-shaft stirring type reactor is most similar to that of the traditional stainless steel reactor, which makes the development and transfer of cell culture process more simple and has been widely used. The current straight-shaft stirring type disposable biological reaction bag on the market is driven by a rigid plastic stirring shaft penetrating the bag body by magnetic coupling of a motor to realize liquid mixing. The stirring system has the following practical problems in use:

[0006] 1. The stirring shaft is made of rigid plastic, and the mechanical strength of plastic is low, which may be broken during transportation. Special designed packaging must be used to reduce the risk. At the same time, due to the rigidity of the stirring shaft, the packaging volume is large, and the transportation and storage cost is high.

[0007] 2. Because disposable reaction bags are pre-sterilized by irradiation, the large packaging volume significantly increases irradiation costs. Furthermore, due to size limitations of irradiation chambers, it will be difficult to find compatible irradiation providers for large-volume reaction bags. This will restrict the establishment of production lines and capacity expansion for reaction bags, and will also make it extremely difficult to further increase the culture volume of this type of reaction bag.

[0008] 3. Currently, the stirring shaft is connected to the drive unit via magnetic coupling. However, the plastic stirring shaft has low mechanical strength, preventing the stirring system from transmitting high torque. This limits the upper limit of the reaction bag's stirring speed. Consequently, the reaction bag is unsuitable for high-speed processes, such as bacterial culture.

[0009] 4. With the development of biotechnology, techniques such as perfusion culture and continuous flow culture are becoming increasingly mature. This will increase the demand for longer-lasting reaction bags. This will pose a greater challenge to the long-term use of plastic agitator shafts.

[0010] 5. Disposable reaction bags often use disposable fiber optic electrodes. These electrodes need to be kept away from air during irradiation sterilization. When using a rigid plastic stirring shaft, it is difficult to create a vacuum in the bag, thus requiring a special device to protect the fiber optic electrodes, which increases costs.

[0011] The information disclosed in this background section is intended only to enhance the understanding of the general background of this utility model and should not be construed as an admission or in any way implying that the information constitutes prior art known to those skilled in the art. Utility Model Content

[0012] The purpose of this invention is to provide a flexible stirring system suitable for disposable bioreactor bags, so as to solve the technical problems existing in the prior art.

[0013] To achieve the above objectives, the present invention adopts the following technical solution:

[0014] This invention provides a flexible stirring system suitable for disposable biological reaction bags, comprising: a flexible shaft and a rigid shaft; the flexible shaft is an axially hollow flexible sleeve, on which blades are mounted, the flexible shaft passes through the reaction bag, and 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, 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 blades to rotate synchronously.

[0015] Preferably, the rigid shaft is connected to a drive device to provide the power required for stirring and mixing.

[0016] Preferably, the rigid shaft has axial telescopic function.

[0017] Preferably, a coupling structure is arranged between the rigid shaft and the paddle fixed on the flexible sleeve, so that the paddle rotates synchronously with the rigid shaft and the flexible shaft.

[0018] Preferably, at least one sliding seal is arranged between the flexible shaft and the reaction bag.

[0019] The stator part of the sliding seal is fixedly connected with the reaction bag.

[0020] The rotor part of the sliding seal is fixedly connected with the flexible shaft.

[0021] The rigid shaft can be sleeved in the sliding seal and the flexible shaft, and drives the flexible shaft to rotate.

[0022] Preferably, both ends of the flexible shaft are connected with the reaction bag through the sliding seal.

[0023] Preferably, one end of the flexible shaft is connected with the reaction bag through the sliding seal, and the other end of the flexible shaft is sealed and connected with a bearing inside the bag body.

[0024] Preferably, the material of the flexible shaft is a flexible material with biosafety.

[0025] Preferably, the material of the flexible shaft is a silica gel tube or a flexible bellows.

[0026] Preferably, the flexible shaft and the paddle are connected by a cable tie or welding.

[0027] The utility model also provides a kind of using method of flexible stirring system suitable for disposable biological reaction bag, it includes: after reaction bag factory, reaction bag and the flexible shaft integrated with it are packaged using vacuum extraction and foldable mode, transport, irradiation (the packaging, transport, irradiation process of reaction bag after factory of using this system, paddle shaft can be perpendicular to flexible shaft, when using, after being inserted rigid shaft, make paddle and flexible shaft coaxial);Reaction bag reaches use site after, one end of rigid shaft is inserted into the flexible shaft of reaction bag, the other end is connected on the driving device of reactor, rigid shaft drives the flexible shaft and paddle synchronous rotation when rotating.

[0028] Using the above technical scheme, the utility model has the following beneficial effects:

[0029] The utility model adopts flexible stirring system design, and can effectively solve the above problems, increase the reliability of equipment operation, while greatly reducing each cost in the use process of reaction bag, including packaging, transport, irradiation, storage and the like. BRIEF DESCRIPTION OF DRAWINGS

[0030] In order to more clearly illustrate the specific embodiments of the present application or the technical solutions in the prior art, the following will briefly introduce the drawings needed to be used in the specific embodiments or the prior art description. Obviously, the drawings described in the following description are some embodiments of the present application, and other drawings can also be obtained by those skilled in the art without creative labor.

[0031] Figure 1 The schematic diagram of the flexible stirring system suitable for the disposable biological reaction bag provided by the embodiment of the present application is shown in the figure.

[0032] Figure 2 The schematic diagram of the flexible shaft bottom blocked and connected with the bearing provided by the embodiment of the present application is shown in the figure.

[0033] Figure 3 The schematic diagram of the shaft seal provided by the embodiment of the present application is shown in the figure.

[0034] Figure 4 The structural schematic diagram of the telescopic shaft provided by the embodiment of the present application is shown in the figure.

[0035] Figure 5 The schematic diagram of the limiting groove in the paddle provided by the embodiment of the present application is shown in the figure.

[0036] Figure legend: 1-rigid shaft; 2-bag body; 3-flexible shaft; 4-paddle; 5-plug; 6-rigid plastic part; 7-shaft seal. Specific embodiments

[0037] The technical solutions of the present application will be described in detail below with reference to the drawings. Obviously, the described embodiments are some embodiments of the present application, not all embodiments. Based on the embodiments of the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0038] The specific embodiments of the present application will be described in detail below with reference to the drawings. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present application, and are not used to limit the present application.

[0039] In combination with Figures 1 to 5As shown, the embodiment provides a flexible stirring system suitable for disposable bioreactor bags, which comprises: a flexible shaft 3 and a rigid shaft 1; the flexible shaft 3 is an axially hollow flexible sleeve, the flexible shaft 3 is provided with a paddle 4, the flexible shaft 3 penetrates the bioreactor bag, the two ends of the flexible shaft 3 are connected with the bioreactor bag respectively, and the flexible shaft 3 can rotate in the interior of the bioreactor bag; the rigid shaft 1 is inserted into the flexible shaft 3, the rigid shaft 1 is used for inputting stirring power and is separated from the interior of the bioreactor bag through the flexible shaft 3, and when the rigid shaft 1 rotates, the flexible shaft 3 and the paddle 4 rotate synchronously.

[0040] In the embodiment, the flexible shaft 3 is composed of the paddle 4 and the flexible sleeve, can be bent and folded, and the form and number of the paddle 4 can be selected according to the culture process.

[0041] Preferably, the flexible sleeve can adopt a mature flexible pipe on the market, such as a silica gel pipe. Meanwhile, a flexible corrugated pipe can also be adopted, which is convenient for further compressing the packaging volume before use of the bioreactor bag.

[0042] Preferably, the connection between the flexible sleeve and the paddle 4 can adopt a plurality of straps to tighten, which guarantees the connection strength and also guarantees the sealing performance.

[0043] The two ends of the flexible shaft 3 are connected with the bioreactor bag, in use, the rigid shaft 1 is inserted into or penetrates through the flexible shaft 3. The two-end connection mode can reduce the shaking of the stirring paddle in the stirring process, is conducive to maintaining the stability of the flow field, strengthens the stability of the cell culture process, and reduces the difficulty of amplification of the culture process.

[0044] Since the stirring shaft rotates, the stirring shaft has relative motion with the bioreactor bag. Therefore, in the connection mode of 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 with the bag body 2, and preferably, a stator made of plastic can be selected and is directly welded with the bag body 2. The rotor part is connected with the flexible sleeve and can be tightened by a strap. There is a sealing element between the rotor and the stator, which can realize dynamic sealing function.

[0045] Preferably, the structure of the sliding sealing component can adopt a mature shaft seal 7 structure on the market. As shown in the accompanying drawings. Figure 3 The outer shell is made of plastic and can be welded with the bag body 2, which is convenient for connection with the bag body 2.

[0046] The sliding sealing components can be respectively installed at the two ends of the flexible shaft 3 and connected with the bag body 2. In use, the rigid shaft 1 penetrates through the two sliding sealing components and the interior of the flexible shaft 3, to realize transmission.

[0047] The flexible shaft 3 can be provided with a sliding sealing assembly only at one end, and the other end is blocked and connected with a bearing fixed on the bag body 2. When the stirring shaft works, both ends are still fixed ends, and the stirring shaft is not easy to shake.

[0048] 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 with a driving device such as a motor on the reactor, serving as a power input mechanism of the stirring system.

[0049] The rigid shaft 1 can be provided with a mechanism coupled with the stirring paddle 4, so as to facilitate the rotation of the rigid shaft 1 together with the flexible shaft 3, and limit the axial displacement of the paddle 4 in the stirring process.

[0050] Preferably, a pin can be arranged on the rigid shaft 1, and a limiting groove is arranged in the inner space of the paddle 4.

[0051] The flexible shaft 3 separates the rigid shaft 1 from the internal space of the reactor bag, preventing the rigid shaft 1 from bringing pollutants into the reactor bag. Therefore, the rigid shaft 1 can be reused, and a non-plastic material with better rigidity can be used.

[0052] Since the rigid shaft 1 can be made of a non-plastic material and can be directly mechanically coupled with a driving motor, when the rigid shaft 1 is inserted, the entire stirring system can transmit a larger torque. This makes the disposable bioreactor bag using the stirring system of the utility model more easily used for more complex culture processes. For example, microbial culture with higher speed process requirements, and perfusion culture that needs to be used for a long time.

[0053] 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. This structure has many disclosed schemes, and in one preferred scheme, the rigid shaft 1 can be designed as a two-stage shaft sleeve. The outer shaft sleeve is processed with a sliding groove, and the inner shaft is provided with a pin at one end. The pin can move up and down in the sliding groove, so that the shaft has a telescopic function, but will not rotate relatively.

[0054] The advantage of the utility model is that the stirring system in the reactor bag is flexible, and the rigid shaft 1 is inserted only when in use. Therefore, after the completion of the manufacture of the reactor bag, it can be vacuumized and folded. The reactor bag no longer has the risk of broken shaft of the stirring paddle during transportation. At the same time, the packaging volume is greatly reduced, which can reduce the transportation and storage costs.

[0055] In addition, due to the great 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 reactor bag 2. The matching irradiation supplier is no longer a difficulty to be considered in the production line construction. At the same time, after vacuumization, the influence of irradiation on the disposable optical fiber electrode is reduced, and the protection required for the optical fiber electrode becomes easy.

[0056] Finally, because the rigid shaft 1 inserted during use can be made of a material with a much higher strength than plastic, such as stainless steel. Therefore, the reaction bag can transmit a greater torque during use, increasing the maximum stirring speed, and the stirring system can also work for a longer duration. This further expands the applicable culture process of the reaction bag.

[0057] The following will be described in detail in conjunction with the accompanying drawings Figure 1 Specifically, the embodiment provides a flexible stirring system suitable for a disposable bioreactor bag, which includes a flexible shaft 3 and a rigid shaft 1. The flexible shaft 3 is made of a bellows and is connected to two paddles 4 by a strap. The top of the flexible shaft 3 is connected to the rotor of a shaft seal 7, and the stator of the shaft seal 7 is made of plastic and is welded to the reaction bag. The bottom of the flexible shaft 3 is sealed by a plug 5, and the plug 5 has a hexagonal recess inside, which 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 connected to and fixed to the reactor. The inside of the plastic part is inlaid with a ceramic bearing, which is connected to the plug 5 at the bottom of the flexible shaft 3, so that the flexible shaft 3 can rotate inside the bag. The flexible shaft 3, the paddles 4, the bearing, the rigid connecting part, and the shaft seal 7 together form a closed system.

[0058] The rigid shaft 1 is composed of a shaft and a sleeve, and the sleeve is designed with a sliding groove, and the shaft is fixed with a pin that passes through the sliding groove of the sleeve. Therefore, the shaft and the sleeve have an axial extension function without affecting the transmission of the rotation torque. The rigid shaft 1 is installed with a pin at the corresponding height position of the paddle 4, and the inside of the paddle 4 has a vertical slot, so that the shaft can pass through the paddle 4 when inserted. At the same time, the paddle 4 is processed with a horizontal limiting groove, and when the pin on the rigid shaft 1 is clamped into the horizontal groove of the paddle 4, the paddle 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.

[0059] When the disposable reaction bag uses this stirring system, after the production of the reaction bag is completed, the stirring shaft integrated with the bag is flexible, and the bag can be vacuumed and folded. The packaging volume is greatly reduced. The reduction of the packaging volume reduces the transportation, storage, and irradiation costs. In particular, the irradiation cost can be greatly reduced, and the large-volume disposable reaction bag is more easily sterilized by irradiation.

[0060] At the same time, the reduction of the air in the bag reduces the impact of irradiation on the disposable optical fiber electrode.

[0061] In addition, the flexible paddle does not need special protection during transportation and has no risk of shaft breakage.

[0062] After the bag reaches the use site, the rigid shaft 1 is inserted and connected with the driving device on the reactor. Since the rigid shaft 1 has large transmission torque, the maximum rotating speed can be improved, the single-use life is prolonged, and the reaction bag using the system can be applied to a more severe process environment.

[0063] Finally, it should be noted that: the above embodiments are only used to illustrate the technical solutions of the present application, but not limited to them; although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that: it can still modify the technical solutions recorded in the foregoing embodiments, or make equivalent replacement for part or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A flexible agitation system suitable for use with a single-use bioreactor bag, comprising: The utility model relates to a flexible shaft and a rigid shaft; the flexible shaft is an axially hollow flexible sleeve, a paddle is mounted on the flexible shaft, the flexible shaft penetrates a reaction bag, two ends of the flexible shaft are connected with the reaction bag respectively, and the flexible shaft can rotate in the interior of 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, the rigid shaft drives the flexible shaft and the paddle to rotate synchronously when rotating. The rigid shaft is connected with a driving device to provide the power required for stirring and mixing. The rigid shaft has an axial telescopic function. A coupling structure is arranged between the rigid shaft and the paddle fixed on the flexible sleeve to make the paddle rotate synchronously with the rigid shaft and the flexible shaft.

2. The flexible mixing system suitable for use with a single-use bioreactor bag of claim 1, wherein, At least one sliding seal is mounted between the flexible shaft and the reaction bag.

3. The flexible mixing system suitable for use with a single-use bioreactor bag of claim 1, wherein, A stator part of the sliding seal is fixedly connected with the reaction bag.

4. The flexible mixing system suitable for use with single-use bioreactor bags of claim 1, wherein, A rotor part of the sliding seal is fixedly connected with the flexible shaft.

5. The flexible mixing system suitable for use with a single-use bioreactor bag of claim 1, wherein, The rigid shaft can be inserted into the sliding seal and the flexible shaft and drive the flexible shaft to rotate. Both ends of the flexible shaft are connected with the reaction bag through the sliding seal. One end of the flexible shaft is connected with the reaction bag through the sliding seal, and the other end of the flexible shaft is sealed and connected with a bearing in the interior of the bag body. The flexible shaft is made of a flexible material with biosafety.

6. The flexible mixing system suitable for use with a single-use bioreactor bag of claim 5, wherein, The flexible shaft and the paddle are connected by a cable tie or welding.

7. The flexible mixing system suitable for use with a single-use bioreactor bag of claim 5, wherein, ​ 8. The flexible mixing system suitable for use with a single-use bioreactor bag of claim 5, wherein, ​ 9. The flexible mixing system suitable for use with a single-use bioreactor bag of claim 5, wherein, ​

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