MRNA (messenger ribonucleic acid) production device and quality control method

Abstract

The invention belongs to the technical field of mRNA production and manufacturing, and discloses an mRNA production device and a quality control method. The mRNA production device provided by the invention comprises a production tank, a reaction bag which is structured to form a detection vessel, a containing assembly with an indirect transmission function, a stirring assembly, a detection assembly for detecting IVT reaction liquid and an automatic sample injector. According to the method, the reaction conditions are accurately controlled, the good uniformity of the reaction solution is kept, the adopted real-time monitoring method and the adopted solution homogenization mode have extremely small damage to the mRNA structure, the problems existing in large-scale industrial production of mRNA in the prior art are effectively solved, and the method has good application prospects.

Description

Technical Field

[0001] The present invention belongs to the technical field of mRNA production and manufacturing, and in particular relates to an mRNA production device and a quality control method. Background Art

[0002] mRNA drugs and / or vaccines refer to a class of substances that deliver mRNA encoding one or more proteins into cells, directly react in the cytoplasm to produce corresponding proteins, change the body's metabolism or induce the body to produce a specific immune response. mRNA drugs and / or vaccines are highly favored due to their high safety, short R&D cycle and low-cost production.

[0003] At present, mRNA with complete structure and correct sequence can be successfully prepared under laboratory conditions, but only trace amounts of mRNA can be obtained under laboratory conditions. However, in the industrial-scale production of mRNA, as the reaction system expands, factors such as pH value, enzyme activity, substrate concentration, product concentration, temperature, and uniformity of the reaction solution have a particularly significant impact on the efficiency and quality of mRNA synthesis; at the same time, the methods used in the prior art to maintain the uniformity of the reaction solution will increase the shear force inside the solution when the reaction system is expanded, thereby causing more significant damage to the mRNA structure; this severely limits the realization of industrial large-scale production of mRNA and has great limitations. Summary of the invention

[0004] The first purpose of the present invention is to provide an mRNA production device, which monitors the reaction process in real time, accurately controls the reaction conditions and maintains good uniformity of the reaction solution. The real-time monitoring method and solution homogenization method used cause minimal damage to the mRNA structure, effectively solving the problems existing in the prior art in achieving industrial large-scale production of mRNA, and has good application prospects.

[0005] The second object of the present invention is to provide a method for quality control of mRNA production.

[0006] Specifically, the mRNA production device provided by the present invention includes: a production tank, wherein a heat transfer liquid is arranged in the production tank; a reaction bag, wherein the reaction bag includes a flexible bag body and a transparent hard part, wherein the transparent hard part is structured to form a detection dish, wherein the detection dish is connected to the flexible bag body to receive the reaction liquid; a containing component, wherein the containing component includes an elastic connecting piece and a placing plate, wherein the elastic connecting piece is connected to the peripheral wall of the production tank, wherein the placing plate is connected to the elastic connecting piece to be suspended in the production tank, and wherein the reaction bag is arranged on the placing plate; and a stirring component, wherein the stirring component drives the heat transfer liquid to flow to drive The storage plate shakes, and the stirring component maintains a non-contact state with the reaction bag and the storage plate; a detection component, the detection component includes an optical detector, a pH detector and a temperature detector; the pH detector and the temperature detector are arranged on the reaction bag; the optical detector includes a transmitter and a receiver, the transmitter and the receiver are relatively arranged on both sides of the detection dish, and the detection light emitted by the transmitter passes through the detection dish to be received by the receiver; an automatic sampler, the automatic sampler is connected to the reaction bag, and the detection component and the automatic sampler signal are connected to control the injection of IVT raw materials.

[0007] Furthermore, the transparent hard portion is structured to form a detection dish protruding from the reaction bag, the transmitter and the receiver are spaced apart on the storage plate to form a snap-in groove, and the detection dish is snap-into the snap-in groove.

[0008] Furthermore, the transparent hard portion is structured to form a plurality of receiving grooves recessed in the reaction bag, a detection dish is formed between two adjacent receiving grooves, and the transmitter and the receiver are respectively snapped into the two adjacent receiving grooves.

[0009] Furthermore, the volume of the reaction bag is 50 to 5000 mL; the volume of the detection dish is 0.1 to 5 mL, and the optical path of the detection dish is 0.001 to 10 mm.

[0010] Furthermore, the reaction bag further includes a fixed hard portion arranged on the outer peripheral side, and the fixed hard portion and the storage plate are connected by bolts to place the reaction bag on the storage plate.

[0011] Furthermore, one end of the elastic connector is connected to the top wall of the production tank, and the storage plate is connected to an end of the elastic connector away from the top wall of the production tank, so that the elastic connector is in a stretched state.

[0012] Furthermore, the storage plate is arranged at an angle.

[0013] Furthermore, the storage plate is configured as a grid structure.

[0014] Furthermore, the stirring assembly is a magnetic stirring assembly and / or a mechanical stirring assembly.

[0015] Furthermore, the magnetic stirring assembly includes a magnetic stirring table and a magnetic rotor, the production tank is arranged on the magnetic stirring table, the magnetic rotor is arranged in the production tank to drive the flow of the thermal transfer fluid, and the magnetic rotor maintains a non-contact state with the reaction bag, the storage plate and the detection assembly.

[0016] Furthermore, the mechanical stirring assembly includes a stirring rod and a stirring motor, the stirring motor drives the stirring rod to rotate, the stirring rod is inserted in the production tank to drive the flow of thermal transfer fluid, and the stirring rod and the mechanical stirring assembly include a stirring rod and a stirring motor, the stirring motor drives the stirring rod to rotate, the stirring rod is inserted in the production tank to drive the flow of thermal transfer fluid, and the stirring rod maintains a non-contact state with the flexible reaction bag and the storage plate.

[0017] Furthermore, the optical detector includes one or more of a Fourier transform infrared spectrometer, an in-situ Raman spectrometer and a particle image analyzer.

[0018] Furthermore, a temperature controller is also provided in the production tank.

[0019] In the quality control method for mRNA production provided by the present invention, the mRNA production is carried out in the above-mentioned mRNA production device, and the quality control method includes: taking the detection component to detect the IVT reaction liquid in the reaction bag, obtaining IVT reaction parameters, and adjusting the IVT reaction conditions based on the IVT reaction parameters; wherein the IVT reaction parameters include one or more of raw material concentration, solution aging state, phosphate concentration, mRNA generation amount, pH value and temperature.

[0020] Furthermore, the method for adjusting the IVT reaction conditions based on the IVT reaction parameters includes: regulating the pH value of the IVT reaction system to be maintained at 7 to 8, regulating the deviation value of the real-time temperature in the IVT reaction from the preset reaction temperature to be 0 to 0.5°C; when the dNTP concentration in the IVT reaction system is reduced to 10 to 30% of the initial concentration, adding dNTP and Mg 2+ , cap analogs, and inorganic pyrophosphatase to 75% to 100% of the initial concentration; when the IVT reaction system ages, adjust the Mg 2+ When the mRNA production amount reaches 10-20 mg / mL, the IVT reaction is stopped.

[0021] Beneficial effects:

[0022] The mRNA production device provided by the present invention mainly includes two parts. The first part is a containing component and a stirring component for maintaining the uniformity of the solution during the IVT reaction. The stirring component is used to disturb the heat transfer fluid in the production tank to flow, and the internal shear force generated by the flow of the heat transfer fluid acts on the placement plate to cause it to shake. Under the action of the shaking of the placement plate, the elastic connecting member generates a reaction force to act on the placement plate to optimize and adjust the movement state of the placement plate. The shaking of the placement plate drives the reaction bag arranged thereon to shake, and the transmission effect of the heat transfer fluid and the containing component is used to homogenize the solution in the reaction bag, and the flow mode of the solution in the reaction bag will not generate too much internal shear force, thereby effectively reducing the damage to the mRNA structure during the solution homogenization process; the second part In order to realize the detection component and automatic sample injector for real-time monitoring of the reaction process and precise control of the reaction conditions, a detection dish is structured on the reaction bag to serve as a container for optical detection. The solution in the detection dish is updated in real time under the action of the containing component and the stirring component and has little impact on the optical detection. Then, the solution in the detection dish is detected by using an optical detector, a pH detector and a temperature detector to obtain real-time information such as raw material concentration, solution aging state, phosphate concentration, mRNA generation, pH value and temperature. Based on the real-time information obtained, the automatic sample injector is fed back to adjust the raw material concentration, pH value, temperature and other conditions to precisely control the reaction conditions and achieve good mRNA preparation effect in the case of an amplified IVT reaction system. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is a schematic diagram of the structure of the mRNA production device provided in the first embodiment of the present invention;

[0024] Figure 2 for Figure 1 AA section view;

[0025] Figure 3 This is a schematic diagram of the structure of a reaction bag in the first embodiment of the present invention;

[0026] Figure 4 This is a schematic diagram of the structure of a reaction bag of an mRNA production device according to a second embodiment of the present invention;

[0027] Figure 5 This is a schematic diagram of the structure of a reaction bag of an mRNA production device according to a third embodiment of the present invention;

[0028] Figure 6 This is a schematic diagram of the structure of a reaction bag of an mRNA production device according to a fourth embodiment of the present invention;

[0029] Figure 7 A schematic diagram of the installation structure of the reaction bag and the containing assembly provided in the first embodiment of the present invention;

[0030] Figure 8 An exploded schematic diagram of the installation structure of the reaction bag and the accommodating assembly provided in the first embodiment of the present invention;

[0031] Fig. 9 for Figure 2 Schematic diagram of the enlarged structure of local part B in the middle.

[0032] Figure numerals: 1. production tank; 2. reaction bag; 21. transparent hard part; 22. fixed hard part; 23. flexible bag body; 3. containing assembly; 31. spring; 32. storage plate; 4. mechanical stirring assembly; 41. stirring rod; 42. stirring motor; 5. detection assembly; 51. optical detector; 52. pH detector; 53. temperature detector; 6. automatic sampler; 7. detection dish; 8. containing tank; 9. transmitter; 10. receiver. DETAILED DESCRIPTION

[0033] Although the present invention can be easily embodied in different forms of embodiments, only some of the specific embodiments are shown in the drawings and will be described in detail in this specification. It should be understood that this description should be regarded as an exemplary illustration of the principles of the invention and is not intended to limit the invention to that described herein.

[0034] Thus, a feature indicated in this specification will be used to illustrate one of the features of an embodiment of the present invention, rather than implying that each embodiment of the present invention must have the described feature. In addition, it should be noted that this specification describes many features. Although some features can be combined together to illustrate possible system designs, these features can also be used in other combinations that are not explicitly described. Thus, unless otherwise stated, the described combinations are not intended to be limiting.

[0035] In the embodiments shown in the drawings, the indications of directions (such as up, down, left, right, front and back) used to explain the structure and movement of various elements of the present invention are not absolute but relative. These descriptions are appropriate when these elements are in the positions shown in the drawings. If the description of the positions of these elements changes, the indications of these directions also change accordingly.

[0036] The technical scheme in the embodiments of the present invention will be described clearly and completely below in conjunction with the accompanying drawings in the embodiments of the present invention. If no specific techniques or conditions are specified in the embodiments, the techniques or conditions described in the literature in the art or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0037] See also Figure 1 and Figure 2 . Figure 1It is a schematic diagram of the structure of the mRNA production device of the first embodiment of the present invention. Figure 2 yes Figure 1 The mRNA production device provided in the first embodiment includes: a production tank 1, a reaction bag 2, a containing component 3, a mechanical stirring component 4, a detection component 5 and an automatic sampler 6.

[0038] See also Figure 3 . Figure 3 It is a schematic diagram of the structure of the reaction bag 2 in the first embodiment. Specifically, the reaction bag 2 includes a transparent hard part 21, a fixed hard part 22 and a flexible bag body 23. The transparent hard part 21 is structured to form a detection dish 7 protruding from the reaction bag 2, and the detection dish 7 is connected to the inside of the reaction bag 2 to receive the IVT reaction liquid, and the volume of the detection dish is 3mL, the optical path is 3mm, and the volume of the reaction bag is 100mL. The fixed hard part 22 is protruding on the side of the flexible bag body 23 away from the transparent hard part (that is, the fixed hard part 22 is arranged on the peripheral side of the reaction bag 2), and the fixed hard part 22 is structured to form a first mounting hole to realize the installation of the reaction bag 2 on the accommodating component 3. A feed port is provided on the flexible bag body 23, and the feed port and the automatic sample injector 6 are connected through a pipeline.

[0039] In the present invention, the method of structuring the transparent hard part 21 to form the detection dish 7 can be but is not limited to the method provided in the first embodiment. Those skilled in the art can make adaptive choices according to actual needs, and the present invention does not impose any special restrictions on it. Figure 4 . Figure 4 1 is a schematic diagram of the structure of the reaction bag 2 of the mRNA production device of the second embodiment of the present invention. The mRNA production device of the second embodiment is basically the same as the first embodiment, except that in the reaction bag 2 of the second embodiment, the transparent hard portion 21 is structured to form a plurality of receiving grooves 8 recessed in the flexible bag body 23 for placing the detection component 5, and the detection dish 7 is enclosed between two adjacent receiving grooves 8.

[0040] In the present invention, the number of the test dishes formed by the structure of the transparent hard part 21 can be but not limited to the number shown in the first embodiment. Those skilled in the art can make adaptive choices according to actual needs, and the present invention does not impose any special restrictions on it. Figure 5 . Figure 5 Schematic diagram of the structure of the reaction bag of the mRNA production device of the third embodiment of the present invention. The mRNA production device of the third embodiment is basically the same as the first embodiment, except that in the reaction bag 2 of the third embodiment, the transparent hard part 21 is structured to form a plurality of test dishes 7 protruding from the flexible bag body 23 and arranged at intervals, and an installation space is formed between two adjacent test dishes for placing the test component 5.

[0041] In the present invention, the position where the fixed hard portion 22 is disposed on the flexible bag body 23 may be, but is not limited to, the position shown in the first embodiment, and those skilled in the art may make an adaptive choice according to actual needs. Figure 6 . Figure 6 Schematic diagram of the structure of the reaction bag of the mRNA production device of the fourth embodiment of the present invention. The mRNA production device of the fourth embodiment is basically the same as the fourth embodiment, except that in the reaction bag 2 of the fourth embodiment, a fixed hard portion 22 is also provided on the side of the reaction bag 2 close to the transparent hard portion 21 to achieve a more stable installation of the reaction bag 2 on the accommodating component 3.

[0042] In the present invention, the volume of the reaction bag 2, the volume of the detection dish 7 and the optical path length can be but are not limited to the sizes shown in the first embodiment. Those skilled in the art can make adaptive choices according to actual needs, and the present invention does not impose any special restrictions on them. In some specific embodiments, the volume of the reaction bag 2 is preferably 50 to 5000 mL, such as 50 mL, 80 mL, 100 mL, 250 mL, 500 mL, 1000 mL, 2500 mL, 5000 mL or any value therebetween; the volume of the detection dish 7 is preferably 0.1 to 5 mL, such as 0.1 mL, 0.5 mL, 1 mL, 3 mL, 5 mL or any value therebetween; the optical path length of the detection dish 7 is preferably 0.001 to 10 mm, such as 0.001 mm, 0.005 mm, 0.01 mm, 0.5 mm, 1 mm, 5 mm, 8 mm, 10 mm or any value therebetween.

[0043] See also Figure 2 , Figure 7 and Figure 8 . Figure 7 It is a schematic diagram of the installation structure of the reaction bag 2 and the accommodating assembly 3 in the first embodiment. Figure 8 It is an exploded schematic diagram of the installation structure of the reaction bag 2 and the accommodating assembly 3 in the first embodiment. Specifically, the accommodating assembly 3 includes a spring 31 and a storage plate 32. One end of the spring 31 is fixedly connected to the inner peripheral wall of the top of the production tank 1, and the spring 31 is arranged along the vertical direction. A fixing clamp is arranged at its lower end. The fixing clamp clamps the outer peripheral side of the storage plate 32 so that the storage plate 32 is arranged in the production tank 1 in a suspended and inclined state, and at this time, the spring 31 is in a stretched state under the action of the storage plate 32. A second mounting hole corresponding to the first mounting hole is opened on the storage plate 32. The side of the reaction bag 2 close to the fixed hard part 22 is fixed to the storage plate 32 through the first mounting hole, the second mounting hole and the bolts passing through the two, and the reaction bag 2 is further fixed to the storage plate 32 by a strap.

[0044] The production tank 1 is filled with water as a heat transfer liquid (not shown in the figure), the placement plate 32 and the reaction bag 2 are completely immersed in the heat transfer liquid, and the placement plate 32 is set to a grid structure to increase the contact area between the reaction bag 2 and the heat transfer liquid, thereby achieving a better heat transfer effect.

[0045] In the present invention, the spring 31 in the accommodating component 3 can also be replaced by an elastic connecting member such as a U-shaped spring sheet, a V-shaped spring sheet, a rubber strip, etc. that has the ability to generate elastic deformation. Technical personnel in this field can make adaptive choices according to actual needs, and the present invention does not impose any special limitations on it.

[0046] In the present invention, the heat transfer liquid contained in the production tank 1 can be but not limited to the water shown in the first embodiment, and can also be a liquid with excellent heat conductivity such as heat transfer oil. Those skilled in the art can make adaptive choices based on actual needs, and the present invention does not impose any special limitations on it.

[0047] See also Figure 2 The mechanical stirring assembly 4 includes a stirring rod 41 and a stirring motor 42. The stirring motor 42 is installed at the bottom of the production tank 1 and is transmission-connected to the stirring rod 41. One end of the stirring rod 41 away from the stirring motor 42 passes through the bottom of the production tank 1 and has a certain distance from the reaction bag 2 and the placement plate 32 so that the stirring rod 41 always maintains a non-contact state with the reaction bag 2 and the placement plate 32 in the working state.

[0048] In the present invention, the mechanical stirring component 4 in the mRNA production device can be replaced by other stirring components that can drive the flow of liquid, such as a magnetic stirring component. The magnetic stirring component specifically includes a magnetic stirring table and a magnetic rotor. The production tank is placed on the magnetic stirring table, and the magnetic rotor is placed in the production tank to drive the flow of the thermal transfer liquid. The magnetic rotor always maintains a non-contact state with the reaction bag and the storage plate in the working state.

[0049] See also Figure 8 and Fig. 9 . Fig. 9 for Figure 2The enlarged structural diagram of the local B part in the figure. The detection component 5 includes an optical detector 51, a pH detector 52 and a temperature detector 53. The optical detector 51 includes a transmitter 9 and a receiver 10. The transmitter 9 and the receiver 10 are fixedly installed on the storage plate 32 at intervals. When the reaction bag 2 is installed on the storage plate 32, the detection dish 7 is located in the gap between the transmitter 9 and the receiver 10, and the detection light emitted by the transmitter 9 is received by the receiver 10 through the detection dish 7. The pH detector 52 and the temperature detector 53 are installed in the reaction bag 2 to detect the temperature and pH value of the solution in the reaction bag 2 in real time. A temperature controller (not shown in the figure) for detecting and controlling the temperature of the heat transfer fluid is also installed in the production tank 1. The real-time data measured by the optical detector 51 and the pH detector 52 are transmitted to the automatic sampler 6 to control the sampling of the IVT raw material, and the temperature data measured by the temperature detector 53 are transmitted to the temperature controller to control the temperature of the solution in the reaction bag 2 by adjusting the temperature of the heat transfer fluid.

[0050] In the present invention, the optical detector 51 in the detection component 5 is a type of device that uses optical principles to detect solutions. Those skilled in the art can make adaptive choices based on actual needs. Specific examples include but are not limited to: one or more of: Fourier transform infrared spectrometer, in-situ Raman spectrometer and particle image analyzer.

[0051] In the first embodiment, the optical detector 51 is configured as a Fourier transform infrared spectrometer; based on the Fourier transform infrared spectrometer, the first embodiment also provides a quality control method for mRNA production.

[0052] In this method, a Fourier transform infrared spectrometer, a pH detector 52 and a temperature detector 53 are used to perform real-time detection of the solution in the reaction bag to obtain one or more IVT reaction parameters such as raw material concentration, solution aging state, phosphate concentration, mRNA production, pH value and temperature, and the IVT reaction conditions are adjusted based on the above IVT reaction parameters.

[0053] More specifically, based on the data measured by the optical detector 51, when the dNTP concentration of the solution in the reaction bag 2 is reduced to 10-30% of the initial concentration, dNTP and Mg are added to the reaction bag 2 through the automatic sampler 6. 2+ , cap analogs, inorganic pyrophosphatase to 75% to 100% of the initial concentration.

[0054] More specifically, it is determined whether the solution in the reaction bag 2 has undergone aging phenomena such as flocculation and / or precipitation. When the solution in the reaction bag 2 has undergone aging, Mg is added to the reaction bag 2 through the automatic sampler 6. 2+ To 75% to 100% of the initial concentration.

[0055] More specifically, based on the data measured by the pH detector 52, when the pH value of the solution in the reaction bag 2 deviates from the range of 7 to 8, Tris-HCl buffer or PBS buffer is added to the reaction bag 2 through the automatic sampler 6 to adjust the pH value of the solution in the reaction bag 2 to maintain at 7 to 8.

[0056] More specifically, based on the data measured by the temperature detector 53, when the temperature of the solution in the reaction bag 2 deviates from the preset temperature by more than 0.5°C, the temperature of the thermal fluid is changed by the temperature controller to adjust the temperature of the solution in the reaction bag 2 so that the deviation value of the real-time temperature of the solution in the reaction bag 2 compared to the preset reaction temperature is maintained at 0 to 0.5°C.

[0057] More specifically, based on the data measured by the optical detector 51, when the concentration of the solution mRNA in the reaction bag 2 is 10-20 mg / mL (ie, the mRNA production amount is 10-20 mg / mL), the reaction bag 2 is taken out from the production tank 1 to terminate the IVT reaction.

[0058] The mRNA production apparatus provided in the first to fourth embodiments is used to prepare mRNA, and the conditions in the preparation process are controlled by the quality control method provided in the first embodiment. The total volume of the reaction solution is 20 mL, and the reaction raw materials, the addition amount and the reaction conditions are specifically shown in Table 1.

[0059] Table 1.

[0060]

[0061] The DNA template includes a nucleotide fragment whose sequence is shown in SEQ ID NO: 1, as shown in Table 2.

[0062] Table 2.

[0063]

[0064] (1) Take 50 μL of the final IVT reaction solution and use an RNA purification kit (NEB, catalog number T2050L) according to the instructions to obtain the purified mRNA product.

[0065] (2) The quality of the purified mRNA product was detected using the RNA mode of the Nanodrop micro-spectrophotometer (in μg), and the mRNA yield (mg / mL) of mRNA prepared using the mRNA production device provided in each embodiment was calculated according to the following formula.

[0066] mRNA yield (mg / mL) = X*21 / 1000

[0067] Wherein, X is the total amount of mRNA obtained after 50 μL of IVT reaction solution sampling and purification.

[0068] (3) The purified mRNA products were detected by capillary electrophoresis (CE), and the integrity (%) of each purified mRNA product was calculated according to the following formula: The integrity (%) of the purified mRNA product provided in each embodiment was calculated according to the following formula.

[0069] mRNA integrity (%) = a / b*100%

[0070] Wherein, a is the area of ​​the target RNA in the mRNA purification product, i.e., the main peak, and b is the peak area of ​​all RNA in the mRNA purification product. The test results are shown in Table 3.

[0071] Table 3.

[0072] Group mRNA yield (mg / mL) mRNA integrity (%) First embodiment 5.9 86.1 Second embodiment 6.1 85.3 Third embodiment 5.6 84.7 Fourth embodiment 6.3 86.2

[0073] From the test results shown in Table 3, it can be seen that the mRNA production devices provided by the first to fourth embodiments of the invention can achieve milligram-level preparation of mRNA, and the mRNA yields are 5.9 mg / mL, 6.1 mg / mL, 5.6 mg / mL and 6.3 mg / mL, respectively. The integrity of the obtained mRNA purification products is above 84.7%, with good mRNA preparation effect.

[0074] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention without departing from the principles and intent of the present invention.

Claims

1. An mRNA production device, characterized in that: The mRNA production device comprises: A production tank, wherein a heat transfer liquid is arranged in the production tank; A reaction bag, the reaction bag comprising a flexible bag body and a transparent hard portion, the transparent hard portion being structured to form a detection dish, the detection dish being connected to the flexible bag body to receive a reaction liquid; A accommodating component, the accommodating component comprises an elastic connecting member and a placing plate, the elastic connecting member is connected to the peripheral wall of the production tank, the placing plate is connected to the elastic connecting member to be suspended in the production tank, and the reaction bag is arranged on the placing plate; A stirring component, wherein the stirring component drives the heat transfer fluid to flow so as to cause the storage plate to shake, and the stirring component maintains a non-contact state with the reaction bag and the storage plate; A detection component, the detection component includes an optical detector, a pH detector and a temperature detector; the pH detector and the temperature detector are arranged on the reaction bag; the optical detector includes a transmitter and a receiver, the transmitter and the receiver are arranged on two sides of the detection dish relative to each other, and the detection light emitted by the transmitter passes through the detection dish to be received by the receiver; The automatic sampler is connected to the reaction bag, and the detection component is connected to the automatic sampler signal to control the injection of the IVT raw material.

2. The mRNA production device according to claim 1, characterized in that The transparent hard part is structured to form a detection dish protruding from the reaction bag, the transmitter and the receiver are arranged on the storage plate at intervals to form a clamping groove, and the detection dish is clamped in the clamping groove; Optionally, the transparent hard portion is structured to form a plurality of receiving grooves recessed in the reaction bag, a detection dish is formed between two adjacent receiving grooves, and the transmitter and the receiver are respectively snapped into the two adjacent receiving grooves.

3. The mRNA production device according to claim 1, characterized in that The volume of the reaction bag is 50-5000 mL; the volume of the detection dish is 0.1-5 mL, and the optical path of the detection dish is 0.001-10 mm.

4. The mRNA production device according to claim 1, characterized in that The reaction bag further includes a fixed hard portion disposed on the outer peripheral side, and the fixed hard portion and the placement plate are connected by bolts to place the reaction bag on the placement plate.

5. The mRNA production device according to claim 1, characterized in that One end of the elastic connector is connected to the top wall of the production tank, and the storage plate is connected to an end of the elastic connector away from the top wall of the production tank, so that the elastic connector is in a stretched state; Optionally, the storage plate is tilted; Optionally, the storage plate is configured as a grid structure.

6. The mRNA production device according to claim 1, characterized in that The stirring assembly is a magnetic stirring assembly and / or a mechanical stirring assembly; Optionally, the magnetic stirring assembly includes a magnetic stirring table and a magnetic rotor, the production tank is disposed on the magnetic stirring table, the magnetic rotor is disposed in the production tank to drive the flow of the thermal fluid, and the magnetic rotor maintains a non-contact state with the reaction bag, the storage plate and the detection assembly; Optionally, the mechanical stirring assembly includes a stirring rod and a stirring motor, the stirring motor drives the stirring rod to rotate, the stirring rod is inserted in the production tank to drive the flow of thermal transfer fluid, and the stirring rod and the mechanical stirring assembly include a stirring rod and a stirring motor, the stirring motor drives the stirring rod to rotate, the stirring rod is inserted in the production tank to drive the flow of thermal transfer fluid, and the stirring rod maintains a non-contact state with the flexible reaction bag and the storage plate.

7. The mRNA production device according to claim 1, characterized in that The optical detector includes one or more of a Fourier transform infrared spectrometer, an in-situ Raman spectrometer, and a particle image analyzer.

8. The mRNA production device according to claim 1, characterized in that A temperature controller is also provided in the production tank.

9. A method for quality control of mRNA production, characterized in that: The mRNA production is carried out in the mRNA production device described in any one of claims 1 to 8, and the quality control method includes: taking the detection component to detect the IVT reaction liquid in the reaction bag, obtaining IVT reaction parameters, and adjusting the IVT reaction conditions based on the IVT reaction parameters; wherein the IVT reaction parameters include one or more of raw material concentration, solution aging state, phosphate concentration, mRNA generation amount, pH value and temperature.

10. The method for quality control of mRNA production according to claim 9, characterized in that: The method for adjusting the IVT reaction conditions based on the IVT reaction parameters includes: The pH value of the IVT reaction system is regulated to be maintained at 7-8, and the deviation value of the real-time temperature in the IVT reaction compared with the preset reaction temperature is regulated to be 0-0.5°C; When the dNTP concentration in the IVT reaction system decreases to 10-30% of the initial concentration, add dNTP and Mg 2+ , cap analogs, inorganic pyrophosphatase to 75% to 100% of the initial concentration; When the IVT reaction system ages, adjust the Mg 2+ To 75% to 100% of the initial concentration; When the amount of mRNA produced reached 10-20 mg / mL, the IVT reaction was stopped.

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