Apparatus for preparing nucleic acid medicine and method for preparing nucleic acid medicine

Abstract

The application relates to the technical field of pharmaceutical equipment and methods, and provides an equipment for preparing nucleic acid drugs and a nucleic acid drug preparation method. Through a first purification operation, a lipid nanoparticle preparation, a second purification operation and other steps, the solution is purified and prepared into a lipid nanoparticle, the effective components of the finally obtained nucleic acid drugs are improved through the two times of purification. Furthermore, the first purification process module, the lipid nanoparticle preparation process module and the second purification process module are connected in a fluid manner, the automatic preparation can be realized, each component such as the first purification process module and the second purification process module is set correspondingly, and the high-efficiency and high-quality nucleic acid drug preparation can be realized.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical equipment and methods, in particular to an equipment for preparing nucleic acid drugs and a nucleic acid drug preparation method. BACKGROUND

[0002] mRNA (Messenger RNA) is a single-stranded ribonucleic acid that carries genetic information (DNA transcription product), mainly has the function of accurately transcribing the genetic information on DNA, and is responsible for translating the genetic information it carries into protein on ribosomes. The mRNA stock preparation is a preparation prepared with mRNA as the core component, which regulates protein expression by delivering genetic information, and is currently mainly applied in the fields of vaccine research and development, gene therapy and protein replacement therapy.

[0003] At present, in the production process of mRNA stock preparation, manual intervention is required, which not only has low production efficiency, but also the solution is easy to be contaminated during transfer. Therefore, an equipment for preparing nucleic acid drugs and a nucleic acid drug preparation method are proposed to solve the above problems. SUMMARY

[0004] The present application provides an equipment for preparing nucleic acid drugs and a nucleic acid drug preparation method to improve the preparation effect of nucleic acid drugs.

[0005] The present application provides an equipment for preparing nucleic acid drugs, comprising: an in vitro transcription process module for providing a stock solution; a first purification process module arranged downstream of the in vitro transcription process module for purifying the stock solution; a lipid nanoparticle preparation process module arranged downstream of the first purification process module to receive the purified stock solution and prepare lipid nanoparticles therefrom; a second purification process module arranged downstream of the lipid nanoparticle preparation process module to purify a solution containing lipid nanoparticles; and an automatic control system for realizing linkage control of the in vitro transcription process module, the first purification process module, the lipid nanoparticle preparation process module and the second purification process module.

[0006] In some embodiments, the first purification process module comprises: a first separation and purification device having a first inlet end, a first outlet end and a first waste liquid outlet end, the first separation and purification device being configured in a first circulation loop having a first purification input end; a first mixing container configured in the first circulation loop and having an inlet connected to the first outlet end and an outlet connected to the first inlet end; a first displacement liquid input end connected to the inlet of the first mixing container; and a pump assembly for driving the flow of the solution.

[0007] In some embodiments, the first purification process module further comprises a first purification collection end connected to the first mixing container; and a first filtration assembly disposed between the first mixing container and the first purification collection end.

[0008] In some embodiments, the first purification process module further comprises a first gas inlet end connected to the first filtration assembly; and a first detection sensor configured to detect a pressure change in a pipeline where the first filtration assembly is located when the first filtration assembly is inputted with gas from the first gas inlet end.

[0009] In some embodiments, the first purification process module further comprises at least one first pre-preparation inlet end; and a second waste liquid collection end; wherein the first separation and purification device is configured between the first pre-preparation inlet end and the second waste liquid collection end by a pipeline.

[0010] In some embodiments, the first mixing container is disposed on a mixing mechanism, the mixing mechanism comprising a mixing drive member; an eccentric connecting member eccentrically connected to the mixing drive member; a supporting member rotatably connected to the eccentric connecting member; when the mixing drive member drives the eccentric connecting member to move, the supporting member and the first mixing container are driven to rotate and shake to mix the liquid in the first mixing container.

[0011] In some embodiments, the first mixing container comprises a container body; an inlet pipe extending into the container body and extending towards the sidewall of the container body; an outlet pipe extending to the bottom of the container body; and a stirring member comprising a stirring drive mechanism and a stirring portion cooperatively connected, the stirring portion being located in the container body.

[0012] In some embodiments, the second purification process module comprises a second separation and purification device having a second inlet end, a second outlet end and a second waste liquid outlet end, the second separation and purification device being configured in a second circulation loop, the second circulation loop having two first purification input ends; a second mixing container configured in the second circulation loop and having an inlet connected to the second outlet end and an outlet connected to the second inlet end; at least two auxiliary liquid input ends connected to the inlet of the second mixing container; and a pump assembly for driving the solution to flow.

[0013] In some embodiments, the second purification process module further comprises a second purification collection end connected to the second mixing container; and a second filtration device disposed between the second mixing container and the second purification collection end.

[0014] In some embodiments, at least one set of pre-purification assembly is further disposed upstream of the first purification process module.

[0015] In some embodiments, the pre-purification assembly comprises a chromatography process module, which comprises: a chromatography main pipeline comprising a first port and a second port connected by fluid, and a third port and a fourth port connected by fluid; a chromatography inlet pipeline connected to the first port; a chromatography column, the inlet of which is connected to the second port, and the outlet of which is connected to the third port; a chromatography outlet pipeline connected to the fourth port.

[0016] In some embodiments, the first port is selectively connectable to the third port, and the second port is selectively connectable to the fourth port.

[0017] In some embodiments, the first port is selectively connectable to the fourth port.

[0018] In some embodiments, a bubble sensor is arranged in the chromatography inlet pipeline; and the device for preparing nucleic acid drugs further comprises a bubble removal pipeline connected to the chromatography inlet pipeline through a bubble trap.

[0019] In some embodiments, in a state where two or more chromatography inlet pipelines are arranged, the two or more chromatography inlet pipelines are collectively connected to a static mixer and then to the chromatography main pipeline, and the static mixer has a bent flow channel.

[0020] In some embodiments, the pre-purification assembly comprises a magnetic bead purification process module, which comprises: at least one magnetic bead purification inlet end; a magnetic bead purification container, the inlet and outlet of which are connected by a pipeline to form a magnetic bead purification circulation loop; and a magnetic force source arranged at the magnetic bead purification container for selectively adsorbing magnetic beads.

[0021] In some embodiments, an oscillation mechanism is further arranged, which is connected to the magnetic bead purification container and drives the solution and magnetic beads in the magnetic bead purification container to oscillate.

[0022] In some embodiments, the magnetic force source comprises a magnetic body and a magnetic force source driving mechanism connected to the magnetic body to drive the magnetic body to move between the adsorption and un-adsorption positions.

[0023] In some embodiments, the automatic control system is used to sequentially pass the stock solution into the in vitro transcription process module, the first purification process module, the lipid nanoparticle preparation process module, and the second purification process module, and control the in vitro transcription process module, the first purification process module, the lipid nanoparticle preparation process module, and the second purification process module to perform process operations.

[0024] Correspondingly, the present application also provides a nucleic acid drug preparation method, which can use any of the aforementioned devices for preparing nucleic acid drugs, and comprises the following steps: purifying the solution through the first purification process module; based on the purified solution, preparing the lipid nanoparticles through the lipid nanoparticle preparation process module; purifying the solution containing the lipid nanoparticles through the second purification process module.

[0025] In some embodiments, the purifying the solution through the first purification process module comprises a purification step, which comprises: making the solution flow through the first separation and purification device multiple times through the first circulation loop; adding the displacement solution to the first mixing container through the first displacement solution input end, and making the displacement solution and the solution circulate in the first circulation loop and flow through the first separation and purification device multiple times.

[0026] In some embodiments, after the purification step, a solution output step is further provided, which comprises: adding the displacement solution to the first separation and purification device through the first displacement solution input end to push the purified solution out of the first separation and purification device; making the solution flow to the first filtration assembly and flow to the first purification collection end after filtration.

[0027] In some embodiments, a post-processing step is further included, which comprises: inputting the gas through the first gas inlet end, and making the gas flow to the second waste liquid collection end after flowing through the first filtration assembly; and detecting whether the first filtration assembly is damaged through the first detection sensor when the gas flows through the first filtration assembly.

[0028] In some embodiments, the purifying the solution containing the lipid nanoparticles through the second purification process module comprises a pre-preparation step, which comprises: inputting the pure water through the second pre-preparation inlet end, and making the pure water flow to the third waste liquid collection end after flowing through the second separation and purification device; inputting the alkali solution through the second pre-preparation inlet end, and making the alkali solution flow to the third waste liquid collection end after flowing through the second separation and purification device; inputting the pure water again through the second pre-preparation inlet end, and making the pure water flow to the third waste liquid collection end after flowing through the second separation and purification device; and inputting the equilibration solution for rinsing through the second pre-preparation inlet end.

[0029] In some embodiments, before the solution is purified by the first purification process module, a magnetic bead purification operation is performed by the magnetic bead purification process module, which includes: introducing the solution into the magnetic bead purification circulation loop through the magnetic bead purification inlet end and circulating for several times; using a magnetic force source to cause the magnetic beads to be adsorbed, the magnetic beads are retained in the magnetic bead purification container, and the solution is discharged to the waste liquid outlet end; introducing a washing liquid through the magnetic bead purification inlet end, the magnetic force source is removed, so that the magnetic beads are released and in contact with the washing liquid, and at the same time, the washing liquid and the magnetic beads are vibrated by the vibration mechanism, after the first preset time, the magnetic force source is moved back and the magnetic beads are fixed, and then the washing liquid is discharged to the waste liquid outlet end; introducing an elution liquid through the magnetic bead purification inlet end, the magnetic force source is removed, so that the magnetic beads are released and in contact with the elution liquid, the elution liquid and the magnetic beads are vibrated by the vibration mechanism, after the second preset time, the magnetic force source is moved back and the magnetic beads are fixed, and the elution liquid is delivered to the downstream other components through the magnetic bead purification outlet end.

[0030] In some embodiments, before the solution is purified by the first purification process module, a chromatography operation is performed by the chromatography process module, which includes: inputting the solution into the chromatography column; performing at least two gradient elutions on the chromatography column by using elution solutions with different concentrations; eluting the chromatography column and collecting the drug solution obtained after elution.

[0031] The present application has the following beneficial effects: The present application provides an apparatus for preparing a nucleic acid drug and a nucleic acid drug preparation method. Through the steps of a first purification operation, lipid nanoparticle preparation, and a second purification operation, the solution is purified and prepared into a lipid nanoparticle. Through the two purifications, the effective ingredient of the finally obtained nucleic acid drug is improved.

[0032] Moreover, the first purification process module, the lipid nanoparticle preparation process module, and the second purification process module are fluidly connected, which can realize automatic preparation. The components such as the first purification process module and the second purification process module are set correspondingly, which is helpful to realize efficient and high-quality nucleic acid drug preparation. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 An in vitro transcription process module is exemplarily shown in a structural schematic view.

[0034] Figure 2 An in vitro transcription process module is exemplarily shown in a top view.

[0035] Figure 3 A mechanism schematic view of a pipetting unit is exemplarily shown.

[0036] Figure 4 An in vitro transcription process module is exemplarily shown in a structural schematic view. Figure 2A partial enlarged view of the middle A part.

[0037] Figure 5 An exemplary structural schematic diagram of a mixing unit is shown.

[0038] Figure 6 An exemplary structural schematic diagram of a hybrid drive mechanism is shown.

[0039] Figure 7 An exemplary structural schematic diagram of a thermal insulation container is shown.

[0040] Figure 8 An exemplary structural schematic diagram of a mixing mechanism is shown. Figure 7 An exemplary top half sectional view of the mixing mechanism is shown.

[0041] Figure 9 An exemplary P-P cross-sectional schematic diagram of the mixing mechanism is shown. Figure 8

[0042] Figure 10 An exemplary schematic diagram of a buffer container and base cooperation is shown.

[0043] Figure 11 An exemplary structural schematic diagram of a buffer container is shown.

[0044] Figure 12 An exemplary structural schematic diagram of a base for adapting a buffer container is shown.

[0045] Figure 13 An exemplary schematic diagram of steps of an in vitro transcription method is shown.

[0046] Figure 14 An exemplary pipeline schematic diagram of a first purification process module is shown.

[0047] Figure 15 An exemplary pipeline schematic diagram of a second purification process module is shown.

[0048] Figure 16 An exemplary structural schematic diagram of a mixing bottle is shown.

[0049] Figure 17 An exemplary pipeline schematic diagram of a chromatography process module is shown.

[0050] Figure 18 An exemplary structural schematic diagram of a magnetic bead purification process module is shown.

[0051] Figure 19 An exemplary pipeline schematic diagram of a magnetic bead purification process module is shown.

[0052] Figure 20 An exemplary structural schematic diagram of a mixing mechanism is shown.

[0053] Figure 21 ​An exemplary top view of a mixing mechanism is shown.

[0054] Figure 22 An exemplary cross-sectional view of A-A of Figure 21

[0055] Figure 23 An exemplary structural diagram of an eccentric connector is shown.

[0056] Figure 24 An exemplary structural diagram of a static mixer is shown.

[0057] Figure 25 An exemplary top half cross-sectional view of a static mixer is shown.

[0058] Figure 26 An exemplary structural diagram of a mounting frame is shown.

[0059] Figure 27 An exemplary flow diagram of a method of preparing a nucleic acid drug is shown.

[0060] ​Legend: 11-work platform, 12-reaction vessel, 100-pipetting unit, 110-first pipetting driving mechanism, 111-first transverse moving mechanism, 112-first rotating mechanism, 113-first vertical moving mechanism, 120-first pipetting piece, 121-pipette tip, 122-pressure source, 123-tip mounting portion, 130-second pipetting driving mechanism, 131-second transverse moving mechanism, 132-second rotating mechanism, 133-second vertical moving mechanism, 140-second pipetting piece, 150-clamping mechanism, 151-clamping piece, 160-refrigeration cabin, 170-waste liquid cabin, 180-buffer container, 1801-magnetic rotor, 1802-second positioning structure, 181-base, 1811-magnetic driving piece, 1812-first positioning structure, 1813-weighing assembly, 191-cold storage reagent storage area, 192-normal temperature reagent storage area, 193-pipette tip storage area, 200-mixing unit, 210-carrier, 211-heat insulation seat, 212-heat preservation container, 213-heat preservation cover, 214-elastic piece, 220-mixing driving mechanism, 221-power source, 222-driving eccentric wheel, 223-first eccentric transmission piece, 224-passive eccentric wheel, 225-second eccentric transmission piece, 226-abutment, 240-inclination assembly, 241-inclination motor, 242-speed reducer, 243-connecting frame, 244-positioning assembly, 300-chromatography process module, 310-chromatography inlet pipeline, 320-chromatography main pipeline, 321-first port, 322-second port, 323-third port, 324-fourth port, 330-chromatography outlet pipeline, 340-waste liquid collection container, 350-static mixer, 351-flow channel, 352-body, 353-liquid medicine inlet end, 354-liquid medicine outlet end, 355-closed cover, 356-sealing ring, 360-bubble removal pipeline,361-bubble trap, 400-magnetic bead purification process module, 410-magnetic bead purification inlet end, 420-magnetic bead purification container, 430-exhaust end, 440-waste liquid outlet end, 450-magnetic bead purification outlet end, 460-magnetic force source, 500-first purification process module, 510-first purification input end, 520-first separation and purification device, 521-first inlet end, 522-first outlet end, 523-first waste liquid outlet end, 524-first waste liquid collection end, 525-first mixing container, 526-first displacement liquid input end, 530-first purification collection end, 531-first filter assembly, 532-first bubble sensor, 540-first pre-preparation inlet end, 541-second waste liquid collection end, 542-first sensing assembly, 550-first gas inlet end, 551-first detection sensor, 700-second purification process module, 710-second purification input end, 720-second separation and purification device, 721-second inlet end, 722-second outlet end, 723-second waste liquid outlet end, 724-third waste liquid collection end, 725-second mixing container, 726-accessory liquid input end, 730-second purification collection end, 731-second filter assembly, 732-second bubble sensor, 740-second pre-preparation inlet end, 741-fourth waste liquid collection end, 742-second sensing assembly, 750-second gas inlet end, 751-second detection sensor, 760-measuring accessory assembly, 810-container body, 820-inlet pipe, 830-outlet pipe, 840-stirring member, 910-mixing driving member, 920-eccentric connecting member, 921-shaft portion, 922-base, 930-bearing, 940-supporting member, 950-flexible wall, 960-position sensor, 970-weight sensor, 1001-frame, 1002-first connecting member, 1003-second connecting member, 1004-hook structure. DETAILED DESCRIPTION

[0061] The technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by a person skilled in the art without creative work are within the protection scope of the present application. In addition, 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. In the present application, the orientation words such as "upper", "lower", "left", "right" generally refer to the upper, lower, left and right in the actual use or working state of the device, and specifically refer to the picture plane direction in the drawings.

[0062] In addition, the terms "first", "second", etc. are used only for descriptive purposes and are not to be construed as indicating or implying relative importance or a specific order of limiting the technical features indicated. Therefore, the features defined as "first", "second", etc. can be explicitly or implicitly included in at least one of the features.

[0063] The present application provides a device for preparing a nucleic acid drug and a nucleic acid drug preparation method, which are described in detail below. It should be noted that the order of description of the following embodiments is not limited as the preferred order of the embodiments of the present application. In the following embodiments, each embodiment is described with emphasis, and the parts not described in detail in a certain embodiment can be referred to the related description of other embodiments.

[0064] The present application provides a device for preparing a nucleic acid drug, which comprises a first purification process module 500 (see Figure 14 ), a lipid nanoparticle preparation process module, and a second purification process module 700 (see Figure 15 ).

[0065] The first purification process module 500 is used to purify the incoming drug solution.

[0066] The lipid nanoparticle preparation process module is arranged downstream of the first purification process module 500 for preparing lipid nanoparticles.

[0067] The second purification process module 700 is arranged downstream of the lipid nanoparticle preparation process module for purifying the solution containing lipid nanoparticles.

[0068] Here, each process module is exemplarily configured with a corresponding disposable consumable assembly, and the upstream disposable consumable assembly and the downstream disposable consumable assembly are connected by sterile docking. For example, the disposable consumable assembly can include pipes and / or pipe connection structures, etc.

[0069] Here, a self-control system can also be provided, which is signal connected with the first purification process module 500, the lipid nanoparticle preparation process module, and the second purification process module 700, so that the self-control system can realize linkage control of the first purification process module 500, the lipid nanoparticle preparation process module, and the second purification process module 700.

[0070] The self-control system can be a central processing unit (CPU), a microcontroller (MCU), a digital signal processor (DSP), a field programmable gate array (FPGA), an application specific integrated circuit (ASIC), or other devices with data processing capability.

[0071] Exemplarily, the automatic control system can control the respective process modules to perform corresponding process procedures according to the requirements of different processes and formulas, and deliver the stock solution obtained by the upstream process module to the downstream process module, so that the respective process modules sequentially process the stock solution in order to obtain the required product.

[0072] The lipid nanoparticle preparation process module uses an existing device, for example, CN120242853A discloses a nanomedicine preparation system and preparation process, which can be used as a lipid nanoparticle preparation process module. Of course, the lipid nanoparticle preparation process module used in the present application does not necessarily have to be the same as this. The structure of this disclosure is only used as an example to illustrate that there are many lipid nanoparticle preparation process modules in the prior art.

[0073] In some embodiments, referring to Figure 14 The first purification process module 500 includes a hollow fiber column for performing the purification operation. It can be understood that the hollow fiber column is used as an example for illustration, but in other embodiments, the hollow fiber column can be replaced by other first separation and purification devices 520, such as a membrane bag, and the examples in the embodiments of the present application do not constitute undue limitations.

[0074] Exemplarily, the first inlet end 521 and the first outlet end 522 of the hollow fiber column are connected to each other by a pipeline to form a first circulation loop, and the first circulation loop has a first purification input end 510 for inputting the solution from the upstream assembly. For example, the first inlet end 521 and the first outlet end 522 can be located at the bottom end and the top end of the hollow fiber column, respectively, and the hollow fiber column further has a first waste liquid outlet end 523 connected to a first waste liquid collection end 524. Of course, this example does not constitute undue limitations on the present application, and in other embodiments, the positions of the first inlet end 521 and the first outlet end 522 can be different.

[0075] In use, the solution from the upstream assembly, such as the solution from the in vitro transcription device, is input into the first circulation loop and input into the hollow fiber column for concentration, and the waste liquid is discharged through the first waste liquid outlet end 523 to the first waste liquid collection end 524, which can be provided with a waste liquid collection container.

[0076] Exemplarily, when performing the purification operation, a displacement liquid is required, and therefore a first displacement liquid input end 526 is further provided, and a first mixing container 525 is provided in the aforementioned first circulation loop. For example, the inlet of the first mixing container 525 is connected to the first displacement liquid input end 526 and the first outlet end 522 of the aforementioned hollow fiber column, and the outlet of the first mixing container 525 is connected to the first inlet end 521 of the aforementioned hollow fiber column.

[0077] Thus, the solution from the upstream device or the solution after the aforementioned concentration operation and the displacement liquid can be input into the first mixing container 525. After the displacement liquid is added, the solution and the displacement liquid are input into the hollow fiber column through the first circulation loop to perform circulation concentration, and the waste liquid is discharged to the first waste liquid collection container 340 through the first waste liquid outlet end 523.

[0078] Thus, the embodiment of the present application first performs circulation concentration on the solution from the upstream through the hollow fiber column, and then performs circulation concentration on the concentrated solution and the displacement liquid, so that a better purification effect is achieved.

[0079] Of course, in some embodiments, the solution from the upstream and the displacement liquid can be directly subjected to circulation concentration, but in this case, a part of the impurities can not be removed.

[0080] In some embodiments, a sensor, for example, a flow sensor, can be arranged in the pipeline between the first waste liquid outlet end 523 and the first waste liquid collection end 524 of the hollow fiber column. When the reading of the flow sensor reaches a preset value, it indicates that the discharged waste liquid has reached a preset amount, that is, the preset purification requirement has been reached, and the circulation concentration stops. For example, a UV sensor can be arranged. When the reading of the UV sensor meets a preset range, it indicates that the concentration of the discharged waste liquid meets the requirement, that is, the preset purification requirement has been reached, and the circulation concentration stops. Of course, in some examples, multiple sensors can be arranged at the same time. When the readings of the multiple sensors all meet the preset requirement, it is determined that the preset purification requirement has been reached, and the circulation concentration stops.

[0081] In some embodiments, the first displacement liquid input end 526 is also connected to the first outlet end 522 of the hollow fiber column, so as to facilitate the displacement of the drug solution in the hollow fiber column and / or the nearby pipeline by the displacement liquid.

[0082] In some embodiments, the first purification process module 500 further comprises a first purification collection end 530 connected to the aforementioned first mixing container 525, so as to collect the purified solution to the first purification collection end 530. For example, a butterfly filter, a capsule filter or various first filter assemblies 531 can be arranged between the first purification collection end 530 and the first mixing container 525 to achieve sterile filtration.

[0083] For example, a first bubble sensor 532 can be arranged upstream of the first filter assembly 531. When bubbles are detected, the collection of the solution is stopped.

[0084] In addition, the purification collection end 530 can be provided with a purification collection container, or can be directly connected to other components downstream, and the like, and the examples in the embodiments of the present application do not unduly limit them.

[0085] In some embodiments, at least one first pre-preparation inlet end 540 and a second waste liquid collection end 541 can also be provided, and the hollow fiber column is arranged between the first pre-preparation inlet end 540 and the second waste liquid collection end 541. The first pre-preparation inlet end 540 is used to input the solution required in the pre-preparation stage of the components such as the hollow fiber column, so as to perform the pre-preparation step. For example, the pre-preparation step can include pure water cleaning, balance liquid rinsing, alkali liquid rinsing, and the like.

[0086] For example, three first pre-preparation inlet ends 540 are provided here. In use, the three first pre-preparation inlet ends 540 can be used to input different solutions to achieve the pre-preparation step. The different solutions flow to the second waste liquid collection end 541 and are discharged after passing through the first inlet end 521 and the first outlet end 522 of the hollow fiber column in sequence.

[0087] For example, the first first pre-preparation inlet end 540 inputs pure water, the pure water flows through the pipeline and the components in the pipeline to achieve pure water cleaning; the second first pre-preparation inlet end 540 inputs balance liquid, the balance liquid flows through the pipeline and the components in the pipeline to achieve balance liquid rinsing, and the balance liquid can be mainly used for calibrating the sensors in the pipeline; and the third first pre-preparation inlet end 540 inputs alkali liquid, the alkali liquid flows through the pipeline and the components in the pipeline to achieve alkali liquid rinsing.

[0088] For example, the first pre-preparation inlet end 540 and the second waste liquid collection end 541 can be provided with a first sensing assembly 542, and / or the first pre-preparation inlet end 540 and the first waste liquid collection end 524 can also be provided with a first sensing assembly 542. The first sensing assembly 542 is used to detect the parameter values of the solution, for example, the first sensing assembly 542 can include any of a flow sensor, a mass sensor, a PH sensor, a UV value sensor, and the like. For another example, the first sensing assembly 542 can be arranged downstream of the hollow fiber column. For another example, the aforementioned balance liquid can be used for calibrating the first sensing assembly 542, that is, when the balance liquid flows, the state of the first sensing assembly 542 is judged by the reading of the first sensing assembly 542.

[0089] In some embodiments, at least one first pre-preparation inlet end 540 is connected to the aforementioned first filter assembly 531, so as to rinse the first filter assembly 531.

[0090] For example, one first pre-preparation inlet end 540, the first filter assembly 531, and the second waste liquid collection end 541 are connected in sequence by a pipeline.

[0091] In some embodiments, a first gas inlet end 550 is also provided, which is connected to the aforementioned first filter assembly 531. In this way, by inputting gas, the first detection sensor 551 can detect whether the first filter assembly 531 is damaged. This is because when the membrane or the like of the first filter assembly 531 is damaged, the detection reading of the first detection sensor 551 will be different from the reading in the normal state.

[0092] Exemplarily, the first gas inlet end 550, the first detection sensor 551, the first filter assembly, and the second waste liquid collection end 541 are connected in sequence through pipelines.

[0093] It can be understood that in addition, a plurality of pump assemblies can be arranged in the pipelines in the first purification process module 500 to drive the solution to flow in the pipelines. The pump assemblies can be peristaltic pumps or the like. For example, the pump assemblies provided in the present embodiment can include P1, P2, and P3. It can be understood that this does not constitute an improper limitation on the present application, and in other embodiments, the pump assemblies can also be arranged in other ways, at other positions, and in other numbers.

[0094] It can be understood that in addition, a plurality of valve assemblies can be arranged in the pipelines in the first purification process module 500 to control the opening and closing of the pipelines. Exemplarily, the valve assemblies provided in the present embodiment can include V1 to V16. It can be understood that this does not constitute an improper limitation on the present application, and in other embodiments, the valve assemblies can also be arranged in other ways, at other positions, and in other numbers, for example, arranged in the components for providing and collecting the solution, etc.

[0095] In this way, based on the first purification process module 500 provided in the present embodiment, a pipeline arrangement and corresponding structure for purifying the solution are provided. On this basis, according to actual needs, a person skilled in the art can conveniently add corresponding pump assemblies and / or valve assemblies, and thus the required control functions can be achieved.

[0096] In some embodiments, please refer to Figure 15 The second purification process module 700 includes a hollow fiber column for performing the purification operation.

[0097] Here, the hollow fiber column is taken as an example for illustration, but it can be understood that in other embodiments, the hollow fiber column can be replaced by other second separation and purification devices 720, such as a membrane bag, and the examples in the present embodiment do not constitute an improper limitation.

[0098] Exemplarily, the second inlet end 721 and the second outlet end 722 of the hollow fiber column are connected to each other by a pipeline to form a second circulation loop, and the second circulation loop has a second purification input end 710 for inputting the solution from the upstream assembly. For example, the second inlet end 721 and the second outlet end 722 can be located at the bottom end and the top end of the hollow fiber column respectively, and the hollow fiber column further has a second waste liquid outlet end 723, which can be connected to a third waste liquid collection end 724. Of course, this example does not constitute an improper limitation on the present application, and in other embodiments, the positions of the second inlet end 721, the second outlet end 722 and the like can also be different.

[0099] In use, the solution from the upstream assembly, for example, the solution from the lipid nanoparticle preparation process module, is input into the second circulation loop and input into the hollow fiber column for concentration, and the waste liquid is discharged through the second waste liquid outlet end 723 to the third waste liquid collection end 724, which can be provided with a waste liquid collection container and the like.

[0100] Exemplarily, in the purification operation, some auxiliary liquids such as displacement liquid, mother liquid, auxiliary material mother liquid and the like are needed, and the amount of auxiliary liquids required can be different according to the actual process requirements.

[0101] Therefore, at least two auxiliary liquid input ends 726 can be further provided to input displacement liquid, mother liquid, auxiliary material mother liquid and the like. In the illustration, an embodiment provided with three auxiliary liquid input ends 726 is exemplarily shown.

[0102] And, the second mixing container 725 is provided in the aforementioned second circulation loop, for example, the inlet of the second mixing container 725 is connected to the auxiliary liquid input end 726 and the second outlet end 722 of the aforementioned hollow fiber column, and the outlet of the second mixing container 725 is connected to the second inlet end 721 of the aforementioned hollow fiber column.

[0103] Therefore, the solution from the upstream device or the solution after the aforementioned concentration operation and the auxiliary liquid can be input into the second mixing container 725. And, after adding at least one auxiliary liquid, the solution and the auxiliary liquid are input into the hollow fiber column through the second circulation loop for circulation concentration, and the waste liquid is discharged through the second waste liquid outlet end 723 to the second waste liquid collection container 340.

[0104] Therefore, the embodiment of the present application first performs circulation concentration on the solution from the upstream through the hollow fiber column, and then performs circulation concentration on the concentrated solution and the auxiliary liquid, so as to achieve a better purification effect.

[0105] Of course, in some embodiments, the solution from upstream and the auxiliary liquid can also be directly circulated and concentrated together, but in this case, part of the impurities can not be removed.

[0106] In some embodiments, in order to more accurately calculate the amount of auxiliary liquid, a metering component can be provided at the auxiliary liquid input end 726. For example, the metering component can be a weighing component, which can weigh the change in weight of the auxiliary liquid container loaded with the auxiliary liquid in real time, so as to determine the amount of auxiliary liquid added.

[0107] Due to the presence of the pipeline, although the metering component such as the weighing component can determine the amount of auxiliary liquid added, part of the auxiliary liquid remains in the pipeline and does not completely enter the second mixing container 725. Therefore, in order to more accurately meter the amount of auxiliary liquid added, a metering auxiliary component 760 can also be provided, which is configured in the pipeline for metering the flow of auxiliary liquid flowing in the pipeline.

[0108] For example, a weighing component can be provided at the auxiliary liquid input end 726 as the metering component; and a bubble sensor or a flow sensor can be configured in the pipeline between the auxiliary liquid input end 726 and the second mixing container 725 as the metering auxiliary component 760. At the initial input, the auxiliary liquid has not yet flowed to the metering auxiliary component 760, at this time only the air originally in the pipeline flows through the metering auxiliary component 760, and the metering auxiliary component 760 does not generate a reading until the auxiliary liquid flows to the metering auxiliary component 760, and the metering auxiliary component 760 begins to generate a reading. Therefore, only when both the metering component and the metering auxiliary component 760 reach the preset reading range, it is confirmed that sufficient auxiliary liquid has been added.

[0109] In addition, in another case, for example, one kind of auxiliary liquid is added first, and another kind of auxiliary liquid is added later, the later-added auxiliary liquid needs to be pushed forward after the previously-added auxiliary liquid to enter the second mixing container 725. At this time, the metering auxiliary component 760 is always generating a reading, but the actual later-added auxiliary liquid has not yet flowed to the second mixing container 725.

[0110] In this case, in combination with the calculation of the capacity of the liquid in the pipeline, the readings of the metering component and the metering auxiliary component 760, a more accurate amount of addition can be determined. For example, the capacity of the liquid in the pipeline can be calculated in advance, and the reading of the metering auxiliary component 760 is subtracted from the pre-calculated capacity of the liquid in the pipeline, and the reading occurring thereafter is used as the amount of the later-added auxiliary liquid, which is more accurate. Further, the actual amount of addition can also be determined by subtracting the pre-calculated capacity of the pipeline from the auxiliary liquid input end 726 to the metering auxiliary component 760 or the second mixing container 725 from the reading of the metering component.

[0111] Exemplarily, the metering auxiliary assembly 760 can be arranged close to the second mixing container 725. For example, after the plurality of auxiliary liquid input ends 726 are connected to each other, they are connected to the metering auxiliary assembly 760, and then connected to the second mixing container 725.

[0112] In some embodiments, a sensor can also be arranged in the pipeline between the second waste liquid outlet end 723 and the third waste liquid collection end 724 of the hollow fiber column, such as a flow sensor. When the reading of the flow sensor reaches a preset value, it indicates that the discharged waste liquid has reached a preset amount, i.e., the preset purification requirement has been met, and the circulating concentration stops. For example, a UV sensor can also be arranged. When the reading of the UV sensor meets a preset range, it indicates that the concentration of the discharged waste liquid has met the requirement, i.e., the preset purification requirement has been met, and the circulating concentration stops. Of course, in some examples, multiple sensors can also be arranged. When the readings of the multiple sensors all meet the preset requirement, it is determined that the preset purification requirement has been met, and the circulating concentration stops.

[0113] In some embodiments, the auxiliary liquid input end 726 is also connected to the second outlet end 722 of the hollow fiber column, so as to facilitate the subsequent displacement of the liquid in the hollow fiber column and / or the nearby pipeline by the displacement liquid.

[0114] In some embodiments, the second purification process module 700 further comprises a second purification collection end 730 connected to the aforementioned second mixing container 725, so as to collect the purified solution to the second purification collection end 730. Exemplarily, a butterfly filter, a capsule filter, or various second filter assemblies 731 can be arranged between the second purification collection end 730 and the second mixing container 725, so as to realize sterile filtration.

[0115] Exemplarily, a second bubble sensor 732 can also be arranged upstream of the second filter assembly 731. When bubbles are detected, the collection of the solution is stopped.

[0116] In addition, a purification collection container can be arranged at the second purification collection end 730, or it can be directly connected to other components downstream, and the examples in the embodiments of the present application do not improperly limit them.

[0117] In some embodiments, at least one second pre-preparation inlet end 740 and a fourth waste liquid collection end 741 can also be arranged, and the hollow fiber column is arranged between the second pre-preparation inlet end 740 and the fourth waste liquid collection end 741. The second pre-preparation inlet end 740 is used to input the solution required in the pre-preparation stage of the hollow fiber column and the like, so as to perform a pre-preparation step. For example, the pre-preparation step can include pure water cleaning, balance liquid rinsing, alkali liquid rinsing, etc.

[0118] Exemplarily, three second pre-preparation inlets 740 are provided. In use, the three second pre-preparation inlets 740 can be used to input different solutions to achieve the pre-preparation step. The different solutions flow through the second inlet 721 and the second outlet 722 of the hollow fiber column in sequence, and the waste liquid formed after the second outlet 722 flows to the fourth waste liquid collection end 741 and is discharged.

[0119] For example, the second pre-preparation inlet 740 inputs pure water, the pure water flows through the pipeline and the components in the pipeline to achieve pure water cleaning; the second pre-preparation inlet 740 inputs a balancing liquid, the balancing liquid flows through the pipeline and the components in the pipeline to achieve balancing liquid rinsing, and the balancing liquid can be mainly used for calibrating the sensor in the pipeline; the third second pre-preparation inlet 740 inputs an alkali solution, and the alkali solution flows through the pipeline and the components in the pipeline to achieve alkali rinsing.

[0120] Exemplarily, a second sensing assembly 742 can be provided between the second pre-preparation inlet 740 and the fourth waste liquid collection end 741, and / or a second sensing assembly 742 can also be provided between the second pre-preparation inlet 740 and the fourth waste liquid collection end 741. The second sensing assembly 742 is used to detect the parameter values of the solution, for example, the second sensing assembly 742 can include any of a flow sensor, a mass sensor, a PH sensor, a UV value sensor, etc. For example, the second sensing assembly 742 can be provided downstream of the hollow fiber column. For example, the aforementioned balancing liquid can be used to calibrate the second sensing assembly 742, that is, when the balancing liquid flows, the state of the second sensing assembly 742 is judged by the reading of the second sensing assembly 742.

[0121] In some embodiments, at least one second pre-preparation inlet 740 is connected to the aforementioned second filter assembly 731 to rinse the second filter assembly 731.

[0122] Exemplarily, one second pre-preparation inlet 740, the second filter assembly 731 and the second sensing assembly 742 are connected in sequence by a pipeline.

[0123] In some embodiments, a first gas inlet end 550 is also provided, and the first gas inlet end 550 is connected to the aforementioned second filter assembly 731. Thus, by inputting gas, the second detection sensor 751 such as a pressure sensor can detect whether the second filter device is damaged. This is because when the membrane structure of the second filter device is damaged, the detection reading of the second detection sensor 751 when the gas passes through will be different from the reading in the normal state.

[0124] Exemplarily, the second gas inlet end 750, the second detection sensor 751, the second filter assembly 731 and the fourth waste liquid collection end 741 are connected in sequence by a pipeline.

[0125] It can be understood that, in addition, a plurality of pump assemblies can be arranged in the second purification process module 700 to drive the solution to flow in the pipelines. The pump assemblies can be peristaltic pumps or the like. For example, the pump assemblies arranged in the present embodiment can include P4, P5 and P6. It can be understood that this does not constitute an improper limitation on the present application, and in other embodiments, the pump assemblies can also be arranged in other ways, at other positions and in other numbers.

[0126] It can be understood that, in addition, a plurality of valve assemblies can be arranged in the second purification process module 700 to control the opening and closing of the pipelines. For example, the valve assemblies arranged in the present embodiment can include V17 to V33. It can be understood that this does not constitute an improper limitation on the present application, and in other embodiments, the valve assemblies can also be arranged in other ways, at other positions and in other numbers, for example, arranged in the components for providing and collecting the solution, etc.

[0127] Thus, based on the second purification process module 700 provided by the present embodiment, a pipeline arrangement and corresponding structure for purifying the solution are provided. On this basis, according to actual needs, a person skilled in the art can conveniently add corresponding pump assemblies and / or valve assemblies, and thus the required control functions can be achieved.

[0128] In some embodiments, referring to Figure 16 , any of the aforementioned first mixing container 525 and second mixing container 725 can include a container body, an inlet pipe extending into the container body and extending towards the side wall of the container body, an outlet pipe extending to the bottom of the container body, and a stirring member. The stirring member includes a stirring driving mechanism and a stirring part coupled thereto, and the stirring part is located in the container body for stirring and mixing the solution. Of course, in other embodiments, any of the first mixing container 525 and the second mixing container 725 can be a liquid storage bag, a liquid storage tank or the like, and the examples in the present embodiment do not constitute an improper limitation.

[0129] In other embodiments, any of the aforementioned first mixing container 525 and second mixing container 725 can be arranged on a mixing mechanism. By driving the mixing mechanism, the first mixing container 525 or the second mixing container 725 can be driven to move to achieve mixing of the liquid in the first mixing container 525 or the second mixing container 725.

[0130] Referring to Figure 20The mixing mechanism can include a mixing driving member 910 and an eccentric connecting member 920, the eccentric connecting member 920 being eccentrically connected to the mixing driving member 910 and being capable of eccentric movement under the driving of the mixing driving member 910. A supporting member 940 is connected to the eccentric connecting member 920 and can also be driven to eccentric movement by the eccentric connecting member 920. Please refer to Figure 21 and Figure 22 The supporting member 940 is used for accommodating the aforementioned first mixing container 525 or second mixing container 725, which are mixing bags. The supporting member 940 is provided with a mounting groove for accommodating and fixing the first mixing container 525 or second mixing container 725. In addition, a bandage or the like can be used to reinforce the connection between the two. Of course, the example in the embodiment does not constitute undue limitation thereto.

[0131] In addition, in some embodiments, the supporting member 940 can be rotatably connected to the eccentric connecting member 920. For example, the eccentric connecting member 920 has a shaft portion 921. Please refer to Figure 23 The shaft portion 921 is arranged on a base 922, and the supporting member 940 is rotatably connected to the shaft portion 921 through a bearing 930. Again, the shaft portion 921 can be arranged obliquely to the horizontal plane. Thus, when the mixing driving member 910 drives the eccentric connecting member 920 to move, the supporting member 940 rotatably connected to the shaft portion 921 rotates and shakes, and the first mixing container 525 or second mixing container 725 mounted thereon can be mixed.

[0132] In further embodiments, please refer to Figure 22 A flexible wall 950 can also be arranged circumferentially on the lower side of the supporting member 940. The flexible wall 950 can be made of rubber or the like. With the movement of the supporting member 940, the flexible wall 950 can correspondingly deform, and the space surrounded by the flexible wall 950 is not easily invaded by dust and components from the outside.

[0133] In further embodiments, a position sensor 960 can also be arranged on one side of the eccentric connecting member 920. The position sensor 960 can be used to identify the position of the supporting member 940. For example, it can be used to identify the number of turns of the movement of the supporting member 940.

[0134] In further embodiments, a weight sensor 970 can also be arranged on the lower side of the supporting member 940. The weight sensor 970 is used for weighing, so that the mass of the medicinal liquid in the first mixing container 525 or second mixing container 725 can be measured.

[0135] In some embodiments, at least one set of pre-purification components can also be arranged upstream of the first purification process module 500.

[0136] In some examples, see Figure 17 The pre-purification assembly includes a chromatography process module 300, which includes a chromatography tubing and a chromatography column (not shown) and a pump assembly configured in the chromatography tubing, the pump assembly being used to drive the movement of the solution in the chromatography tubing. The chromatography tubing includes a chromatography inlet tubing 310, a chromatography outlet tubing 330, and a chromatography main tubing 320, which includes a first port 321 and a second port 322 fluidly connected, and a third port 323 and a fourth port 324 fluidly connected.

[0137] The first port 321 is connected to the chromatography inlet tubing 310, the second port 322 and the third port 323 are respectively connected to the inlet and the outlet of the chromatography column, and the fourth port 324 is connected to the chromatography outlet tubing 330. Thus, after the solution enters the chromatography tubing from the chromatography inlet tubing 310, it can flow to the chromatography column through the first port 321 and the second port 322, and flow to the chromatography outlet tubing 330 from the third port 323 and the fourth port 324.

[0138] Exemplarily, the first port 321 can be selectively connected to the third port 323, and the second port 322 can be selectively connected to the fourth port 324. Thus, after the solution enters the chromatography tubing from the chromatography inlet tubing 310, it can flow to the chromatography column through the first port 321 and the third port 323, and flow to the chromatography outlet tubing 330 from the second port 322 and the fourth port 324.

[0139] Exemplarily, the first port 321 can be selectively connected to the fourth port 324, so that in some cases, the solution can directly enter the chromatography outlet tubing 330 after passing through the first port 321 and the fourth port 324 from the chromatography inlet tubing 310. For example, when calibrating, cleaning or performing other operations on the chromatography process module 300, the liquid can directly flow through this path.

[0140] In some embodiments, a sensing assembly is configured in the chromatography tubing, which can include any of a bubble sensor, a pressure sensor, a flow sensor, a mass sensor, a PH sensor, a UV value sensor, etc. for different functions. Exemplarily, a bubble sensor, a pressure sensor and a flow sensor can be configured in the chromatography inlet tubing 310. Exemplarily, a PH sensor and a UV value sensor can be configured in the chromatography outlet tubing 330.

[0141] In some embodiments, based on the embodiment in which a bubble sensor is provided in the chromatography tubing, the chromatography tubing further includes a bubble removal tubing 360, which is connected to the chromatography inlet tubing 310 through a bubble trap 361.

[0142] It can be understood that valves can be arranged between the various ports, so as to selectively connect or shut off the various ports.

[0143] The chromatography inlet pipeline 310 is arranged in two parts, and the inlet ends A1 and A2 are arranged in one chromatography inlet pipeline 310, and the inlet ends B1 and B2 are arranged in the other chromatography inlet pipeline 310. However, in other embodiments, the chromatography inlet pipeline 310 can be arranged with more or fewer inlet ends, and / or, in other embodiments, the chromatography inlet pipeline 310 can be arranged in one or other number of parts. The examples in the embodiments of the present application do not constitute undue limitations thereon.

[0144] Here, in the embodiments in which two or more chromatography inlet pipelines 310 are arranged, the two or more chromatography inlet pipelines 310 are commonly connected to a static mixer 350, and the static mixer 350 has a flow channel 351 with at least one bend, so that when multiple different liquids flow into the static mixer 350, the liquids collide with the wall of the bent flow channel 351, thereby promoting the mixing of the liquids. For example, in order to achieve better mixing effect, the flow channel 351 can have at least two bends.

[0145] Such a static mixer 350 can achieve mixing effect without being powered.

[0146] For example, referring to Figure 24 and Figure 25 , the static mixer 350 further includes a body 352, the body 352 has a liquid inlet end 353 and a liquid outlet end 354, and the flow channel 351 is arranged on the body 352 and fluidly connected between the liquid inlet end 353 and the liquid outlet end 354. Moreover, the body 352 is provided with a closure cover 355 for cooperating with the body 352 and closing the flow channel 351. For example, a sealing ring 356 can be further arranged between the flow channel 351 and the closure cover 355.

[0147] The chromatography outlet pipeline 330 is arranged in one part, and is provided with an outlet end C1 and an outlet end C2, the outlet end C1 is connected to the waste liquid collection container 340, and the outlet end C2 can be used to output the solution after chromatography, which can be connected to other pipelines or components downstream. However, in other embodiments, the chromatography inlet pipeline 310 can be arranged with more outlet ends, and / or, in other embodiments, the chromatography outlet pipeline 330 can be arranged in multiple parts. The examples in the embodiments of the present application do not constitute undue limitations thereon.

[0148] It is understood that, in addition, the chromatography process module 300 may also include several pump assemblies configured in various pipelines to drive the solution and allow the solution to flow in the various pipelines. The pump assemblies may be peristaltic pumps, etc. For example, the pump assemblies provided in this embodiment may include P9 and P10. It is understood that this does not constitute an undue limitation on this application; in other embodiments, the pump assemblies may also employ other configurations, locations, and quantities.

[0149] It is understood that, in addition, the chromatography process module 300 may also include several valve assemblies configured in various pipelines to control the on / off state of the pipelines. Exemplarily, the valve assemblies provided in the embodiments of this application may include V41 to V57. It is understood that this does not constitute an undue limitation on this application; in other embodiments, the valve assemblies may also employ other configuration methods, locations, and numbers, for example, being configured in various components that provide and collect solutions.

[0150] In other examples, please refer to Figure 18 and Figure 19 The pre-purification component includes a magnetic bead purification process module 400, which can utilize specific ligands modified on the surface of magnetic beads to bind with target molecules, and use a magnetic field to separate the magnetic beads from impurities, ultimately releasing a high-purity sample.

[0151] Here, the magnetic bead purification process module 400 includes at least one magnetic bead purification inlet 410 and a magnetic bead purification container 420. The magnetic bead purification inlet 410 is fluidly connected to the magnetic bead purification container 420, so that the solution can be input into the magnetic bead purification container 420 through the magnetic bead purification inlet 410.

[0152] The magnetic bead purification inlet 410 is used to input solutions from upstream and various other required solutions, such as solutions from the in vitro transcription device, as well as elution buffers and washing buffers. Multiple magnetic bead purification inlets 410 can be provided, or multiple solutions can be shared; this application does not impose undue limitations on this. For example, three inlets can be provided to respectively input the solution used for in vitro transcription, the elution buffer, and the washing buffer. Furthermore, in some examples, a storage container for storing solutions can be provided at the magnetic bead purification inlet 410.

[0153] For example, please refer to Figure 19 The inlet and outlet of the magnetic bead purification container 420 can be connected by pipelines to form a magnetic bead purification circulation loop, thereby allowing the solution to be circulated multiple times to achieve better magnetic bead purification effect.

[0154] Further, the magnetic bead purification container 420 can be provided with an exhaust port in addition to the inlet and outlet for solution inlet and outlet. The exhaust port is connected to an exhaust end 430. In addition, a gas collection container or the like can be provided at the exhaust end 430.

[0155] In use, the gas in the pipeline and various components can be exhausted through the exhaust port.

[0156] In some examples, a liquid sensor can also be provided on the pipeline between the exhaust port and the exhaust end 430.

[0157] When the magnetic bead purification process module 400 starts to work, the solution starts to enter the pipeline and move to the magnetic bead purification container 420 under the drive of the pump assembly or the like. The gas in the pipeline and the magnetic bead purification container 420 is pushed out and exits through the exhaust port. Until the solution nearly fills the magnetic bead purification container 420, the solution starts to flow out of the exhaust port. When the liquid sensor detects the solution, it means that the exhaust is complete, and the pipeline between the exhaust port and the exhaust end 430 can be closed by the valve assembly.

[0158] In addition, the magnetic bead purification container 420 is provided with a magnetic source 460, which can be a magnet or the like, for selectively adsorbing magnetic beads. When the magnetic beads in the solution pass through the magnetic bead purification container 420, the magnetic source 460 can exert a magnetic force to adsorb the magnetic beads, so that the magnetic beads are retained in the magnetic bead purification container 420.

[0159] Here, the outlet of the magnetic bead purification container 420 is also connected to a waste liquid outlet end 440, which can be provided with a collection container. After the combination of the required components is completed, for example, the solution passes through the magnetic bead purification container 420 or multiple times through the magnetic bead purification circulation loop, the solution is discharged to the waste liquid outlet end 440.

[0160] Then the magnetic beads are washed, and the washing liquid is introduced into the magnetic bead purification container 420. Here, the magnetic beads can be selectively adsorbed and desorbed by the magnetic source 460, so that the magnetic beads can be better washed in the washing liquid.

[0161] For example, the magnetic source 460 is movably arranged, so that the magnetic beads can be selectively adsorbed and desorbed by moving the position of the magnetic source 460. For example, the magnetic source 460 is directly or indirectly connected to a magnetic source 460 drive mechanism, such as a motor or the like, which drives the magnetic source 460 to move, so as to move between the adsorption and desorption positions.

[0162] Further, the magnetic bead purification container 420 is also provided with a vibration mechanism, such as a vibration motor, so that in the desorption state, the magnetic bead purification container 420 is subjected to a vibration action, so that the magnetic beads can be better washed in the washing liquid.

[0163] After the washing is completed, the washing solution is discharged to the waste solution outlet end 440.

[0164] Here, a magnetic bead purification outlet end 450 is also provided, which is connected to the outlet of the magnetic bead purification container 420. For example, the effective components combined on the magnetic beads can be eluted into the solution by passing the elution solution through the magnetic bead purification inlet end 410, and then the solution is transported to the downstream other components, such as the first purification process module 500, etc. through the magnetic bead purification outlet end 450.

[0165] In addition, the magnetic beads in the solution described above can be automatically added to the solution by a mechanical hand, a magnetic bead supply pipeline connected to the magnetic bead purification process module 400, etc., or can be manually added by artificial means. The examples in the embodiments of the present application do not improperly limit them.

[0166] It can be understood that in addition, the magnetic bead purification process module 400 can also include a plurality of pump assemblies arranged in the pipelines, so as to drive the solution and make the solution flow in the pipelines. The pump assembly can be a peristaltic pump, etc. For example, the pump assembly provided in the embodiment can include P7 and P8. It can be understood that it does not constitute an improper limitation on the present application, and in other embodiments, the pump assembly can also be arranged in other ways, arranged in other positions and arranged in other quantities.

[0167] It can be understood that in addition, the magnetic bead purification process module 400 can also include a plurality of valve assemblies arranged in the pipelines, so as to control the opening and closing of the pipelines. For example, the valve assemblies provided in the embodiments of the present application can include V34 to V40. It can be understood that it does not constitute an improper limitation on the present application, and in other embodiments, the valve assembly can also be arranged in other ways, arranged in other positions and arranged in other quantities, such as being arranged in the components for providing and collecting the solution, etc.

[0168] It can be understood that the pre-purification assembly can simultaneously include the magnetic bead purification process module 400 and the chromatography process module 300, or can only include one of them. When both the magnetic bead purification process module 400 and the chromatography process module 300 are included, the order of their arrangement can be selected as needed, and the examples in the embodiments of the present application do not constitute an improper limitation.

[0169] In some embodiments, the device for preparing nucleic acid drugs in the embodiments of the present application can also include at least one mounting bracket, which can be used to mount the process module. For example, the magnetic bead purification process module 400, etc.

[0170] Here, please refer to Figure 26The mounting bracket includes a frame 1001, and a plurality of first connecting members 1002 and a plurality of second connecting members 1003 arranged on the frame, wherein the first connecting members 1002 extend along a first direction, the second connecting members 1003 extend along a second direction, and the first direction and the second direction are staggered. For example, the first direction is a vertical direction, and the second direction is a horizontal direction. Of course, in other embodiments, the first direction and the second direction are not limited to this arrangement.

[0171] Here, since the first connecting members 1002 and the second connecting members 1003 are staggered with each other, a plurality of staggered points are formed in the frame, which can be used to mount at least one of various different components, such as the magnetic bead purification container 420, the valve assembly, the pump assembly, etc. Thus, after completing the process flow, the tubing and other consumables can be quickly replaced, and since the positions of the components for multiple uses are fixed, the operation of replacing the tubing and other consumables can be very convenient and can be easily achieved by a mechanical hand or other mechanical means.

[0172] In some embodiments, the bottom end of the first connecting member 1002 can also be provided with a hook structure 1004 to connect the required components.

[0173] It can be understood that the mounting bracket is not only limited to being used to mount the magnetic bead purification process module 400, but can also be used to mount other process modules, and the principle is the same.

[0174] Please refer to Figure 1 and Figure 2 The device for preparing a nucleic acid drug can also include an in vitro transcription device arranged upstream to provide a drug solution completed by in vitro transcription, which can then be supplied to the first purification process module 500, or can be supplied to the pre-purification assembly first and then to the first purification process module 500. That is, the in vitro transcription device can be located upstream of the pre-purification assembly and the first purification process module 500.

[0175] Here, it can include a pipetting unit 100 and a mixing unit 200.

[0176] The pipetting unit 100 can be used to pipette at least two reactants into a reaction vessel 12 (the reaction vessel 12 can be seen in Figure 7 The mixing unit 200 can be used to control the reaction vessel 12 within a preset temperature range and mix the reactants in the reaction vessel 12 to achieve in vitro transcription.

[0177] Thus, by arranging the pipetting unit 100 and the mixing unit 200, in vitro transcription operation can be effectively achieved, and compared with the operation mode of adding various reactants to a stirred tank by manual operation in the prior art, the efficiency is improved.

[0178] The reactants are usually liquid reagents, which can be stored in the reactant container before the in vitro transcription operation. The reactant container can be a test tube, other glass bottle or other container, for example, it can be a Schlenk bottle. The number and type of added reactants will vary according to the actual process requirements. The subsequent exemplary description in the embodiments of the present application does not constitute undue limitation, and those skilled in the art can adjust the number and type of reactants according to actual needs.

[0179] Here, please refer to Figure 1 In order to facilitate the arrangement of various components, a work platform 11 can be provided, and various components can be arranged on the work platform 11. For example, the pipetting unit 100 and the mixing unit 200 can be arranged on the work platform 11. Of course, in other embodiments, the work platform 11 can not be provided, and the examples in the present application do not constitute undue limitation.

[0180] Exemplarily, the in vitro transcription process module can further include a refrigeration compartment 160, a waste liquid compartment 170 and a buffer container 180. The refrigeration compartment 160 is used to refrigerate the reactants, because part of the reactants need to be stored in an appropriate temperature range. The waste liquid compartment 170 is used to collect the waste liquid generated during the process operation. The waste liquid outlet of the in vitro transcription process module or other process module can be connected to the waste liquid compartment 170. The buffer container 180 can be used to store qualified liquid medicine after the in vitro transcription process is completed, so as to be supplied to other process modules subsequently.

[0181] Exemplarily, at least part of the refrigeration compartment 160 and the waste liquid compartment 170 are located below the work platform 11, so as to make full use of the space below the work platform, improve the compactness of the overall process module, and reduce the occupied area. The buffer container 180 is arranged above the work platform, so as to facilitate subsequent use and provide to other process modules.

[0182] In addition, the work platform 11 is further provided with a refrigerated reagent storage area 191, a normal temperature reagent storage area 192 and a pipette tip storage area 193. The refrigerated reagent storage area 191 can be located at the refrigeration compartment 160. Exemplarily, the refrigerated reagent storage area 191, the normal temperature reagent storage area 192 and the pipette tip storage area 193 are located on the same side of the pipetting unit 100. Further, the refrigerated reagent storage area 191, the normal temperature reagent storage area 192, the pipette tip storage area 193 and the waste liquid compartment 170 are located on the same side of the pipetting unit 100, so as to facilitate the pipetting unit 100 to take and discard.

[0183] In addition, a laminar flow device can be arranged above the work platform 11, so that each device can be located in a laminar flow environment, thereby achieving sterile isolation.

[0184] Here, refer to Figure 3 The taking unit 100 comprises a first taking member 120 and a first taking driving mechanism 110 connected therewith, the first taking driving mechanism 110 being configured to drive the first taking member 120 to move so as to take at least two reactants into the reaction vessel 12.

[0185] For example, the first taking driving mechanism 110 can comprise a first lateral moving mechanism 111, a first rotating mechanism 112 and a first vertical moving mechanism 113, the first rotating mechanism 112 being arranged on the first lateral moving mechanism 111, whereby the first lateral moving mechanism 111 can drive the first rotating mechanism 112 to move laterally. The first vertical moving mechanism 113 is arranged on the first rotating mechanism 112, whereby the first rotating mechanism 112 can drive the first vertical moving mechanism 113 to rotate. The first vertical moving mechanism 113 is connected to the first taking member 120, whereby the first taking member 120 can be driven to move vertically.

[0186] Further, the first taking member 120 can be driven by the first taking driving mechanism 110 to move laterally, rotate in the horizontal plane and move vertically.

[0187] For example, the first lateral moving mechanism 111 can comprise a linear module arranged laterally; the first rotating mechanism 112 can be a motor directly or indirectly connected to the slider of the first lateral moving mechanism 111 through a connecting member; the first vertical moving mechanism 113 can comprise a linear module arranged vertically, which is directly or indirectly connected to the first rotating mechanism 112 through a connecting member; and the first taking member 120 is connected to the slider of the first vertical moving mechanism 113.

[0188] Of course, it can be understood that the structure of the first taking driving mechanism 110 and the structure and connection position of each component thereof are not limited to the above examples, as long as the first taking member 120 can be driven to move to the desired position.

[0189] For example, the first taking member 120 can comprise a pipette tip 121 and a pressure source 122 connected to the pipette tip 121 to form a negative pressure for adsorbing reactants. For example, the pressure source 122 can be a pump or the like. By changing the pressure of the pressure source 122, the pipette tip 121 can be used to suck and release reactants.

[0190] For example, the first pipetting member 120 further comprises a tip mounting portion 123, which can be connected to the pipetting tip 121 in a detachable manner by means of plugging or the like. In addition, the tip mounting portion 123 can be provided with an air channel, so that the pipetting tip 121 mounted on the tip mounting portion 123 can be connected to the pressure source 122 in a cooperative manner.

[0191] For another example, the pipetting tip 121 can be a disposable Tip head or the like, and different pipetting tips 121 can be replaced when different reactants are pipetted.

[0192] In some examples, the first rotating mechanism 112 can be further provided with a rotary encoder, and the rotary encoder can be used to obtain rotary parameters, which can include the angular displacement, angular velocity or the like of the output shaft of the first rotating mechanism 112. In addition, a pipetting tip placement area can be provided in advance, and a plurality of pipetting tips 121 can be arranged in the pipetting tip placement area to be connected to the tip mounting portion 123 in a cooperative manner. The position parameters of the plurality of pipetting tips 121 can be obtained by pre-positioning, and the rotary parameters required to move to the position of each pipetting tip 121 can be obtained by calculating the position of the tip mounting portion 123, the position of the first lateral moving mechanism 111 and the position parameters of the pipetting tips 121. Thus, the tip mounting portion 123 can be accurately moved to the position of the pipetting tip 121 and connected to the pipetting tip 121 in a cooperative manner by controlling the rotary parameters of the rotary encoder.

[0193] In addition, in some examples, the pressure source 122 can be used to intermittently form negative pressure, so that the reactant can be repeatedly sucked and released by repeatedly changing the negative pressure to stop or the positive pressure to negative pressure, i.e., the reactant can be agitated by changing the air pressure, so that the reactant can be mixed.

[0194] In some embodiments, please continue to refer to Figure 3 , the pipetting unit 100 can further comprise a second pipetting member 140 and a second pipetting driving mechanism 130 connected in a cooperative manner. The second pipetting driving mechanism 130 is used to drive the second pipetting member 140 to move, so as to pipette the reactant container. Thus, the reactant container can be pipetted to the required position.

[0195] In addition, the reactant container can further comprise a cover (not shown in the figure), and the second pipetting member 140 can be used to pipette the cover, so as to realize the opening operation. That is, the second pipetting member 140 can be used to pipette at least one of the reactant container and the cover.

[0196] The cooperative connection between the cover and the reactant container can be a threaded connection, an interference fit or the like. It can be understood that the examples in the present embodiment do not constitute undue limitation.

[0197] Further, the second moving and taking driving mechanism 130 can drive the second moving and taking member 140 to move to the required position.

[0198] Further, through the setting of the second moving and taking driving mechanism 130, the second moving and taking member 140 can be driven by the second moving and taking driving mechanism 130 to realize the lateral movement, the rotation in the horizontal plane and the vertical movement.

[0199] For example, the second lateral moving mechanism 131 can include a linear module arranged laterally; the second rotating mechanism 132 can be a motor directly or indirectly connected to the slider of the second lateral moving mechanism 131 through a connecting member; the second vertical moving mechanism 133 can include a linear module arranged vertically, which is directly or indirectly connected to the second rotating mechanism 132 through a connecting member; and the second moving and taking member 140 is connected to the slider of the second vertical moving mechanism 133.

[0200] Of course, it can be understood that the structure of the second moving and taking driving mechanism 130 and the structure and connection position of each component thereof are not limited to the above examples, as long as the second moving and taking member 140 can be driven to move to the required position.

[0201] For example, the second moving and taking member 140 can be a motor or a pneumatic gripper or a mechanical hand or the like.

[0202] In some embodiments, referring to Figure 2 The aforementioned moving and taking unit 100 can further include a clamping mechanism 150 for clamping and fixing the reactant container. For example, the second moving and taking member 140 can move the reactant container to the position of the clamping mechanism 150, and the clamping mechanism 150 clamps and fixes the reactant container.

[0203] Here, for example, referring to Figure 4 The clamping mechanism 150 includes a clamping member 151 and a clamping driving mechanism (not shown in the figure) connected thereto. The clamping member 151 can be a gripper or the like, and the clamping driving mechanism can be a motor or the like. When the second moving and taking member 140 moves the reactant container to the position of the clamping member 151, the clamping driving mechanism drives the clamping member 151 to move to clamp and fix the reactant container.

[0204] In this case, a plurality of clamping mechanisms 150 can be provided as needed, for example, two clamping mechanisms 150 are provided side by side in the schematic view shown. Figure 4 Of course, the examples in the embodiments of the present application do not constitute improper limitations thereon, and in other embodiments, the clamping mechanism 150 can also be provided in other quantities, and the arrangement position thereof can also be different.

[0205] Referring to Figure 5 , the mixing unit 200 described above can include a carrier 210, a mixing driving mechanism 220, and a temperature control mechanism (not shown in the figure).

[0206] The carrier 210 is used to detachably fix the reaction vessel 12, the mixing driving mechanism 220 is connected to the carrier 210 to drive the carrier 210 to reciprocate, and the temperature control mechanism is directly or indirectly connected to the reaction vessel 12 to transfer heat to the reaction vessel 12.

[0207] Thus, at the mixing unit 200, the reactants can be controlled by the temperature control mechanism within a preset temperature range and driven by the mixing driving mechanism 220 to be mixed uniformly, so as to realize enzyme reaction and in vitro transcription.

[0208] Referring to Figure 6 , the mixing driving mechanism 220 includes a power source 221 and an eccentric transmission structure connected in cooperation, and the carrier 210 is connected to the eccentric transmission structure. Thus, under the drive of the power source 221, the carrier 210 can rotate through the transmission of the eccentric transmission structure. Since the reaction vessel 12 is detachably fixed on the carrier 210, the carrier 210 can further drive the reaction vessel 12 to rotate, so as to realize the shaking of the reactants in the reaction vessel 12.

[0209] Exemplarily, the power source 221 can be a motor or the like. Exemplarily, the eccentric transmission mechanism includes a driving eccentric wheel 222, which is transmissionally connected to the output shaft of the power source 221. The driving eccentric wheel 222 is connected with a first eccentric transmission member 223 arranged eccentrically, and specifically, the first eccentric transmission member 223 can be arranged non-coaxially with the output shaft of the power source 221. The first eccentric transmission member 223 is used to connect the carrier 210, and in some examples, the end of the first eccentric transmission member 223 away from the driving eccentric wheel 222 can extend in the radial direction to form a carrier surface for connecting the carrier 210, so as to improve the stability of the connection.

[0210] In further embodiments, the eccentric transmission mechanism can further be provided with a passive eccentric wheel 224 rotatably arranged on a base 226, and a second eccentric transmission member 225 eccentrically arranged on the passive eccentric wheel 224, in particular, the second eccentric transmission member 225 can be arranged non-coaxially with the center of the passive eccentric wheel 224. The second eccentric transmission member 225 is also used to connect the carrier 210, so as to improve the stability of the carrier 210 in motion. In some examples, the second eccentric transmission member 225 can extend in a radial direction at one end close to the carrier 210, so as to form a carrier surface for connecting the carrier 210, thereby improving the stability of the connection. Further, the area of the carrier surface of the second eccentric transmission member 225 can be greater than the area of the carrier surface of the first eccentric transmission member 223.

[0211] In some examples, the passive eccentric wheel 224 is arranged in a plurality, and the plurality of passive eccentric wheels 224 are arranged at intervals around the circumference of the driving eccentric wheel, for example, can be uniformly arranged at intervals. For example, in Figure 6 , 3 passive eccentric wheels 224 are uniformly arranged at intervals around the circumference of 1 driving eccentric wheel. Of course, the examples in the present embodiments do not constitute undue limitations thereon.

[0212] Please refer to Figure 5 , the carrier 210 can include an insulation container 212, which can be arranged on the aforementioned hybrid drive mechanism 220 to be driven and reciprocated by the hybrid drive mechanism 220, for example, the insulation container 212 can be arranged directly or indirectly on the first eccentric transmission member 223 and the second eccentric transmission member 225. Exemplarily, the carrier 210 includes an insulation seat 211, an insulation container 212 and an insulation cover 213, the insulation seat 211 is arranged on the first eccentric transmission member 223 and the second eccentric transmission member 225, the insulation container 212 is assembled in the insulation seat 211, and the insulation container 212 has an openable insulation cover 213.

[0213] Please refer to Figure 7 , which shows that the reaction vessel 12 is placed in the insulation container 212, and the insulation cover 213 is opened and removed, exemplarily the reaction vessel 12 here is a conical flask. Among them, the insulation cover 213 can be removed by the aforementioned second removal member 140, so as to realize opening and removal.

[0214] Exemplarily, please combine Figure 8 and mainly refer to Figure 9 , at least two elastic members 214, such as spring top wires, can be arranged in the insulation container 212, for example, the elastic members 214 can be arranged at intervals in the circumferential direction. Exemplarily, there are three elastic members 214 arranged at intervals in the circumferential direction here.

[0215] Thus, when the reaction vessel 12 is located in the heat preservation container 212, the elastic member 214 is abutted between the heat preservation container 212 and the reaction vessel 12. When the mixing driving mechanism 220 drives the heat preservation container 212 and the reaction vessel 12 to move, the elastic member 214 helps to achieve the buffering and positioning effects, preventing the inner wall of the heat preservation container 212 and the outer wall of the reaction vessel 12 from colliding with each other, and at the same time, the elastic member 214 also plays a positioning role on the reaction vessel 12, so as to facilitate the clamping and moving of the reaction vessel 12.

[0216] The temperature control mechanism can include a heating assembly (not shown in the figure), which can be arranged in the heat preservation container 212 or at the bottom of the heat preservation container 212, so as to heat the reaction vessel 12 in the heat preservation container 212.

[0217] In addition, in some embodiments, referring to Figure 5 The mixing unit 200 can further include an inclination assembly 240 connected to one side of the carrier 210, so as to drive one side of the carrier 210 to lift up, so that the carrier 210 and the reaction vessel 12 thereon are in an inclined state, thereby facilitating the taking out of the solution after the reaction.

[0218] For example, the inclination assembly 240 can include an inclination motor 241, which can be directly or indirectly connected to a connecting frame 243, and the mixing driving mechanism 220 and the carrier 210 can be directly or indirectly arranged on the connecting frame 243, so that when the inclination motor 241 is started, the inclination of the mixing driving mechanism 220 and the carrier 210 can be achieved. Here, a speed reducer 242 can be transmissionally connected between the inclination motor 241 and the carrier 210.

[0219] In some embodiments, referring to Figure 5 The mixing unit 200 can further include a positioning assembly 244 for clamping and fixing the reaction vessel 12, so as to move the cover of the reaction vessel 12 by the second moving member 140. The positioning assembly 244 can be an electrically driven clamping jaw, a pneumatically driven clamping jaw, etc.

[0220] When the second moving member 140 moves the cover of the reaction vessel 12, the positioning assembly 244 can clamp the neck of the reaction vessel 12 to achieve fixation, so that the second moving member 140 can facilitate the moving of the cover of the reaction vessel 12.

[0221] In some embodiments, referring to Figure 10The buffer container 180 is also provided. Exemplarily, the buffer container 180 can be connected to the reaction vessel 12 through a suction pipe assembly. For example, after the reaction vessel 12 is tilted by the tilting assembly 240, the suction head of the suction pipe assembly is driven and moved into the reaction vessel 12 by a motor, a mechanical hand or other mechanism, so that the liquid medicine is sucked into the buffer container 180 through the pipeline of the suction pipe assembly and through the pump or other components arranged in the pipeline.

[0222] In some embodiments, the buffer container 180 is assembled on a base 181. Please refer to Figure 11 The bottom of the buffer container 180 is provided with a magnetic rotor 1801. Please also refer to Figure 12 The base 181 is provided with a magnetic driving member 1811, which is used to generate a magnetic field driving force to drive the magnetic rotor 1801 to rotate, thereby realizing the mixing of the liquid medicine.

[0223] The base 181 can be provided with a first positioning structure 1812, and the buffer container 180 can be provided with a second positioning structure 1802, so that the two can be quickly matched and disassembled. For example, one of the first positioning structure 1812 and the second positioning structure 1802 is a protrusion, and the other is a groove, and the two can be interference fit to realize clamping and the like.

[0224] In some embodiments, please refer to Figure 10 The base 181 can also be provided with a weighing assembly 1813 to weigh the liquid medicine in the buffer container 180.

[0225] In some embodiments, in order to better realize in vitro transcription, a premixing unit can also be provided upstream of the mixing unit 200 to better realize the mixing between the reactants before the reaction. In addition, in some embodiments, the premixing assembly can also be used to realize the IVT reaction and the co-transcription capping reaction. In some embodiments, the reactants can also be further added and mixed to complete the tailing reaction. After the completion of the reaction, the enzyme termination reaction is performed.

[0226] The premixing unit can include a premixing container and a premixing assembly. The premixing assembly can include a premixing carrier and a premixing driving mechanism connected to the premixing carrier to drive the premixing carrier to reciprocate to realize mixing. Exemplarily, the premixing driving mechanism includes a premixing motor connected to the premixing carrier through an eccentric transmission member to drive the premixing carrier to move. The premixing carrier can be a carrier table or a clamping jaw, etc.

[0227] In some examples, the structure of the premixing assembly can also be the same as or similar to that of the aforementioned mixing driving mechanism 220.

[0228] In actual use, the reagents are loaded into the reagent containers before being pipetted by the first pipetting member 120, and the reagent container of any reagent can be used as a premixing container. Thus, the reagent container can be used as a premixing container, thereby reducing the consumables and also reducing the process steps of pipetting reagents.

[0229] In some embodiments, the carrier 210 reciprocates along a first trajectory, and the premixing carrier reciprocates along a second trajectory, the first trajectory being different from the second trajectory. For example, the first trajectory is arranged along a horizontal plane, and the second trajectory is arranged along a vertical plane. By mixing in different directions, a better mixing effect can be achieved.

[0230] In some embodiments, the carrier 210 reciprocates at a first frequency, and the premixing carrier reciprocates at a second frequency, the first frequency being higher than the second frequency. Thus, a better premixing can be achieved in the early stage, and the reaction requirements of the enzyme reaction can be met by the reciprocation at the second frequency in the later stage.

[0231] Correspondingly, the present application also provides a nucleic acid drug preparation method, which can use the device for preparing a nucleic acid drug provided in any of the preceding embodiments.

[0232] Please refer to Figure 27 The method comprises the following steps S400 to S600.

[0233] In step S400, the input solution is purified by the first purification process module 500.

[0234] Exemplarily, step S400 comprises a purification step, which comprises the following steps.

[0235] The solution is caused to flow through the first separation and purification device 520 multiple times by the first circulation loop.

[0236] The displacement solution is added to the first mixing container 525 through the first displacement solution input end 526, and the displacement solution and the solution are caused to circulate in the first circulation loop and flow through the first separation and purification device 520 multiple times.

[0237] After the purification step, a solution output step is further provided, which comprises the following steps.

[0238] The displacement solution is added to the first separation and purification device 520 through the first displacement solution input end 526 to push out the purified solution from the first separation and purification device 520.

[0239] The solution is caused to flow to the first filtration assembly 531 and flow to the first purification collection end 530 after filtration.

[0240] After the solution outputting step, a post-processing step is further arranged, which includes the following steps.

[0241] The gas is input through the first gas input end 550, and flows to the second waste liquid collection end 541 after flowing through the first filter assembly 531.

[0242] When the gas flows through the first filter assembly 531, whether the first filter assembly 531 is damaged is detected by the first detection sensor 551.

[0243] In step S500, based on the purified solution, a lipid nanoparticle is prepared by a lipid nanoparticle preparation process module.

[0244] The method for preparing the lipid nanoparticle is a prior art, and the embodiments of the present application will not make too much description.

[0245] In step S600, the solution containing the lipid nanoparticle is purified by the second purification process module 700.

[0246] The step S600 includes a pre-preparation step, which includes the following steps.

[0247] The pure water is input through the second pre-preparation input end 740, and flows to the third waste liquid collection end 724 after flowing through the second separation purification device 720.

[0248] The alkali solution is input through the second pre-preparation input end 740, and flows to the third waste liquid collection end 724 after flowing through the second separation purification device 720.

[0249] The pure water is input again through the second pre-preparation input end 740, and flows to the third waste liquid collection end 724 after flowing through the second separation purification device 720.

[0250] The balancing solution is input through the second pre-preparation input end 740 for rinsing.

[0251] In some examples, other steps after the pre-preparation step are similar to step S400, and specific descriptions can be referred to the descriptions in other embodiments of the present application. In order to avoid that the application file is too long, the steps will not be described again.

[0252] In some embodiments, before the solution is purified by the first purification process module 500, a magnetic bead purification operation is further performed by the magnetic bead purification process module 400, and the magnetic bead purification operation includes the following steps.

[0253] The solution is input into the magnetic bead purification circulation loop through the magnetic bead purification input end 410, and circulates for several times.

[0254] The magnetic beads are adsorbed by the magnetic force source 460, and the magnetic beads are retained in the magnetic bead purification container 420, and the solution is discharged to the waste liquid outlet end 440.

[0255] The washing liquid is introduced through the magnetic bead purification inlet end 410, the magnetic force source 460 is removed, so that the magnetic beads are released and contacted with the washing liquid, and the washing liquid and the magnetic beads are vibrated by the vibration mechanism, and after the first preset time, the magnetic force source 460 is moved back and the magnetic beads are fixed, and then the washing liquid is discharged to the waste liquid outlet end 440.

[0256] The elution liquid is introduced through the magnetic bead purification inlet end 410, the magnetic force source 460 is removed, so that the magnetic beads are released and contacted with the elution liquid, and the elution liquid and the magnetic beads are vibrated by the vibration mechanism, and after the second preset time, the magnetic force source 460 is moved back and the magnetic beads are fixed, and the elution liquid is transported to the downstream other components through the magnetic bead purification outlet end 450.

[0257] The first preset time and the second preset time are both set according to the process requirements and the actual situation, and the two can be the same or different, and the examples in the present application do not constitute improper limitation.

[0258] In some embodiments, before the solution is purified by the first purification process module 500, a chromatography operation is performed by the chromatography process module 300, and the chromatography operation includes the following steps.

[0259] The solution is input into the chromatography column.

[0260] The chromatography column is gradient eluted at least twice by the elution solution, and the concentration of the elution solution used in each gradient elution is different.

[0261] The chromatography column is eluted, and the drug solution obtained after elution is collected.

[0262] In some embodiments, before the magnetic bead purification operation, or the chromatography operation, or the first purification operation, an in vitro transcribed solution is obtained by the in vitro transcription device, and the above operations are performed on the solutions.

[0263] In some embodiments, the preparation method of the nucleic acid drug solution further includes an in vitro transcription method, which can use the in vitro transcription process module provided in any of the preceding embodiments. The in vitro transcription method is used to prepare a drug solution for subsequent first purification and / or pre-purification operations.

[0264] Here, the in vitro transcription method includes the following steps S100 to S200.

[0265] In S100, at least two reactants are removed to the reaction vessel 12 by the removal unit 100.

[0266] Here, in some embodiments, before S100, the at least two reactants can also be premixed by a premixing assembly. Illustratively, when premixing is performed, the reactant container of any reactant is used as a premixing container.

[0267] Here, in some embodiments, when any of the reactants is removed by the removing unit 100, negative pressure is intermittently formed to mix the reactants.

[0268] In S200, the reaction vessel 12 is driven to move back and forth by the mixing unit 200, and the temperature of the reaction vessel 12 is controlled within a preset temperature range to achieve enzyme reaction.

[0269] Illustratively, the mixing unit 200 controls the temperature of the reaction vessel 12 to be 37 degrees and incubates the reactants therein for 3H. Then, other solutions are injected into the reaction vessel 12 again by the removing unit 100, and the reaction vessel 12 is again subjected to constant temperature oscillation operation. It can be understood that the specific temperature, duration, and other parameters of constant temperature oscillation are related to the specific process, and in different embodiments, they can have different choices, and the examples in the embodiments of the present application do not constitute undue limitations.

[0270] In some embodiments, after the enzyme reaction is completed, one side of the carrier 210 is lifted by the tilting assembly 240 to facilitate the removal of the solution after the reaction.

[0271] In the in vitro transcription process module and the in vitro transcription method provided in the embodiments of the present application, the in vitro transcription process module includes a first removing piece 120 and a first removing driving mechanism 110 connected in cooperation, the first removing driving mechanism 110 drives the first removing piece 120 to move to remove at least two reactants into a reaction vessel 12; then, the reaction vessel 12 is driven to move back and forth by a mixing unit 200, and the mixing unit 200 transmits heat to the reaction vessel 12 by a temperature control mechanism of the mixing unit 200 to achieve enzyme reaction. Thus, efficient in vitro transcription operation is achieved.

[0272] In addition, at least one premixing can be performed before the enzyme reaction to improve the effect and efficiency of in vitro transcription.

[0273] In addition, through the cooperation of the second removing piece 140 and the second removing driving mechanism 130, the efficiency of in vitro transcription operation can be better improved.

[0274] After the in vitro transcription operation is completed, through the steps of first purification operation, lipid nanoparticle preparation, second purification operation, etc., the solution is purified and prepared into a lipid nanoparticle, and through the two purifications, the effective ingredient of the nucleic acid drug obtained finally is improved.

[0275] Furthermore, the relevant operations can be carried out using automated equipment for preparing nucleic acid drugs, eliminating the need for manual operation of the entire process and thus improving preparation efficiency.

[0276] Example 1

[0277] Here, the in vitro transcription operation in the preparation method of nucleic acid drugs is explained using the example of two reactants. It is understood that unless otherwise specified, the order of the steps described in this application does not represent a restriction on their order.

[0278] In specific operation, the second transfer member 140 transfers the two reactant containers to the clamping mechanism 150, which clamps and secures the two reactant containers. Furthermore, the second transfer member 140 can also be used to remove the lids of the reactant containers to open them.

[0279] The first transfer element 120 moves to the position of one of the reactant containers and repeatedly draws in and releases the reactants in the reactant container by intermittently creating negative pressure, thereby achieving mixing.

[0280] After mixing, the first transfer member 120 transfers the reactant to the reactant container of another reactant.

[0281] The second transfer member 140 transfers a reactant container containing two reactants to a premixing unit, which shakes the reactant container to achieve premixing.

[0282] Exemplarily, the aforementioned mixing and / or premixing steps can achieve the mixing of at least two reactants, thereby enabling the IVT reaction and co-transcriptional capping reaction. In some embodiments, reactants may be further added and mixed to complete the tailing reaction. After these reactions are completed, an enzyme termination reaction is performed.

[0283] After premixing, the first transfer device 120 transfers the solution from the reactant container to the reactor dish 12, and the second transfer device 140 closes the insulated lid 213 and / or the lid of the reactor dish 12. Here, the drug solution is incubated and the enzyme-terminating reaction is initiated, for example, by incubating at 37°C for 3 hours.

[0284] The reactor vessel 12 is placed on the support 210. The temperature control mechanism heats the reactor vessel to a preset temperature range, and the mixing drive mechanism 220 drives the reactor vessel 12 to reciprocate to realize the enzyme reaction.

[0285] After the enzyme reaction is completed, the second pipettor 140 opens the heat preservation cover 213 and / or the cover of the reaction vessel 12. When the cover of the reaction vessel 12 is opened, the reaction vessel 12 can be clamped by the positioning assembly 244 to facilitate the second pipettor 140 to pipette the cover of the reaction vessel 12.

[0286] After the cover is removed, the tilting assembly 240 tilts the reaction vessel 12 to facilitate the removal of the solution.

[0287] Embodiment 2

[0288] When more reactants are required according to the process requirements, the second pipettor 140 can be used to add more reactants according to the process requirements.

[0289] For example, the second pipettor 140 can be used to pipette three reactants into the reactant container of any one of the reactants for pre-mixing.

[0290] For another example, after or before the first pipettor 120 pipettes the solution in the pre-mixed reactant container into the reaction vessel 12, the first pipettor 120 can be used to add other reactants to the reaction vessel 12.

[0291] Embodiment 3

[0292] When the first purification operation is performed, a pre-preparation step is first performed.

[0293] In the pre-preparation step, pure water can be input through the first pre-preparation inlet end 540, and the pure water flows through the first separation and purification device and then flows to the second waste liquid collection end 541, so as to realize the cleaning of the hollow fiber and the like.

[0294] Then, alkali solution can be input through the first pre-preparation inlet end 540, and the alkali solution flows through the first separation and purification device and then flows to the second waste liquid collection end 541. Then, pure water can be input again for cleaning, and the flow path is the same.

[0295] Then, the balance liquid can be input through the first pre-preparation inlet end 540 for rinsing. The balance liquid flows through the first separation and purification device and then flows to the first waste liquid collection end 524 and the second waste liquid collection end 541 respectively.

[0296] During the rinsing of the balance liquid, each first sensing assembly 542 in the pipeline can be calibrated. For example, the first sensing assembly 542 includes a PH sensor, and the PH sensor can be calibrated by comparing the value when the balance liquid flows through the PH sensor with a reference value.

[0297] After the pre-preparation step is completed, the purification step is performed.

[0298] In the purification step, the solution from the upstream, such as the solution from the in vitro transcription device, can be circulated in the first circulation loop, and then can flow through the first separation and purification device multiple times to achieve purification.

[0299] Then, the displacement solution can be added to the first mixing container 525 through the first displacement solution input end 526, and the displacement solution and the aforementioned solution can be circulated in the first circulation loop, and then can flow through the first separation and purification device multiple times to achieve purification.

[0300] After the purification step is completed, a solution output step is performed.

[0301] In the solution output step, the displacement solution can be added to the first separation and purification device through the first displacement solution input end 526 to fully push out the purified solution from the first separation and purification device, which helps to reduce loss.

[0302] The displacement solution has a preset amount of input, which is determined by prior calculation to avoid adding too much displacement solution and flowing to the first purification collection end 530 and the first filter assembly 531.

[0303] After that, the solution flows to the first filter assembly 531 and flows to the first purification collection end 530 after filtration.

[0304] After the solution output step is completed, a post-processing step can also be performed.

[0305] In the post-processing step, pure water can be input through the first pre-preparation import end 540, and after the pure water flows through the first separation and purification device, it flows to the second waste liquid collection end 541, thereby achieving cleaning.

[0306] In addition, gas can also be input through the first gas import end 550, and after the gas flows through the first filter assembly, it flows to the second waste liquid collection end 541, thereby helping to empty the liquid in the pipeline. And when the gas flows through the first filter assembly, with the help of the first detection sensor 551 such as a pressure sensor, whether the first filter assembly is damaged can be detected.

[0307] After the first output operation is completed, the produced liquid is transported to the downstream lipid nanoparticle preparation process module through the pipeline for the preparation of lipid nanoparticles.

[0308] After the preparation operation of the lipid nanoparticles is completed, a second purification operation can be performed through the second purification process module 700.

[0309] When performing the second purification operation, a pre-preparation step is first performed.

[0310] In the pre-preparation step, pure water can be input through the second pre-preparation inlet 740. After the pure water flows through the second separation and purification device, it flows to the third waste liquid collection end 724, thereby achieving the cleaning of hollow fibers, etc.

[0311] Then, alkaline solution is introduced through the second pre-preparation inlet 740. After flowing through the second separation and purification device, the alkaline solution flows to the second waste liquid collection end 541. Then, pure water can be introduced again for cleaning, and the flow path is the same.

[0312] Then, the equilibration solution can be introduced through the second pre-preparation inlet 740 for rinsing. After flowing through the second separation and purification device, the equilibration solution is divided into two streams, flowing to the third waste liquid collection end 724 and the fourth waste liquid collection end 741 respectively.

[0313] During the rinsing process with the equilibration fluid, each of the second sensing components 742 in the pipeline can be calibrated. For example, the second sensing component 742 includes a pH sensor, which can be calibrated by comparing the value when the equilibration fluid flows through it with a reference value.

[0314] After the preparatory steps are completed, the purification step is carried out.

[0315] In the purification step, the solution from the upstream, such as the solution from the lipid nanoparticle preparation process module, can be circulated in the second circulation loop and then flow through the second separation and purification device multiple times to achieve purification.

[0316] Then, replacement liquid, mother liquor, auxiliary material mother liquor, etc. can be added to the second mixing container 725 through the second replacement liquid inlet, and the replacement liquid and the aforementioned solutions can be circulated together in the second circulation loop, so that they can flow through the second separation and purification device multiple times to achieve purification.

[0317] After the purification step is completed, the solution output step is performed.

[0318] In the solution output step, replacement fluid can be added to the second separation and purification device through the second replacement fluid inlet to fully push the purified solution out of and / or close to the second separation and purification device. This step helps to reduce losses.

[0319] The replacement fluid has a preset flow rate, which is determined by prior calculation to prevent excessive addition of replacement fluid and its flow into the second purification and collection container and the second filter assembly 731.

[0320] Subsequently, the solution flows to the second filtration assembly 731 and, after filtration, flows to the second purification and collection container.

[0321] After the solution output step is completed, a post-processing step can be performed.

[0322] In the post-processing step, pure water can be input through the second pre-preparation inlet end 740, and after the pure water flows through the second separation and purification device, it flows to the fourth waste liquid collection end 741, so as to realize cleaning.

[0323] In addition, gas can also be input through the second gas inlet end 750, and after the gas flows through the second filter device, it flows to the fourth waste liquid collection end 741, thereby helping to empty the liquid in the pipeline. And when the gas flows through the second filter device, by means of the second detection sensor 751 such as a pressure sensor, it can be detected whether the second filter device is damaged.

[0324] Embodiment 4

[0325] Before the first purification operation is performed, a magnetic bead purification operation can be performed through the magnetic bead purification process module 400.

[0326] The solution from the upstream, such as the in vitro transcription device, is added with magnetic beads, and then is input into the magnetic bead purification circulation loop through the magnetic bead purification inlet end 410 and circulates for several times.

[0327] Then, the magnetic source 460 at the magnetic bead purification container 420 is started, and during the solution flow, the magnetic beads are adsorbed by the magnetic source 460, so that the magnetic beads and the solution are separated, the magnetic beads are left in the magnetic bead purification container 420, and the solution is discharged to the waste liquid outlet end 440.

[0328] Then, the washing liquid is input through the magnetic bead purification inlet end 410, and in this process, the magnetic source 460 is removed, so that the magnetic beads are released and contacted with the washing liquid, and at the same time, the washing liquid and the magnetic beads are vibrated by the oscillation mechanism to better contact with each other. After the washing is completed, the magnetic source 460 is moved back and fixes the magnetic beads, and then the washing liquid is discharged to the waste liquid outlet end 440.

[0329] Thereafter, the eluent is input again through the magnetic bead purification inlet end 410, and in this process, the magnetic source 460 is removed, so that the magnetic beads are released and contacted with the eluent, and at the same time, the eluent and the magnetic beads are vibrated by the oscillation mechanism to better contact with each other. After the elution is completed, the magnetic source 460 is moved back and fixes the magnetic beads, and then the eluent is transported to the downstream other components, such as the first purification component, through the magnetic bead purification outlet end 450.

[0330] Embodiment 5

[0331] Before the first purification operation is performed, a chromatography operation can be performed through the chromatography process module 300.

[0332] In the chromatography operation, a calibration solution is first input through the chromatography inlet pipeline 310, and the calibration solution flows from the first port 321 to the fourth port 324 without flowing through the chromatography column, and then enters the chromatography outlet pipeline 330. During this process, the readings of various sensing components in the pipeline are calibrated to confirm that the readings of the sensing components are consistent with the parameters that the calibration solution should have, thereby confirming the state of the sensing components.

[0333] Then, a solution such as an equilibration solution is input through the chromatography inlet pipeline 310, and the solution flows from the first port 321 and the second port 322 to the chromatography column, and then flows from the third port 323 and the fourth port 324 to the chromatography outlet pipeline 330.

[0334] The above steps are preparation steps for the chromatography operation. If the chromatography process module 300 has completed related calibration, column equilibration, and other operations in advance through other means, the above steps can be omitted.

[0335] The solution from the upstream, such as the solution from the in vitro transcription device, is input into the chromatography inlet pipeline 310, and the solution flows from the first port 321 and the second port 322 to the chromatography column, and then flows from the third port 323 and the fourth port 324 to the chromatography outlet pipeline 330. At this time, the required substances are retained in the chromatography column, and other solutions are discharged.

[0336] Then, a washing solution is input into the chromatography column through the chromatography inlet pipeline 310 for washing. The washing solution can be an alkaline solution to discharge the aforementioned other solutions remaining in the chromatography column. Here, in some examples, the washing can be performed more than twice, and each time a washing solution with a different concentration is used for washing to achieve gradient washing.

[0337] Then, an elution solution is input through the chromatography inlet pipeline 310, and the elution solution flows from the first port 321 and the second port 322 to the chromatography column, and then flows from the third port 323 and the fourth port 324 to the chromatography outlet pipeline 330. Thus, the required substances on the chromatography column are eluted and dissolved in the elution solution. The elution solution containing the required substances is input into the subsequent downstream component, such as the first purification process module 500, through the chromatography outlet pipeline 330.

[0338] It can be understood that in the embodiments of the present application, for the purpose of explanation, the names of some required solutions in the chromatography, magnetic bead purification, first purification, second purification, and other steps may be similar or the same, such as elution solution, but in different components, the specific solutions used in the actual process will be determined according to the specific process requirements, and it does not mean that the components of the solutions used in each different component are the same or different.

[0339] It can be understood that the meanings of the terms in the embodiments of the present application are the same, and the specific implementation details of the contents not described in detail for a certain embodiment can be referred to the description in other embodiments, the example illustration and technical effects shown by the foregoing embodiments can be correspondingly implemented, and for the repeated parts, the present embodiment will not make further description.

[0340] The above describes in detail the device for preparing nucleic acid drugs and the nucleic acid drug preparation method provided by the present application, the principles and implementation manners of the present application are described by applying specific examples, the above embodiment description is only for helping to understand the method of the present application and its core idea; meanwhile, for those skilled in the art, according to the idea of the present application, the specific implementation manners and application ranges will have changes, and in view of the above, the content of the specification should not be understood as limiting the present application.

Claims

1. An apparatus for preparing nucleic acid drugs, characterized in that, include: In vitro transcription process module, used to provide the stock solution; The first purification process module is located downstream of the in vitro transcription process module and is used to purify the stock solution. A lipid nanoparticle preparation process module is located downstream of the first purification process module to receive the purified stock solution and prepare it into lipid nanoparticles. The second purification process module is located downstream of the lipid nanoparticle preparation process module to purify the solution containing lipid nanoparticles. An automated control system is used to achieve coordinated control of the in vitro transcription process module, the first purification process module, the lipid nanoparticle preparation process module, and the second purification process module. as well as The mounting bracket includes a frame and a plurality of first connectors and a plurality of second connectors disposed on the frame. The first connectors extend along a first direction and the second connectors extend along a second direction. The first and second directions are staggered to form a plurality of staggered points for mounting various components of the device for preparing nucleic acid drugs. As a result, since the positions of the reusable components are fixed, the operation of replacing consumables is very convenient and easy to implement.

2. The apparatus for preparing nucleic acid drugs according to claim 1, characterized in that, The first purification process module includes: The first separation and purification device has a first inlet end, a first outlet end and a first waste liquid outlet end. The first separation and purification device is configured in a first circulation loop, and the first circulation loop has a first purification input end. A first mixing container is configured in the first circulation loop, with its inlet connected to the first outlet and its outlet connected to the first inlet. The first displacement fluid inlet is connected to the inlet of the first mixing container; and Pump assembly used to drive the flow of solution.

3. The apparatus for preparing nucleic acid drugs according to claim 2, characterized in that, The first purification process module also includes: A first purification and collection end is connected to the first mixing container; and A first filtration component is disposed between the first mixing container and the first purification collection end.

4. The apparatus for preparing nucleic acid drugs according to claim 3, characterized in that, The first purification process module also includes: The first gas inlet is connected to the first filter assembly; and The first detection sensor is used to detect pressure changes in the pipeline where the first filter assembly is located when gas is input into the first filter assembly at the first gas inlet end.

5. The apparatus for preparing nucleic acid drugs according to claim 2, characterized in that, The first purification process module also includes: At least one first pre-prepared inlet; and a second waste liquid collection end; The first separation and purification device is configured between the first pre-preparation inlet and the second waste liquid collection end via a pipeline.

6. The apparatus for preparing nucleic acid drugs according to claim 2, characterized in that, The first mixing container is disposed on a mixing mechanism, the mixing mechanism comprising: Mixing drive component; An eccentric connector is eccentrically connected to the mixing drive. The support member is rotatably connected to the eccentric connector; When the mixing drive unit drives the eccentric connector to move, it can cause the support and the first mixing container to rotate and shake, so as to mix the medicine liquid in the first mixing container.

7. The apparatus for preparing nucleic acid drugs according to claim 1, characterized in that, The second purification process module includes: The second separation and purification device has a second inlet end, a second outlet end and a second waste liquid outlet end. The second separation and purification device is configured in a second circulation loop. The second circulation loop has two first purification input ends. The second mixing container is configured in the second circulation loop, and its inlet is connected to the second outlet end and its outlet is connected to the second inlet end; At least two auxiliary liquid inlets are connected to the inlet of the second mixing container; and Pump assembly used to drive the flow of solution.

8. The apparatus for preparing nucleic acid drugs according to claim 7, characterized in that, The second purification process module also includes: The second purification and collection end is connected to the second mixing container; and The second filtration device is disposed between the second mixing container and the second purification collection end.

9. The apparatus for preparing nucleic acid drugs according to claim 1, characterized in that, At least one set of pre-purification components is also provided upstream of the first purification process module.

10. The apparatus for preparing nucleic acid drugs according to claim 9, characterized in that, The pre-purification component includes a chromatography process module, which includes: The chromatography main pipeline includes a first port and a second port for fluid connection, as well as a third port and a fourth port for fluid connection; The chromatography inlet pipe is connected to the first port; A chromatography column, the inlet of which is connected to the second port and the outlet of which is connected to the third port; The chromatography outlet pipe is connected to the fourth port.

11. The apparatus for preparing nucleic acid drugs according to claim 10, characterized in that, The first port may be selectively connected to the third port, and the second port may be selectively connected to the fourth port.

12. The apparatus for preparing nucleic acid drugs according to claim 10, characterized in that, The first port may be selectively connected to the fourth port.

13. The apparatus for preparing nucleic acid drugs according to claim 10, characterized in that, A bubble sensor is installed in the chromatography inlet pipeline; The equipment for preparing nucleic acid drugs also includes a bubble removal pipeline, which is connected to the chromatography inlet pipeline via a bubble trap.

14. The apparatus for preparing nucleic acid drugs according to claim 10, characterized in that, With two or more chromatography inlet lines provided, the two or more chromatography inlet lines are connected together to a static mixer and then to the chromatography main line, the static mixer having a bend in the flow channel.

15. The apparatus for preparing nucleic acid drugs according to claim 9, characterized in that, The pre-purification component includes a magnetic bead purification process module, which includes: At least one magnetic bead is used for purification at the inlet end; A magnetic bead purification container, with its inlet and outlet connected by pipes to form a magnetic bead purification circulation loop; and A magnetic source, located at the magnetic bead purification container, is used to selectively adsorb magnetic beads.

16. The apparatus for preparing nucleic acid drugs according to claim 15, characterized in that, It also includes an oscillation mechanism connected to the magnetic bead purification container and driving the solution and magnetic beads inside the magnetic bead purification container to oscillate.

17. The apparatus for preparing nucleic acid drugs according to claim 15, characterized in that, The magnetic source includes a magnetic body and a magnetic source driving mechanism. The magnetic source driving mechanism is connected to the magnetic body to drive the magnetic body to move between adsorption and desorption positions.

18. The apparatus for preparing nucleic acid drugs according to claim 1, characterized in that, The automatic control system is used to sequentially introduce the stock solution into the in vitro transcription process module, the first purification process module, the lipid nanoparticle preparation process module, and the second purification process module, and to control the in vitro transcription process module, the first purification process module, the lipid nanoparticle preparation process module, and the second purification process module to perform process operations.

19. A method for preparing a nucleic acid drug, using the apparatus for preparing a nucleic acid drug as described in any one of claims 1 to 18, characterized in that, Includes the following steps: The stock solution was prepared by in vitro transcription process using an in vitro transcription process module; The original solution is purified through the first purification process module; The purified stock solution was delivered to the lipid nanoparticle preparation process module, and lipid nanoparticles were prepared through the lipid nanoparticle preparation process module. as well as The solution containing lipid nanoparticles is purified using the second purification process module.

20. The method for preparing nucleic acid drugs according to claim 19, characterized in that, The purification of the stock solution through the first purification process module includes a purification step, which includes: The original solution is passed through the first separation and purification device multiple times via the first circulation loop; The replacement solution is added to the first mixing container through the first replacement solution inlet, and the replacement solution and the original solution are circulated together in the first circulation loop and flow through the first separation and purification device multiple times.

21. The method for preparing nucleic acid drugs according to claim 20, characterized in that, Following the purification step, a solution output step is also provided, which includes: The replacement fluid is added to the first separation and purification device through the first replacement fluid inlet to push the purified original solution out of the first separation and purification device. The purified stock solution flows to the first filtration component and, after filtration, flows to the first purification collection end.

22. The method for preparing nucleic acid drugs according to claim 20, characterized in that, It also includes a post-processing step, which includes: Gas is introduced through the first gas inlet end, and after flowing through the first filter component, the gas flows to the second waste liquid collection end. As the gas flows through the first filter assembly, a first detection sensor detects whether the first filter assembly is damaged.

23. The method for preparing nucleic acid drugs according to claim 19, characterized in that, The purification of the solution containing lipid nanoparticles via the second purification process module includes a pre-preparation step, which includes: Pure water is introduced through the second pre-preparation inlet, and after flowing through the second separation and purification device, it flows to the third waste liquid collection end. The alkaline solution is introduced through the second pre-preparation inlet, and after flowing through the second separation and purification device, it flows to the third waste liquid collection end. Pure water is introduced again through the second pre-preparation inlet. After flowing through the second separation and purification device, the pure water flows to the third waste liquid collection end. The rinsing process involves introducing equilibration fluid through the second pre-prepared inlet.

24. The method for preparing nucleic acid drugs according to claim 19, characterized in that, Before purifying the stock solution through the first purification process module, a magnetic bead purification operation is performed through the magnetic bead purification process module. The magnetic bead purification operation includes: The raw solution is introduced into the magnetic bead purification circulation loop through the magnetic bead purification inlet and circulated several times. The magnetic beads are attracted by a magnetic source and retained in the magnetic bead purification container, while the original liquid is discharged to the waste liquid outlet. Washing liquid is introduced through the inlet of the magnetic bead purification system. The magnetic source is removed, which releases the magnetic bead from its fixation and brings it into contact with the washing liquid. At the same time, the washing liquid and the magnetic bead are vibrated by the oscillation mechanism. After washing for the first preset time, the magnetic source is moved back and fixes the magnetic bead. Then the washing liquid is discharged to the waste liquid outlet. Eluent is introduced through the magnetic bead purification inlet. The magnetic source is removed, causing the magnetic beads to be released from fixation and come into contact with the eluent. The oscillation mechanism causes the eluent and magnetic beads to vibrate. After elution for a second preset time, the magnetic source is moved back and fixes the magnetic beads. The eluent is then transported to other downstream components through the magnetic bead purification outlet.

25. The method for preparing nucleic acid drugs according to claim 19, characterized in that, Before purifying the stock solution using the first purification process module, a chromatography operation is performed using a chromatography process module. The chromatography operation includes: The stock solution is fed into the chromatography column; The chromatography column is subjected to at least two gradient elutions using an elution solution of different concentrations for each gradient elution. The chromatography column was eluted, and the resulting eluted solution was collected.

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