Equipment for preparing nucleic acid medicine and preparation method of nucleic acid medicine

Abstract

The invention relates to the technical field of pharmaceutical equipment and methods, and provides equipment for preparing a nucleic acid medicine and a preparation method of the nucleic acid medicine, through the steps of first purification operation, lipid nanoparticle preparation, second purification operation and the like, purification of a solution is achieved, and the solution is prepared into lipid nanoparticles. The effective components of the finally obtained nucleic acid medicine are increased through two times of purification. Besides, the first purification process module, the lipid nanoparticle preparation process module and the second purification process module which are in fluid connection are arranged, automatic preparation can be achieved, meanwhile, the first purification process module, the second purification process module and other components are correspondingly arranged, and efficient and high-quality nucleic acid medicine preparation can be achieved.

Description

Technical Field

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

[0002] Messenger RNA (mRNA) is a single-stranded RNA that carries genetic information (a product of DNA transcription). Its primary function is to accurately transcribe the genetic information from DNA and translate it into protein on the ribosome. mRNA bulk preparations are pharmaceuticals based on mRNA as their core ingredient. They regulate protein expression by transmitting genetic information and are currently used in vaccine development, gene therapy, and protein replacement therapy.

[0003] At present, the production process of mRNA bulk preparations requires a lot of manual participation, which not only leads to low production efficiency but also makes the solution easily contaminated during the transfer process. Therefore, to address the above problems, an apparatus and method for preparing nucleic acid drugs are proposed. Summary of the Invention

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

[0005] The present application provides an apparatus for preparing a nucleic acid drug, comprising: an in vitro transcription process module for providing a stock solution; a first purification process module, disposed downstream of the in vitro transcription process module, for purifying the stock solution; a lipid nanoparticle preparation process module, disposed downstream of the first purification process module, for receiving the purified stock solution and preparing it into lipid nanoparticles; a second purification process module, disposed downstream of the lipid nanoparticle preparation process module, for purifying a solution containing lipid nanoparticles; and an automatic control system for realizing 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.

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

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

[0008] In some embodiments, the first purification process module further includes: a first gas inlet end connected to the first filter component; and a first detection sensor for detecting pressure changes in the pipeline in which the first filter component is located when gas is input to the first filter component at the first gas inlet end.

[0009] In some embodiments, the first purification process module further includes: at least one first pre-prepared inlet port; and a second waste liquid collection port; wherein the first separation and purification device is configured between the first pre-prepared inlet port and the second waste liquid collection port through a pipeline.

[0010] In some embodiments, the first mixing container is arranged on a mixing mechanism, and the mixing mechanism includes: a mixing drive; an eccentric connecting member, eccentrically connected to the mixing drive; a supporting member, rotatably connected to the eccentric connecting member; when the mixing drive drives the eccentric connecting member to move, it can drive the supporting member and the first mixing container to rotate and shake, so as to mix the medicinal liquid in the first mixing container.

[0011] In some embodiments, the first mixing container includes: a container body; an inlet pipe, which extends into the container body and then extends toward the side wall of the container body; an outlet pipe, which extends to the bottom of the container body; and a stirring member, including a stirring drive mechanism and a stirring part that are connected in a mating manner, and the stirring part is located in the container body.

[0012] In some embodiments, the second purification process module includes: a second separation and purification device having a second inlet, a second outlet and a second waste liquid outlet, 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 being configured in the second circulation loop, and its inlet being connected to the second outlet and its outlet being connected to the second inlet; at least two auxiliary liquid input ends being 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 includes: a second purification collection end connected to the second mixing container; and a second filtering device disposed between the second mixing container and the second purification collection end.

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

[0015] In some embodiments, the pre-purification component includes a chromatography process module, which includes: a chromatography main line, including a first port and a second port connected to the fluid, and a third port and a fourth port connected to the fluid; a chromatography inlet line connected to the first port; a chromatography column, whose inlet is connected to the second port and whose outlet is connected to the third port; and a chromatography outlet line 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 configured in the chromatography inlet pipeline; the apparatus for preparing nucleic acid drugs further comprises a bubble exclusion pipeline, which is connected to the chromatography inlet pipeline through a bubble trap.

[0019] In some embodiments, when two or more chromatography inlet pipelines are provided, the two or more chromatography inlet pipelines are 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 component includes a magnetic bead purification process module, which includes: 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 source located at the magnetic bead purification container for selectively adsorbing magnetic beads.

[0021] In some embodiments, an oscillation mechanism is further included, 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 source includes a magnetic body and a magnetic source driving mechanism, wherein the magnetic source driving mechanism is connected to the magnetic body to drive the magnetic body to move between an adsorbed position and a de-adsorbed position.

[0023] In some embodiments, the automatic control system is used to pass the raw liquid into the in vitro transcription process module, the first purification process module, the lipid nanoparticle preparation process module and the second purification process module in sequence, 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] Accordingly, the present application also provides a method for preparing a nucleic acid drug, which can use any of the aforementioned devices for preparing nucleic acid drugs, and includes the following steps: purifying the solution through a first purification process module; based on the purified solution, preparing lipid nanoparticles through a lipid nanoparticle preparation process module; and purifying the solution containing lipid nanoparticles through a second purification process module.

[0025] In some embodiments, the purification of the solution by the first purification process module includes a purification step, which includes: allowing the solution to flow through a first separation and purification device multiple times through a first circulation loop; adding a replacement fluid to a first mixing container through a first replacement fluid input end, and allowing the replacement fluid and the solution to circulate together 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, and the solution output step includes: adding a replacement fluid to the first separation and purification device through the first replacement fluid input end to push the purified solution out of the first separation and purification device; allowing the solution to flow to the first filter component, and after filtration, flowing to the first purification collection end.

[0027] In some embodiments, a post-processing step is also included, which includes: inputting gas through the first gas inlet end, and the gas flows through the first filter component and then flows to the second waste liquid collection end; when the gas flows through the first filter component, detecting whether the first filter component is damaged by the first detection sensor.

[0028] In some embodiments, the purification of the solution containing lipid nanoparticles by the second purification process module includes a pre-preparation step, which includes: inputting pure water through the second pre-preparation inlet, the pure water flows through the second separation and purification device, and then flows to the third waste liquid collection end; inputting alkali solution through the second pre-preparation inlet, the alkali solution flows through the second separation and purification device, and then flows to the third waste liquid collection end; inputting pure water again through the second pre-preparation inlet, the pure water flows through the second separation and purification device, and then flows to the third waste liquid collection end; inputting balancing liquid through the second pre-preparation inlet for rinsing.

[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, and the magnetic bead purification operation includes: passing the solution into the magnetic bead purification circulation loop through the magnetic bead purification inlet and circulating it several times; adsorbing the magnetic beads by the magnetic source, retaining the magnetic beads in the magnetic bead purification container, and discharging the solution to the waste liquid outlet; passing the washing liquid through the magnetic bead purification inlet, removing the magnetic source, so that the magnetic beads are released and contacted with the washing liquid, and at the same time, the oscillation mechanism causes the washing liquid and the magnetic beads to vibrate, after washing for a first preset time, the magnetic source is moved back and fixed the magnetic beads, and then the washing liquid is discharged to the waste liquid outlet; passing the eluent through the magnetic bead purification inlet, removing the magnetic source, so that the magnetic beads are released and contacted with the eluent, the oscillation mechanism causes the eluent and the magnetic beads to vibrate, after eluting for a second preset time, the magnetic source is moved back and fixed the magnetic beads, and the eluent is transported to other downstream components through the magnetic bead purification outlet.

[0030] In some embodiments, before purifying the solution through the first purification process module, a chromatography operation is performed through a chromatography process module, and the chromatography operation includes: inputting the solution into a chromatography column; gradient eluting the chromatography column at least twice with an elution solution, and the concentration of the elution solution used in each gradient elution is different; 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 nucleic acid drugs and a method for preparing nucleic acid drugs, which achieves purification of the solution and prepares it into lipid nanoparticles through the first purification operation, lipid nanoparticle preparation, and second purification operation. The effective components of the nucleic acid drug finally obtained are increased through the two purification steps.

[0032] In addition, a first purification process module, a lipid nanoparticle preparation process module, and a second purification process module that are fluid-connected are provided to realize automated preparation. At the same time, corresponding settings are made for each component such as the first purification process module and the second purification process module, which helps to achieve efficient and high-quality nucleic acid drug preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 The schematic diagram of the structure of an in vitro transcription process module is shown as an example.

[0034] Figure 2 A top view of an in vitro transcription process module is shown as an example.

[0035] Figure 3 A schematic diagram of the mechanism of a removal unit is shown as an example.

[0036] Figure 4 Exemplary Figure 2A partial enlarged schematic diagram of part A.

[0037] Figure 5 A structural schematic diagram of a mixing unit is shown as an example.

[0038] Figure 6 A structural schematic diagram of a hybrid drive mechanism is shown as an example.

[0039] Figure 7 A schematic structural diagram of a heat-insulating container is shown as an example.

[0040] Figure 8 An example is shown Figure 7 A top half-section view of .

[0041] Figure 9 Exemplary Figure 8 Schematic diagram of PP cross section.

[0042] Figure 10 A schematic diagram illustrating the cooperation between a buffer container and a base is shown as an example.

[0043] Figure 11 A schematic structural diagram of a buffer container is shown as an example.

[0044] Figure 12 A schematic structural diagram of a base for adapting a buffer container is shown as an example.

[0045] Figure 13 A schematic diagram illustrating the steps of an in vitro transcription method is shown.

[0046] Figure 14 The piping diagram of the first purification process module is shown as an example.

[0047] Figure 15 The piping diagram of the second purification process module is shown as an example.

[0048] Figure 16 The schematic diagram of the structure of the mixing bottle is shown as an example.

[0049] Figure 17 The piping diagram of the chromatography process module is shown as an example.

[0050] Figure 18 The schematic diagram of the structure of the magnetic bead purification process module is shown as an example.

[0051] Figure 19 The schematic diagram of the pipeline of the magnetic bead purification process module is shown as an example.

[0052] Figure 20 A structural diagram of a mixing mechanism is shown as an example.

[0053] Figure 21A top view of a mixing mechanism is shown as an example.

[0054] Figure 22 Exemplary Figure 21 Cross-sectional view of section AA.

[0055] Figure 23 The structural diagram of the eccentric connecting piece is shown as an example.

[0056] Figure 24 A schematic structural diagram of a static mixer is shown as an example.

[0057] Figure 25 A top half-section view of a static mixer is shown as an example.

[0058] Figure 26 A structural diagram of an installation frame is shown as an example.

[0059] Figure 27 A schematic flow chart illustrating a method for preparing a nucleic acid drug is shown.

[0060] Explanation of reference numerals in the figure: 11-working platform, 12-reaction vessel, 100-pipetting unit, 110-first pipetting drive mechanism, 111-first lateral movement mechanism, 112-first rotation mechanism, 113-first vertical movement mechanism, 120-first pipetting member, 121-pipette tip, 122-pressure source, 123-tip mounting portion, 130-second pipetting drive mechanism, 131-second lateral movement mechanism, 132-second rotation mechanism, 133 -second vertical moving mechanism, 140-second removing member, 150-clamping mechanism, 151-clamping member, 160-refrigeration chamber, 170-waste liquid chamber, 180-buffer container, 1801-magnetic rotor, 1802-second positioning structure, 181-base, 1811-magnetic drive member, 1812-first positioning structure, 1813-weighing component, 191-refrigerated preparation storage area, 192-normal temperature preparation storage area, 193 pipette tip storage area, 20 0-mixing unit, 210-carrying member, 211-insulating seat, 212-insulating container, 213-insulating cover, 214-elastic member, 220-mixing drive mechanism, 221-power source, 222-driving eccentric wheel, 223-first eccentric transmission member, 224-passive eccentric wheel, 225-second eccentric transmission member, 226-base, 240-tilting assembly, 241-tilting motor, 242-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-drug liquid inlet end, 354-drug liquid outlet end, 355-closing cover, 356-sealing ring, 360-bubble removal pipeline,361-bubble trap, 400-magnetic bead purification process module, 410-magnetic bead purification inlet, 420-magnetic bead purification container, 430-exhaust end, 440-waste liquid outlet, 450-magnetic bead purification outlet, 460-magnetic source, 500-first purification process module, 510-first purification input, 520-first separation and purification device, 521-first inlet, 522-first outlet, 523-first waste liquid outlet, 524-first waste Liquid collection end, 525-first mixing container, 526-first replacement liquid input end, 530-first purification collection end, 531-first filter component, 532-first bubble sensor, 540-first pre-preparation inlet end, 541-second waste liquid collection end, 542-first sensor component, 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-auxiliary liquid input end, 730-second purification collection end, 731-second filter component, 732-second bubble sensor, 740-second pre-preparation inlet end, 741-fourth waste liquid collection end, 742-second sensor component, 750-second gas inlet end, 751-second detection sensor, 760 - Metering Auxiliary Component, 810 - Container Body, 820 - Inlet Pipe, 830 - Outlet Pipe, 840 - Stirring Element, 910 - Mixing Drive Element, 920 - Eccentric Connector, 921 - Shaft, 922 - Base, 930 - Bearing, 940 - Support Element, 950 - Flexible Wall, 960 - Position Sensor, 970 - Weight Sensor, 1001 - Frame, 1002 - First Connector, 1003 - Second Connector, 1004 - Hook Structure. DETAILED DESCRIPTION

[0061] The technical solutions in the embodiments of the present application will be clearly and completely described below in conjunction with the drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without making creative work are within the scope of protection of the present application. In addition, it should be understood that the specific implementation methods 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, unless otherwise specified, the directional words used, such as "up", "down", "left", and "right", generally refer to the up, down, left, and right of the device in actual use or working state, specifically the drawing direction in the accompanying drawings.

[0062] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be understood to indicate or imply relative importance or implicitly specify the quantity of the technical features indicated. Thus, features defined as "first" or "second" may explicitly or implicitly include at least one of these features.

[0063] The present application provides an apparatus for preparing a nucleic acid drug and a method for preparing a nucleic acid drug, each of which is described in detail below. It should be noted that the order in which the following embodiments are described does not limit the preferred order of the embodiments of the present application. Furthermore, in the following embodiments, the description of each embodiment has its own emphasis. For portions not described in detail in one embodiment, please refer to the relevant descriptions of other embodiments.

[0064] The present application provides an apparatus for preparing nucleic acid drugs, comprising a first purification process module 500 (see Figure 14 ), lipid nanoparticle preparation process module and the 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 to prepare lipid nanoparticles.

[0067] The second purification process module 700 is disposed downstream of the lipid nanoparticle preparation process module to purify the solution containing lipid nanoparticles.

[0068] Here, illustratively, each process module is configured with a corresponding disposable consumable assembly, and the upstream disposable consumable assembly is connected to the downstream disposable consumable assembly via a sterile docking method. For example, the disposable consumable assembly may include a pipe and / or a pipe connection structure.

[0069] Here, an automatic control system can also be set up, which is signal-connected to the first purification process module 500, the lipid nanoparticle preparation process module and the second purification process module 700, so that the automatic control system can realize the linkage control of the first purification process module 500, the lipid nanoparticle preparation process module and the second purification process module 700.

[0070] The automatic 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 capabilities.

[0071] For example, the automatic control system can control each process module to carry out the corresponding process flow according to the requirements of different processes and formulas, and transport the raw liquid obtained by the upstream process module to the downstream process module, and enable each process module to process the raw liquid in sequence to obtain the required product.

[0072] The lipid nanoparticle preparation process module uses existing equipment. 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 this application is not necessarily the same as that disclosed herein. The structure of the disclosed document is used as an example here only. There are many lipid nanoparticle preparation process modules in the prior art.

[0073] In some embodiments, see Figure 14 The first purification process module 500 includes a hollow fiber column for performing the purification operation. It is understood that the hollow fiber column is used as an example for the description herein. However, in other embodiments, the hollow fiber column may be replaced with another first separation and purification device 520, such as a membrane package, and the examples in the embodiments of the present application do not constitute an undue limitation thereto.

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

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

[0076] Exemplarily, when performing a purification operation, a replacement fluid is required, so a first replacement fluid input port 526 is also 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 replacement fluid input port 526 and the first outlet port 522 of the aforementioned hollow fiber column, and the outlet of the first mixing container 525 is connected to the first inlet port 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 replacement fluid can be input into the first mixing container 525. Moreover, after the replacement fluid is added, the solution and the replacement fluid are input into the hollow fiber column through the first circulation loop for cyclic concentration, and the waste liquid is discharged into the first waste liquid collection container 340 through the first waste liquid outlet port 523.

[0078] Therefore, in the embodiment of the present application, the solution from the upstream is first circulated and concentrated through the hollow fiber column, and then the concentrated solution and the replacement fluid are circulated and concentrated together, thereby achieving a better purification effect.

[0079] Of course, in some embodiments, the solution from upstream and the replacement fluid may be directly circulated and concentrated together, but in this case, some impurities may not be eliminated.

[0080] In some embodiments, a sensor may be further provided in the pipeline between the first waste liquid outlet port 523 and the first waste liquid collection port 524 of the hollow fiber column, for example, a flow sensor may be provided. 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 met, and the circulating concentration stops. For another example, a UV sensor may be provided. When the reading of the UV sensor meets the preset range, it indicates that the concentration of the discharged waste liquid has met the requirements, that is, the preset purification requirement has been met, and the circulating concentration stops. Of course, in some examples, multiple sensors may also be provided at the same time. When the readings of multiple sensors all meet the preset requirements, it is determined that the preset purification requirement has been met, and the circulating concentration stops.

[0081] In some embodiments, the first replacement fluid input end 526 is further connected to the first outlet end 522 of the hollow fiber column, so that the replacement fluid can be used to push out the medical solution in the hollow fiber column and / or nearby pipelines.

[0082] In some embodiments, the first purification process module 500 further includes a first purification collection end 530, which is connected to the aforementioned first mixing container 525 to collect the purified solution to the first purification collection end 530. For example, a first filter assembly 531 such as a butterfly filter or a capsule filter may be provided 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 may be provided upstream of the first filter assembly 531 , and when bubbles are detected, the collection of the solution is stopped.

[0084] In addition, a purification collection container may be provided at the first purification collection end 530 , or the first purification collection end 530 may be directly connected to other downstream components, etc. 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 port 540 and a second waste liquid collection port 541 may also be provided, and the hollow fiber column is arranged between the first pre-preparation inlet port 540 and the second waste liquid collection port 541. The first pre-preparation inlet port 540 is used to input the solution required for the pre-preparation stage into the hollow fiber column and other components to perform the pre-preparation steps. For example, the pre-preparation steps may include pure water cleaning, balancing liquid rinsing, alkaline solution rinsing, etc.

[0086] For example, three first pre-preparation inlet ports 540 are provided. During use, the three first pre-preparation inlet ports 540 can be used to input different solutions to implement the pre-preparation step. The waste liquid formed after the different solutions sequentially pass through the first inlet port 521 and the first outlet port 522 of the hollow fiber column flows to the second waste liquid collection port 541 and is discharged.

[0087] For example, the first first pre-prepared inlet end 540 inputs pure water, and the pure water flows through the pipeline and the components in the pipeline to achieve pure water cleaning; the second first pre-prepared inlet end 540 inputs balancing liquid, and the balancing liquid flows through the pipeline and the components in the pipeline to achieve balancing liquid rinsing, and the balancing liquid can mainly be used to calibrate the sensor in the pipeline; the third first pre-prepared inlet end 540 inputs alkaline solution, and the alkaline solution flows through the pipeline and the components in the pipeline to achieve alkaline solution rinsing.

[0088] As another example, a first sensor assembly 542 may be provided between the first pre-prepared inlet port 540 and the second waste liquid collection port 541, and / or a first sensor assembly 542 may also be provided between the first pre-prepared inlet port 540 and the first waste liquid collection port 524. The first sensor assembly 542 is used to detect various parameter values ​​of the solution. For example, the first sensor assembly 542 may include any one of a flow sensor, a mass sensor, a pH sensor, a UV value sensor, and the like. For another example, the first sensor assembly 542 may be provided downstream of the hollow fiber column. For another example, the aforementioned balancing solution may be used to calibrate the first sensor assembly 542, that is, when the balancing solution flows through, the state of the first sensor assembly 542 is determined by the reading of the first sensor assembly 542.

[0089] In some embodiments, at least one first pre-prepared inlet port 540 is connected to the aforementioned first filter assembly 531 for rinsing the first filter assembly 531 .

[0090] Illustratively, a first pre-prepared inlet port 540, a first filter assembly 531 and a second waste liquid collection port 541 are sequentially connected via pipelines.

[0091] In some embodiments, a first gas inlet port 550 is further provided, connected to the aforementioned first filter assembly 531. Thus, by inputting gas, a first detection sensor 551, such as a pressure sensor, can be used to detect whether the first filter assembly 531 is damaged. This is because if the membrane or other structures of the first filter assembly 531 are damaged, the detection reading of the first detection sensor 551 when gas passes through will be different from the reading under normal conditions.

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

[0093] It is understood that, in addition, a number of pump assemblies configured in various pipelines can be provided in the first purification process module 500 to drive the solution and cause the solution to flow in the various pipelines. The pump assembly can be a peristaltic pump, etc. For example, the pump assembly provided in this embodiment can include P1, P2, and P3. It is understood that this does not constitute an undue limitation to the present application. In other embodiments, the pump assembly can also adopt other settings, settings, and settings.

[0094] It is understood that, in addition, a number of valve assemblies configured in various pipelines can be provided in the first purification process module 500 to control the on-off of the pipelines. For example, the valve assemblies provided in the embodiment of the present application may include V1 to V16. It is understood that this does not constitute an undue limitation to the present application. In other embodiments, the valve assemblies may also be provided in other ways, positions, and quantities, such as being provided in various components for providing and collecting solutions.

[0095] Thus, based on the first purification process module 500 provided in the embodiment of the present application, a pipeline arrangement and corresponding structure for purifying a solution are provided. On this basis, according to actual needs, those skilled in the art can easily add corresponding pump components and / or valve components to achieve the desired control function.

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

[0097] Here, the hollow fiber column is used as an example for explanation, but it can be understood that in other embodiments, the hollow fiber column can also be replaced by other second separation and purification devices 720, such as membrane packages, etc. The examples in the embodiments of the present application do not constitute an undue limitation thereto.

[0098] Exemplarily, the second inlet end 721 and the second outlet end 722 of the hollow fiber column are interconnected 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 component. For example, the second inlet end 721 and the second outlet end 722 can be located at the bottom and top of the hollow fiber column, respectively, and a second waste liquid outlet end 723 is further provided on one side of the hollow fiber column, and the second waste liquid outlet end 723 can be connected to the third waste liquid collection end 724. Of course, this example does not constitute an undue limitation to the present application. In other embodiments, the positions of the second inlet end 721 and the second outlet end 722, etc. may also be different.

[0099] When in use, the solution from the upstream component, such as 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 port 723 to the third waste liquid collection port 724. The third waste liquid collection port 724 can be provided with a waste liquid collection container, etc.

[0100] For example, during the purification operation, some auxiliary liquids are required, such as replacement liquid, mother liquor, auxiliary material mother liquor, etc. The amount of auxiliary liquid required may also vary depending on the actual process requirements.

[0101] Therefore, at least two auxiliary liquid input ports 726 may be provided for inputting auxiliary liquids such as replacement liquid, mother liquid, auxiliary material mother liquid, etc. In the figure, an embodiment with three auxiliary liquid input ports 726 is exemplarily shown.

[0102] In addition, a 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] Thus, 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. Moreover, 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 cyclic concentration, and the waste liquid is discharged to the second waste liquid collection container 340 through the second waste liquid outlet port 723.

[0104] Therefore, in the embodiment of the present application, the solution from the upstream is first circulated and concentrated through the hollow fiber column, and then the concentrated solution and the auxiliary liquid are circulated and concentrated together, thereby achieving a better purification effect.

[0105] Of course, in some embodiments, the solution from upstream and the auxiliary liquid may be directly circulated and concentrated together, but in this case, some impurities may not be eliminated.

[0106] In some embodiments, in order to more accurately calculate the amount of auxiliary liquid used, 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 measure the weight change of the auxiliary liquid container loaded with auxiliary liquid in real time, thereby determining the amount of auxiliary liquid added.

[0107] Due to the presence of the pipeline, although metering components such as a weighing component can determine the amount of auxiliary liquid added, some of the auxiliary liquid actually remains in the pipeline and does not completely enter the second mixing container 725. Therefore, in order to more accurately measure the amount of auxiliary liquid added, a metering auxiliary component 760 can be provided. The metering auxiliary component 760 is configured in the pipeline to measure the flow rate of the auxiliary liquid flowing through the pipeline.

[0108] For example, a weighing assembly can be provided at the auxiliary liquid input end 726 to serve as a metering assembly. A bubble sensor or flow sensor, such as a flow sensor, can be installed in the pipeline between the auxiliary liquid input end 726 and the second mixing container 725 to serve as an auxiliary metering assembly 760. During initial addition, the auxiliary liquid has not yet flowed to the auxiliary metering assembly 760. At this point, only the air already in the pipeline flows through the auxiliary metering assembly 760, and the auxiliary metering assembly 760 does not generate a reading. Only when the auxiliary liquid has flowed to the auxiliary metering assembly 760 does the auxiliary metering assembly 760 begin to generate a reading. Therefore, sufficient auxiliary liquid is not confirmed to have been added until both the metering assembly and the auxiliary metering assembly 760 reach a preset reading range.

[0109] In another case, for example, if one auxiliary liquid is added first and then another auxiliary liquid is added, the second auxiliary liquid needs to push the first auxiliary liquid forward before it can enter the second mixing container 725. In this case, the metering auxiliary component 760 continues to generate readings, but the second auxiliary liquid has not actually flowed into the second mixing container 725.

[0110] In this case, a more accurate amount can be determined by combining the calculated capacity of the liquid in the pipeline with the readings of the metering assembly and the auxiliary metering assembly 760. For example, the pre-calculated capacity of the liquid in the pipeline can be used, and the reading of the auxiliary metering assembly 760 can be subtracted from the pre-calculated capacity of the liquid in the pipeline. The subsequent reading can be used as the amount of the auxiliary liquid added for a more accurate calculation. Furthermore, the actual amount can be determined by subtracting the pre-calculated capacity of the pipeline from the auxiliary liquid input end 726 to the auxiliary metering assembly 760 or the second mixing container 725 from the reading of the metering assembly.

[0111] As another example, the metering auxiliary component 760 can be disposed near the second mixing container 725. For example, the plurality of auxiliary liquid input ports 726 are connected to each other, then to the metering auxiliary component 760, and then to the second mixing container 725.

[0112] In some embodiments, a sensor may be provided in the pipeline between the second waste liquid outlet port 723 and the third waste liquid collection port 724 of the hollow fiber column, for example, a flow sensor may be provided. 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 met, and the circulating concentration stops. For another example, a UV sensor may be provided. When the reading of the UV sensor meets the preset range, it indicates that the concentration of the discharged waste liquid has met the requirements, that is, the preset purification requirement has been met, and the circulating concentration stops. Of course, in some examples, multiple sensors may also be provided at the same time. When the readings of multiple sensors all meet the preset requirements, 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 further connected to the second outlet end 722 of the hollow fiber column, so that the liquid medicine in the hollow fiber column and / or the adjacent pipeline can be pushed out by the replacement fluid.

[0114] In some embodiments, the second purification process module 700 further includes a second purification collection end 730, which is connected to the aforementioned second mixing container 725 to collect the purified solution to the second purification collection end 730. For example, a second filter assembly 731 such as a butterfly filter or a capsule filter may be provided between the second purification collection end 730 and the second mixing container 725 to achieve sterile filtration.

[0115] For example, a second bubble sensor 732 may be provided upstream of the second filter assembly 731 , and when bubbles are detected, the collection of the solution is stopped.

[0116] In addition, a purification collection container may be provided at the second purification collection end 730 , or the second purification collection end 730 may be directly connected to other downstream components, etc. The examples in the embodiments of the present application do not unduly limit them.

[0117] In some embodiments, at least one second pre-preparation inlet port 740 and a fourth waste liquid collection port 741 may also be provided, and the hollow fiber column is arranged between the second pre-preparation inlet port 740 and the fourth waste liquid collection port 741. The second pre-preparation inlet port 740 is used to input the solution required for the pre-preparation stage into the hollow fiber column and other components to perform the pre-preparation steps. For example, the pre-preparation steps may include pure water cleaning, balancing liquid rinsing, alkaline solution rinsing, etc.

[0118] For example, three second pre-preparation inlet ports 740 are provided. During use, the three second pre-preparation inlet ports 740 can be used to input different solutions to implement the pre-preparation step. The waste liquid formed after the different solutions sequentially pass through the second inlet port 721 and the second outlet port 722 of the hollow fiber column flows to the fourth waste liquid collection port 741 and is discharged.

[0119] For example, the second second pre-prepared inlet port 740 inputs pure water, and the pure water flows through the pipeline and the components in the pipeline to achieve pure water cleaning; the second second pre-prepared inlet port 740 inputs balancing liquid, and the balancing liquid flows through the pipeline and the components in the pipeline to achieve balancing liquid rinsing, and the balancing liquid can mainly be used to calibrate the sensor in the pipeline; the third second pre-prepared inlet port 740 inputs alkaline solution, and the alkaline solution flows through the pipeline and the components in the pipeline to achieve alkaline solution rinsing.

[0120] Exemplarily again, a second sensor assembly 742 may be provided between the second pre-prepared inlet port 740 and the fourth waste liquid collecting port 741, and / or a second sensor assembly 742 may also be provided between the second pre-prepared inlet port 740 and the fourth waste liquid collecting port 741, and the second sensor assembly 742 is used to detect the various parameter values ​​of the solution, such as the second sensor assembly 742 may include any one of a flow sensor, a mass sensor, a pH sensor, a UV value sensor, etc. For another example, the second sensor assembly 742 may be provided downstream of the hollow fiber column. For another example, the aforementioned balance solution may be used to calibrate the second sensor assembly 742, that is, when the balance solution flows through, the state of the second sensor assembly 742 is judged by the reading of the second sensor assembly 742.

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

[0122] Illustratively, a second pre-prepared inlet port 740, a second filter assembly 731 and a second sensor assembly 742 are sequentially connected via pipelines.

[0123] In some embodiments, a first gas inlet port 550 is further provided, connected to the aforementioned second filter assembly 731. Thus, by inputting gas, a second detection sensor 751, such as a pressure sensor, can be used to detect whether the second filter device is damaged. This is because if the membrane or other structures of the second filter device are damaged, the detection reading of the second detection sensor 751 when gas passes through will be different from the reading under normal conditions.

[0124] Illustratively, the second gas inlet port 750 , the second detection sensor 751 , the second filter assembly 731 and the fourth waste liquid collection port 741 are connected in sequence through pipelines.

[0125] It is understood that, in addition, a number of pump assemblies configured in various pipelines can be provided in the second purification process module 700 to achieve driving of the solution and to cause the solution to flow in the various pipelines. The pump assembly can be a peristaltic pump or the like. For example, the pump assembly provided in this embodiment can include P4, P5, and P6. It is understood that this does not constitute an undue limitation to the present application. In other embodiments, the pump assembly can also adopt other settings, settings, and settings.

[0126] It is understood that, in addition, a number of valve assemblies configured in various pipelines can be provided in the second purification process module 700 to control the on-off of the pipelines. For example, the valve assemblies provided in the embodiment of the present application may include V17 to V33. It is understood that this does not constitute an undue limitation to the present application. In other embodiments, the valve assemblies may also be provided in other ways, positions, and quantities, such as being provided in various components for providing and collecting solutions.

[0127] Thus, based on the second purification process module 700 provided in the embodiment of the present application, a pipeline arrangement and corresponding structure for purifying the solution are provided. On this basis, according to actual needs, those skilled in the art can easily add corresponding pump components and / or valve components to achieve the desired control function.

[0128] In some embodiments, see Figure 16 Any of the aforementioned first mixing container 525 and the second mixing container 725 may include a container body, an inlet pipe, an outlet pipe and a stirring member. The inlet pipe extends into the container body and then extends toward the side wall of the container body, and the outlet pipe extends to the bottom of the container body. The stirring member includes a stirring drive mechanism and a stirring portion that are connected in a matching manner. The stirring portion is located in the container body to stir and mix 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, etc., and the examples in the embodiments of the present application do not constitute an undue limitation thereto.

[0129] In other embodiments, any of the first mixing container 525 and the second mixing container 725 can be mounted on a mixing mechanism. The mixing mechanism can be driven to move the first mixing container 525 or the second mixing container 725 to achieve mixing of the liquid medicine inside the first mixing container 525 or the second mixing container 725.

[0130] See also Figure 20The mixing mechanism may include a mixing drive 910 and an eccentric connecting member 920. The eccentric connecting member 920 is eccentrically connected to the mixing drive 910 and can move eccentrically under the drive of the mixing drive 910. The supporting member 940 is connected to the eccentric connecting member 920 and can also be driven by the eccentric connecting member 920 to move eccentrically. Figure 21 and Figure 22 The supporting member 940 is used to accommodate the aforementioned first mixing container 525 or the second mixing container 725. The first mixing container 525 and / or the second mixing container 725 are mixing bags. The supporting member 940 is provided with a mounting groove, which can accommodate and fix the first mixing container 525 or the second mixing container 725. In addition, the connection between the two can be reinforced with straps or the like. Of course, the examples in this embodiment do not constitute an 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. Figure 23 The shaft 921 is mounted on a base 922, and the supporting member 940 is rotatably connected to the shaft 921 via a bearing 930. For another example, the shaft 921 can be tilted relative to the horizontal plane. Thus, when the mixing drive 910 drives the eccentric connector 920 to move, the supporting member 940, which is rotatably connected to the shaft 921, rotates and shakes, thereby mixing the first mixing container 525 or the second mixing container 725 mounted thereon.

[0132] For further examples, please refer to Figure 22 A flexible wall 950 may be provided in the circumferential direction of the lower side of the supporting member 940. The flexible wall 950 may be made of rubber or other materials. As the supporting member 940 moves, the flexible wall 950 may be deformed accordingly. The space surrounded by the flexible wall 950 is not easily invaded by external dust and components.

[0133] In a further embodiment, a position sensor 960 may be provided on one side of the eccentric connecting member 920. The position sensor 960 may be used to identify the position of the supporting member 940. For example, the position sensor 960 may be used to identify the number of revolutions of the supporting member 940.

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

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

[0136] For some examples, see Figure 17 The pre-purification assembly includes a chromatography process module 300, which includes chromatography tubing, a chromatography column (not shown) disposed within the tubing, and a pump assembly for driving the solution within the tubing. The chromatography tubing includes a chromatography inlet tubing 310, a chromatography outlet tubing 330, and a main chromatography tubing 320. The main chromatography tubing 320 includes a first port 321 and a second port 322 for fluid connection, as well as a third port 323 and a fourth port 324 for fluid connection.

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

[0138] For example, 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 pipeline from the chromatography inlet pipeline 310, it flows to the chromatography column through the first port 321 and the third port 323, and flows to the chromatography outlet pipeline 330 from the second port 322 and the fourth port 324.

[0139] As another example, the first port 321 can be selectively connected to the fourth port 324. Thus, in some cases, a solution can flow directly from the chromatography inlet line 310 through the first port 321 and the fourth port 324 into the chromatography outlet line 330. For example, when performing calibration, cleaning, or other operations on the chromatography process module 300, the liquid can flow directly through this passage.

[0140] In some embodiments, a sensor assembly is configured in the chromatography pipeline. To achieve different functions, the sensor assembly can include any of a bubble sensor, a pressure sensor, a flow sensor, a mass sensor, a pH sensor, a UV sensor, etc. For example, the chromatography inlet pipeline 310 can be configured with a bubble sensor, a pressure sensor, and a flow sensor. For another example, the chromatography outlet pipeline 330 can be configured with a pH sensor and a UV sensor.

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

[0142] It is understandable that valves may be provided between the ports, thereby enabling the ports to be selectively connected or disconnected.

[0143] Here, two chromatography inlet lines 310 are provided. One chromatography inlet line 310 is provided with inlet ends A1 and A2, and the other chromatography inlet line 310 is provided with inlet ends B1 and B2. However, in other embodiments, the chromatography inlet line 310 may be provided with more or fewer inlet ends, and / or, in other embodiments, the chromatography inlet line 310 may be provided with one or another number of lines. The examples in the embodiments of the present application are not intended to constitute undue limitations thereto.

[0144] Here, in an embodiment where two or more chromatography inlet lines 310 are provided, the two or more chromatography inlet lines 310 are commonly connected to a static mixer 350. The static mixer 350 has at least one curved flow channel 351. As a result, when multiple different drug solutions flow into the static mixer 350, the drug solutions collide with the walls of the curved flow channel 351, thereby promoting mixing of the drug solutions. For example, to achieve a better mixing effect, the flow channel 351 may have at least two bends.

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

[0146] For example, see Figure 24 and Figure 25 The static mixer 350 further includes a body 352 having a liquid medicine inlet 353 and a liquid medicine outlet 354. A flow channel 351 is disposed on the body 352 and fluidically connected between the liquid medicine inlet 353 and the liquid medicine outlet 354. Furthermore, a closing cap 355 is disposed on the body 352 to cooperate with the body 352 and close the flow channel 351. As another example, a sealing ring 356 may be disposed between the flow channel 351 and the closing cap 355.

[0147] The chromatography outlet line 330 is provided here as one, 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 chromatographic solution, which can be connected to other downstream pipelines or components. However, in other embodiments, the chromatography inlet line 310 can be provided with more outlet ends, and / or, in other embodiments, the chromatography outlet line 330 can be provided with multiple lines. The examples in the embodiments of the present application do not constitute an undue limitation thereto.

[0148] It is understood that, in addition, the chromatography process module 300 may further include a number of pump assemblies configured in each pipeline to achieve driving of the solution and to allow the solution to flow in each pipeline. The pump assembly may be a peristaltic pump or the like. For example, the pump assembly provided in this embodiment may include P9 and P10. It is understood that this does not constitute an undue limitation to the present application. In other embodiments, the pump assembly may also be provided in other ways, positions, and quantities.

[0149] It is understood that, in addition, the chromatography process module 300 may further include a number of valve assemblies configured in various pipelines to control the on / off of the pipelines. For example, the valve assemblies provided in the embodiments of the present application may include V41 to V57. It is understood that this does not constitute an undue limitation to the present application. In other embodiments, the valve assemblies may also be provided in other ways, positions, and quantities, such as being provided in various components for providing and collecting solutions.

[0150] For other examples, see Figure 18 and Figure 19 The pre-purification component includes a magnetic bead purification process module 400. The magnetic bead purification process module 400 can use specific ligands modified on the surface of magnetic beads to bind to target molecules, separate the magnetic beads from impurities through a magnetic field, and finally release a high-purity sample.

[0151] Here, the magnetic bead purification process module 400 includes at least one magnetic bead purification inlet end 410 and a magnetic bead purification container 420 . The magnetic bead purification inlet end 410 is fluidically 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 end 410 .

[0152] Among them, the magnetic bead purification inlet port 410 is used to input solutions from upstream and various required solutions, such as solutions from in vitro transcription equipment, as well as eluents, washing solutions, etc. The magnetic bead purification inlet port 410 can be provided with multiple ports, or can be shared by multiple solutions. The embodiments of this application do not impose any inappropriate restrictions on them. For example, three ports can be provided to respectively input solutions for completing in vitro transcription, eluents, and washing solutions. For example, in some examples, a storage container for storing solutions can be provided at the magnetic bead purification inlet port 410.

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

[0154] As another example, in addition to the inlet and outlet for the solution, the magnetic bead purification container 420 may also be provided with an exhaust port connected to an exhaust port 430. In addition, a gas collection container or the like may be provided at the exhaust port 430.

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

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

[0157] When the magnetic bead purification process module 400 begins operation, driven by the pump assembly and other components, the solution begins to enter the pipeline and move toward the magnetic bead purification container 420. Gas in the pipeline and magnetic bead purification container 420 is pushed out and exits through the exhaust port. Once the solution nearly fills the magnetic bead purification container 420, the solution begins to flow out of the exhaust port. When the liquid sensor detects the presence of solution, exhaust is complete, and the valve assembly can be used to close the pipeline between the exhaust port and the exhaust port 430.

[0158] Furthermore, magnetic source 460 is provided at magnetic bead purification container 420. Magnetic source 460 can be a magnet, etc., and is used to selectively attract magnetic beads. As the magnetic beads in the solution pass through magnetic bead purification container 420, magnetic source 460 can apply a magnetic force to attract the magnetic beads, causing them to remain in magnetic bead purification container 420.

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

[0160] The magnetic beads are then washed by introducing a washing solution into the magnetic bead purification container 420. Here, the magnetic source 460 can selectively adsorb and desorb the magnetic beads, thereby enabling the magnetic beads to obtain a better washing effect in the washing solution.

[0161] For example, the magnetic source 460 is movably provided, thereby enabling selective adsorption and desorption 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 driving mechanism, such as a motor, and the magnetic source 460 driving mechanism drives the magnetic source 460 to move, thereby moving the magnetic source 460 between the adsorption and desorption positions.

[0162] As another example, the magnetic bead purification container 420 is further provided with an oscillation mechanism, such as an oscillation motor, so that in the desorbed state, an oscillation effect is applied to the magnetic bead purification container 420 so that the magnetic beads can be better washed in the washing solution.

[0163] After washing is completed, the washing liquid is discharged to the waste liquid outlet port 440.

[0164] A magnetic bead purification outlet 450 is also provided here, which is connected to the outlet of the magnetic bead purification container 420. For example, an eluent can be introduced through the magnetic bead purification inlet 410 to elute the active ingredients bound to the magnetic beads into a solution, and then the solution is transported through the magnetic bead purification outlet 450 to other downstream components, such as the downstream first purification process module 500.

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

[0166] It is understood that, in addition, the magnetic bead purification process module 400 may also include a number of pump assemblies configured in various pipelines to drive the solution and allow the solution to flow in various pipelines. The pump assembly may be a peristaltic pump, etc. For example, the pump assemblies provided in this embodiment may include P7 and P8. It is understood that this does not constitute an undue limitation to the present application. In other embodiments, the pump assembly may also adopt other settings, settings, and settings.

[0167] It is understood that, in addition, the magnetic bead purification process module 400 may further include a number of valve assemblies configured in various pipelines to control the on-off of the pipelines. For example, the valve assemblies provided in the embodiment of the present application may include V34 to V40. It is understood that this does not constitute an undue limitation to the present application. In other embodiments, the valve assemblies may also be provided in other ways, positions, and quantities, such as being provided in various components for providing and collecting solutions.

[0168] It is understood that the pre-purification component may include both the magnetic bead purification process module 400 and the chromatography process module 300, or may include only one of them. When both the magnetic bead purification process module 400 and the chromatography process module 300 are included, their order of installation may be selected as needed, and the examples in the present application do not constitute an undue limitation thereto.

[0169] In some embodiments, the apparatus for preparing nucleic acid drugs in the embodiments of the present application may further include at least one mounting bracket, which may be used to mount a process module, such as the magnetic bead purification process module 400.

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

[0171] Here, because the first connector 1002 and the second connector 1003 are interlaced, multiple interlaced points are formed in the frame, which can be used to install various components, such as at least one of the magnetic bead purification container 420, the valve assembly, and the pump assembly. Therefore, after the process is completed, consumables such as tubing can be quickly replaced. Since the positions of reusable components are fixed, the operation of replacing tubing and other consumables can be very convenient and can be easily achieved through mechanized means such as a robot.

[0172] In some embodiments, a hook structure 1004 may be further provided at the bottom end of the first connecting member 1002 to facilitate connection with desired components.

[0173] It is understandable that the mounting bracket is not limited to being used for mounting the magnetic bead purification process module 400 , but can also be used for mounting other process modules, and the principles are the same.

[0174] See also Figure 1 and Figure 2 The equipment for preparing nucleic acid drugs may further include an in vitro transcription device, which is arranged upstream to provide a drug solution that has completed in vitro transcription. The drug solution that has completed in vitro transcription may then be supplied to the first purification process module 500, or may first be supplied to a pre-purification component and then to the first purification process module 500. In other words, the in vitro transcription device may be located upstream of the pre-purification component and the first purification process module 500.

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

[0176] The transfer unit 100 can be used to transfer at least two reactants to a reaction vessel 12 (the reaction vessel 12 can be seen Figure 7 As shown in FIG, 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 setting up the transfer unit 100 and the mixing unit 200, the in vitro transcription operation can be effectively realized, and its efficiency is improved compared with the prior art operation method of manually adding various reactants into the stirring tank.

[0178] The reactants are typically liquid reagents that can be stored in a reactant container prior to the in vitro transcription operation. The reactant container can be a test tube, other glass bottles, or other containers, such as a vial. The amount and type of reactants added will vary depending on the actual process requirements, and the subsequent exemplary descriptions in the embodiments of this application do not constitute an undue limitation thereto. Those skilled in the art can adjust the amount and type of reactants according to actual needs.

[0179] Here, see 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 transfer unit 100 and the mixing unit 200 can both be arranged on the work platform 11. Of course, in other embodiments, the work platform 11 may not be provided, and the examples in this application do not constitute an undue limitation thereto.

[0180] Exemplarily, the in vitro transcription process module here may also include a refrigeration chamber 160, a waste liquid chamber 170 and a buffer container 180. The refrigeration chamber 160 is used to refrigerate the reactants because some reactants need to be stored within an appropriate temperature range; the waste liquid chamber 170 is used to collect waste liquid generated during the process operation, and the waste liquid outlet end of the in vitro transcription process module or other process modules can be connected to the waste liquid chamber 170; the buffer container 180 can be used to store qualified drug liquid after the in vitro transcription process is completed, so that it can be subsequently supplied to other process modules.

[0181] As another example, at least portions of the refrigeration chamber 160 and waste liquid chamber 170 are located below the work platform 11 to fully utilize the space below the work platform, improve the compactness of the overall process module, and reduce the occupied area. The buffer container 180 is located above the work platform for easy access and supply to other process modules.

[0182] In addition, the work platform 11 is also provided with a refrigerated preparation storage area 191, a room temperature preparation storage area 192, and a pipette tip storage area 193. The refrigerated preparation storage area 191 can be located in the aforementioned refrigeration chamber 160. In another exemplary embodiment, the refrigerated preparation storage area 191, the room temperature preparation storage area 192, and the pipette tip storage area 193 are all located on the same side of the pipetting unit 100. Furthermore, the refrigerated preparation storage area 191, the room temperature preparation storage area 192, the pipette tip storage area 193, and the waste liquid chamber 170 are all located on the same side of the pipetting unit 100, so as to facilitate the use and disposal of the pipetting unit 100.

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

[0184] Here, see Figure 3 The transfer unit 100 includes a first transfer member 120 and a first transfer drive mechanism 110 that are cooperatively connected. The first transfer drive mechanism 110 is used to drive the first transfer member 120 to move so as to transfer at least two reactants into the reaction vessel 12 .

[0185] For example, the first removal drive mechanism 110 may include a first transverse movement mechanism 111, a first rotation mechanism 112, and a first vertical movement mechanism 113. The first rotation mechanism 112 is disposed on the first transverse movement mechanism 111, thereby driving the first rotation mechanism 112 to move transversely. The first vertical movement mechanism 113 is disposed on the first rotation mechanism 112, thereby driving the first vertical movement mechanism 113 to rotate. The first vertical movement mechanism 113 is connected to the first removal member 120, thereby driving the first removal member 120 to rise and fall vertically.

[0186] Furthermore, through the provision of the first removing drive mechanism 110 , the first removing member 120 can be driven by the first removing drive mechanism 110 , thereby achieving lateral movement, rotation within a horizontal plane, and vertical movement.

[0187] For example, the first transverse moving mechanism 111 may include a transversely arranged linear module; the first rotating mechanism 112 may be a motor, which is directly or indirectly connected to the slider of the first transverse moving mechanism 111 through a connecting member; the first vertical moving mechanism 113 may include a vertically arranged linear module, which is directly or indirectly connected to the first rotating mechanism 112 through a connecting member; the first removing member 120 is connected to the slider of the first vertical moving mechanism 113.

[0188] Of course, it is understandable that the structure of the first removal drive mechanism 110 and the structures and connection positions of its components are not limited to the above examples, as long as they can drive the first removal member 120 to move to a desired position.

[0189] For example, the first removal member 120 may include a pipette tip 121 and a pressure source 122. The pressure source 122 is connected to the pipette tip 121 to generate a negative pressure to absorb the reactants. For example, the pressure source 122 may be a pump. By varying the pressure of the pressure source 122, the reactants can be absorbed and released.

[0190] For example, the first removal member 120 further includes a tip mounting portion 123, which can be detachably connected to the pipette tip 121 by plugging or other means. In addition, an air channel can be provided on the tip mounting portion 123 so that the pipette tip 121 mounted on the tip mounting portion 123 can be connected to the pressure source 122.

[0191] For another example, the pipette tip 121 may be a disposable tip, and different pipette tips 121 may be replaced when transferring different reactants.

[0192] In some examples, a rotary encoder may be further provided at the first rotating mechanism 112, and rotational parameters may be obtained through the rotary encoder. The rotational parameters may include the angular displacement and angular velocity of the output shaft of the first rotating mechanism 112. In addition, a pipette tip placement area is pre-set, and a plurality of pipette tips 121 are provided in the pipette tip placement area for mating with the tip mounting portion 123. The position parameters of the plurality of pipette tips 121 are obtained by pre-positioning. By calculating the position of the tip mounting portion 123, the position of the first lateral movement mechanism 111, and the position parameters of the pipette tips 121, the rotational parameters required to move to the position of each pipette tip 121 can be obtained. Then, by controlling the rotational parameters of the rotary encoder, the tip mounting portion 123 can be accurately moved to the position of the pipette tip 121 and mated with the pipette tip 121.

[0193] In addition, in some examples, the aforementioned pressure source 122 is also used to intermittently form negative pressure, thereby repeatedly absorbing and releasing reactants through repeated changes of negative pressure-stop or positive pressure-negative pressure, that is, stirring the reactants through changes in air pressure, thereby mixing the reactants.

[0194] In some embodiments, please refer to Figure 3 The aforementioned removal unit 100 may further include a second removal member 140 and a second removal drive mechanism 130 that are coupled together. The second removal drive mechanism 130 is used to drive the second removal member 140 to move to remove the reactant container. Thus, the reactant container can be removed to a desired position.

[0195] In addition, illustratively, the reactant container may further include a lid (not shown), and the second removal member 140 may also be used to remove the lid, thereby achieving an opening operation. In other words, the second removal member 140 may be used to remove at least one of the reactant container and the lid.

[0196] The connection between the cover and the reactant container may be a threaded fit or an interference fit, etc. It is understood that the examples in this embodiment do not constitute an undue limitation thereto.

[0197] As another example, the second removal drive mechanism 130 may include a second transverse movement mechanism 131, a second rotation mechanism 132, and a second vertical movement mechanism 133. The second rotation mechanism 132 is disposed on the second transverse movement mechanism 131, thereby driving the second transverse movement mechanism 132 to move transversely. The second vertical movement mechanism 133 is disposed on the second rotation mechanism 132, thereby driving the second vertical movement mechanism 133 to rotate. The second vertical movement mechanism 133 is connected to the second removal member 140, thereby driving the second removal member 140 to rise and fall vertically.

[0198] Furthermore, through the provision of the second removing drive mechanism 130 , the second removing member 140 can be driven by the second removing drive mechanism 130 , thereby achieving lateral movement, rotation within a horizontal plane, and vertical movement.

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

[0200] Of course, it is understandable that the structure of the second removal drive mechanism 130 and the structures and connection positions of its components are not limited to the above examples, as long as they can drive the second removal member 140 to move to a desired position.

[0201] For example, the second removal member 140 may be an electric or pneumatic gripper or a robotic arm.

[0202] In some embodiments, see Figure 2 The aforementioned removal unit 100 may further include a clamping mechanism 150 for clamping and fixing the reactant container. For example, the second removal member 140 may remove the reactant container to the clamping mechanism 150 position, and the clamping mechanism 150 clamps and fixes the reactant container.

[0203] Here, for example, see Figure 4 The clamping mechanism 150 includes a clamping member 151 and a clamping drive mechanism (not shown) that are matched and connected. The clamping member 151 can be a clamping claw, etc., and the clamping drive mechanism can be a motor, etc. When the second removal member 140 moves the reactant container to the clamping member 151, the clamping drive mechanism drives the clamping member 151 to move to clamp and fix the reactant container.

[0204] Here, a plurality of clamping mechanisms 150 may be provided as required, for example, Figure 4 In the schematic diagram shown, two clamping mechanisms 150 are arranged in parallel. Of course, the examples in the embodiments of the present application do not constitute an undue limitation thereto. In other embodiments, the clamping mechanisms 150 may also be provided in other numbers and their arrangement positions may also be different.

[0205] See also Figure 5 The aforementioned mixing unit 200 may include a carrier 210, a mixing drive mechanism 220 and a temperature control mechanism (not shown).

[0206] The carrier 210 is used to detachably fix the reaction vessel 12 . The hybrid drive mechanism 220 is connected to the carrier 210 to drive the carrier 210 to move back and forth. 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 within a preset temperature range by the temperature control mechanism and driven by the mixing drive mechanism 220 to be mixed, so as to achieve an enzyme reaction and further achieve in vitro transcription.

[0208] Please refer to Figure 6 The mixing drive mechanism 220 includes a power source 221 and an eccentric transmission structure that are coupled together. The carrier 210 is connected to the eccentric transmission structure. Driven by the power source 221, the carrier 210 rotates via the eccentric transmission structure. Since the reaction vessel 12 is detachably secured to the carrier 210, the reaction vessel 12 on the carrier 210 can be further rotated to achieve uniform mixing of the reactants within the reaction vessel 12.

[0209] Exemplarily, the power source 221 can be a motor or the like. In another exemplary embodiment, the eccentric transmission mechanism includes a driving eccentric wheel 222, which is transmission-connected to the output shaft of the aforementioned power source 221. An eccentrically arranged first eccentric transmission member 223 is connected to the driving eccentric wheel 222. 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 to the bearing member 210. In some examples, the end of the first eccentric transmission member 223 away from the driving eccentric wheel 222 can extend in a radial direction to form a bearing surface for connecting to the bearing member 210, thereby improving the stability of the connection.

[0210] In a further embodiment, the eccentric transmission mechanism may further be provided with a passive eccentric wheel 224, which is rotatably disposed on a base 226, and an eccentrically disposed second eccentric transmission member 225 is connected to the passive eccentric wheel 224. Specifically, the second eccentric transmission member 225 may be non-coaxially disposed with respect to the center of the circle of the passive eccentric wheel 224. The second eccentric transmission member 225 is also used to connect the support member 210 to improve the stability of the support member 210 during movement. In some examples, the second eccentric transmission member 225 may extend in a radial direction at one end close to the support member 210 to form a bearing surface for connecting to the support member 210, thereby improving the stability of the connection. Furthermore, the area of ​​the bearing surface of the second eccentric transmission member 225 may be greater than the area of ​​the bearing surface of the first eccentric transmission member 223.

[0211] In some examples, the passive eccentric wheel 224 is provided in a plurality, and the plurality of passive eccentric wheels 224 are arranged at intervals around the circumference of the active eccentric wheel, for example, they can be arranged at even intervals. Figure 6 In the embodiment, three passive eccentric wheels 224 are evenly spaced around the circumference of one active eccentric wheel. Of course, the examples in the present embodiment do not constitute improper restrictions thereto.

[0212] Please refer to Figure 5 The carrier 210 may include a heat-insulating container 212. The heat-insulating container 212 may be disposed on the aforementioned hybrid drive mechanism 220 so as to be driven and reciprocated by the hybrid drive mechanism 220. For example, the heat-insulating container 212 may be directly or indirectly disposed on the first eccentric transmission member 223 and the second eccentric transmission member 225. Exemplarily, the carrier 210 includes a heat-insulating seat 211, a heat-insulating container 212, and a heat-insulating cover 213. The heat-insulating seat 211 is disposed on the first eccentric transmission member 223 and the second eccentric transmission member 225. The heat-insulating container 212 is assembled in the heat-insulating seat 211, and the heat-insulating container 212 has an openable heat-insulating cover 213.

[0213] Please refer to Figure 7 , which shows that the reaction vessel 12 is placed in the heat-insulating container 212, and the heat-insulating cover 213 is opened and removed. For example, the reaction vessel 12 is a conical flask. The heat-insulating cover 213 can be removed by the second removal member 140 to achieve opening and removal.

[0214] For example, please combine Figure 8 And mainly refer to Figure 9 At least two elastic members 214, such as spring top wires, may be provided in the heat-insulating container 212. The elastic members 214 may be spaced apart along the circumference. For example, three elastic members 214 are spaced apart along the circumference.

[0215] Therefore, when the reaction vessel 12 is located in the heat-insulating container 212, the elastic member 214 is held between the heat-insulating container 212 and the reaction vessel 12. When the hybrid drive mechanism 220 drives the heat-insulating container 212 and the reaction vessel 12 to move, the elastic member 214 helps to achieve a buffering and positioning effect, preventing the inner wall of the heat-insulating container 212 and the outer wall of the reaction vessel 12 from colliding with each other. At the same time, the elastic member 214 also plays a role in positioning the reaction vessel 12, so as to facilitate the gripping and removal of the reaction vessel 12.

[0216] The temperature control mechanism may include a heating component (not shown), which may be disposed in the thermal insulation container 212 or at a location such as the bottom of the thermal insulation container 212 to heat the reaction vessel 12 in the thermal insulation container 212 .

[0217] In addition, in some embodiments, please refer to Figure 5 The mixing unit 200 may further include a tilting assembly 240, which is connected to one side of the carrier 210 to facilitate driving one side of the carrier 210 to lift up, thereby placing the carrier 210 and the reaction vessel 12 thereon in a tilted state, thereby facilitating the removal of the solution that has completed the reaction.

[0218] For example, the tilt assembly 240 may include a tilt motor 241, which may be directly or indirectly connected to a connecting frame 243. The hybrid drive mechanism 220 and the carrier 210 may be directly or indirectly mounted on the connecting frame 243. Thus, when the tilt motor 241 is activated, the hybrid drive mechanism 220, the carrier 210, etc. may be tilted. A speed reducer 242 may be coupled between the tilt motor 241 and the carrier 210.

[0219] In some embodiments, see Figure 5 The mixing unit 200 may further include a positioning assembly 244 for clamping and fixing the reaction vessel 12 so that the second removal member 140 can remove the cover of the reaction vessel 12. The positioning assembly 244 may be an electric gripper, a pneumatic gripper, or the like.

[0220] When the second removing member 140 removes the lid of the reaction vessel 12 , the positioning assembly 244 can clamp the neck of the reaction vessel 12 to achieve fixation, thereby making it easier for the second removing member 140 to remove the lid of the reaction vessel 12 .

[0221] In some embodiments, see Figure 10, the aforementioned buffer container 180 is also provided. For example, the buffer container 180 can be connected to the aforementioned reaction vessel 12 via a pipette assembly. For example, after the tilting assembly 240 drives the reaction vessel 12 to tilt, the pipette head of the pipette assembly is driven by a motor, a manipulator, or other mechanism and moves into the reaction vessel 12, thereby sucking the drug solution into the buffer container 180 through the pipe of the pipette assembly and components such as a pump configured in the pipe.

[0222] In some embodiments, the buffer container 180 is mounted on a base 181. Figure 11 , a magnetic rotor 1801 is provided at the bottom of the buffer container 180, please combine 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 achieving mixing of the liquid medicine.

[0223] The base 181 may be provided with a first positioning structure 1812, and the buffer container 180 may be provided with a second positioning structure 1802, so that the two can be quickly engaged and disassembled. For example, one of the first positioning structure 1812 and the second positioning structure 1802 may be a protrusion and the other may be a groove, and the two may be interference-fitted to achieve a snap-on connection.

[0224] In some embodiments, see Figure 10 A weighing component 1813 may also be provided on the base 181 to weigh the liquid medicine in the buffer container 180 .

[0225] In some embodiments, to better facilitate in vitro transcription, a premixing unit can be provided upstream of mixing unit 200 to facilitate mixing of the reactants prior to the reaction. Furthermore, in some embodiments, the premixing unit can also be used to facilitate both the IVT reaction and the co-transcription capping reaction. In some embodiments, further reactants can be added and mixed to complete the tailing reaction. Following completion of these reactions, an enzyme termination reaction is performed.

[0226] The premixing unit may include a premixing container and a premixing assembly. The premixing assembly may include a premixing carrier and a premixing drive mechanism. The premixing drive mechanism is connected to the premixing carrier to drive the premixing carrier to move back and forth to achieve mixing. Exemplarily, the premixing drive mechanism includes a premixing motor connected to the premixing carrier via an eccentric transmission member to drive the premixing carrier. The premixing carrier may be a carrier platform or a clamping jaw, etc.

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

[0228] In actual use, the reactants are loaded into the reactant container before being removed by the first removal member 120. The reactant container of any reactant can be used as a premix container. Thus, the reactant container can be used as a premix container, thereby reducing consumables and reducing the process steps for removing the reactants.

[0229] In some embodiments, the carrier 210 reciprocates along a first trajectory, while the premix carrier reciprocates along a second trajectory, where the first trajectory and the second trajectory are different. For example, the first trajectory is arranged along a horizontal plane, while the second trajectory is arranged along a vertical plane. By performing mixing operations in different directions, a better mixing effect can be achieved.

[0230] In some embodiments, the frequency of the reciprocating movement of the carrier 210 is a first frequency, and the frequency of the reciprocating movement of the premixing carrier is a second frequency. The first frequency is higher than the second frequency, thereby enabling better premixing to be achieved in the early stage and the reaction requirements of the enzyme reaction to be met through the reciprocating movement of the second frequency in the later stage.

[0231] Accordingly, the present application also provides a method for preparing a nucleic acid drug, which can adopt the device for preparing a nucleic acid drug provided in any of the aforementioned embodiments.

[0232] See also Figure 27 The method includes 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 includes a purification step, and the purification step includes the following steps.

[0235] The solution is passed through the first separation and purification device 520 multiple times through the first circulation loop.

[0236] The replacement fluid is added to the first mixing container 525 through the first replacement fluid input port 526 , and the replacement fluid and the solution are circulated together 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 provided, and the solution output step includes the following steps.

[0238] The replacement fluid is added to the first separation and purification device 520 through the first replacement fluid input port 526 to push the purified solution out of the first separation and purification device 520 .

[0239] The solution is allowed to flow toward the first filtering component 531 , and then flows toward the first purification collection end 530 after being filtered.

[0240] A post-processing step is provided after the solution outputting step, and the post-processing step includes the following steps.

[0241] Gas is input through the first gas inlet port 550 , and flows through the first filter assembly 531 and then flows to the second waste liquid collection port 541 .

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

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

[0244] The method for preparing lipid nanoparticles is a prior art and will not be described in detail in the examples of this application.

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

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

[0247] Pure water is input through the second pre-prepared inlet port 740 , flows through the second separation and purification device 720 , and then flows to the third waste liquid collection port 724 .

[0248] Alkali liquid is input through the second pre-prepared inlet port 740 , flows through the second separation and purification device 720 , and then flows to the third waste liquid collection port 724 .

[0249] Pure water is input again through the second pre-prepared inlet port 740 , and after passing through the second separation and purification device 720 , the pure water flows to the third waste liquid collection port 724 .

[0250] The balancing liquid is input through the second pre-prepared inlet port 740 for rinsing.

[0251] In some examples, other steps after the pre-preparation step are similar to step S400. For details, please refer to the description in other embodiments of this application specification. In order to avoid the application document being too lengthy, no further details will be given here.

[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 . The magnetic bead purification operation includes the following steps.

[0253] The solution is passed into the magnetic bead purification circulation loop through the magnetic bead purification inlet port 410 and circulated several times.

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

[0255] The washing liquid is introduced through the magnetic bead purification inlet 410, and the magnetic source 460 is moved away, so that the magnetic beads are released and come into contact with the washing liquid. At the same time, the washing liquid and the magnetic beads are vibrated by the oscillation mechanism. After the first preset washing time, the magnetic source 460 is moved back and fixes the magnetic beads, and then the washing liquid is discharged to the waste liquid outlet 440.

[0256] The eluent is introduced through the magnetic bead purification inlet port 410, and the magnetic source 460 is moved away, so that the magnetic beads are released and come into contact with the eluent. The eluent and magnetic beads are vibrated by the oscillation mechanism. After the second preset elution time, the magnetic source 460 is moved back and the magnetic beads are fixed, and the eluent is transported to other downstream components through the magnetic bead purification outlet port 450.

[0257] The first preset time and the second preset time are both set according to process requirements and actual conditions. The two may be the same or different, and the examples in this application do not constitute an undue limitation to them.

[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 was input into the chromatography column.

[0260] The chromatography column is subjected to at least two gradient elutions using the eluent, and the concentration of the eluent used in each gradient elution is different.

[0261] The chromatography column is eluted and the eluted drug solution is collected.

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

[0263] In some embodiments, the method for preparing the nucleic acid solution further comprises an in vitro transcription method, which can employ the in vitro transcription process module provided in any of the aforementioned embodiments. The in vitro transcription method is used to prepare the 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 pipetted into the reaction vessel 12 by the pipetting unit 100 .

[0266] Here, in some embodiments, before S100, at least two reactants may be premixed by a premixing component. Exemplarily, during the premixing, a 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 removal unit 100 , negative pressure is intermittently generated 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 an enzyme reaction.

[0269] For example, mixing unit 200 controls the temperature of reaction vessel 12 at 37°C and incubates the reactants therein for 3 hours. Subsequently, additional solution is injected into reaction vessel 12 again via pipetting unit 100, and reaction vessel 12 is subjected to a constant temperature oscillation operation again. It will be appreciated that the specific temperature and duration of the constant temperature oscillation are process-dependent and may vary in different embodiments, and the examples in the present application are not intended to constitute undue limitations thereto.

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

[0271] In the in vitro transcription process module and in vitro transcription method provided in the embodiments of the present application, the in vitro transcription process module includes a first removal member 120 and a first removal drive mechanism 110 that are coupled together. The first removal drive mechanism 110 drives the first removal member 120 to move, thereby transferring at least two reactants into a reaction vessel 12. Subsequently, the mixing unit 200 drives the reaction vessel 12 to reciprocate, and the temperature control mechanism of the mixing unit 200 transfers heat to the reaction vessel 12 to achieve an enzymatic reaction. Thus, efficient in vitro transcription is achieved.

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

[0273] In addition, the cooperation between the second removing member 140 and the second removing driving mechanism 130 can further improve the efficiency of the in vitro transcription operation.

[0274] After completing the in vitro transcription operation, the solution is purified and prepared into lipid nanoparticles through the first purification operation, lipid nanoparticle preparation, and second purification operation. The effective components of the nucleic acid drug finally obtained are increased through the two purifications.

[0275] Furthermore, related operations can be performed using automated equipment for the preparation of nucleic acid drugs, eliminating the need for manual operation of the entire process, thereby improving preparation efficiency.

[0276] Example 1

[0277] Here, the in vitro transcription operation in the method for preparing nucleic acid drugs is explained by taking the use of two reactants as an example. It should be understood that unless explicitly stated, the order of description of the various steps in this application document does not represent a limitation on their order.

[0278] During specific operation, the second removal member 140 removes the two reactant containers to the clamping mechanism 150, which clamps and fixes the two reactant containers. In addition, the second removal member 140 can also be used to remove the lid of the reactant container to open the reactant container.

[0279] The first removal member 120 moves to the position of one of the reactant containers, and repeatedly absorbs and releases the reactant in the reactant container by intermittently generating negative pressure, thereby achieving mixing.

[0280] After mixing, the first removal unit 120 transfers the reactant to a reactant container of another reactant.

[0281] The second removing member 140 removes the reactant container loaded with two reactants to the premixing unit, and the premixing unit shakes the reactant container to achieve premixing.

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

[0283] After premixing, the first pipette 120 pipettes the solution in the reactant container into the reaction vessel 12, and the second pipette 140 closes the heat-insulating cover 213 and / or the lid of the reaction vessel 12. Here, the drug solution is incubated and the enzyme termination reaction is performed, for example, at 37° for 3 hours.

[0284] The reaction vessel 12 is disposed on the carrier 210 . The temperature control mechanism heats the reaction vessel to a preset temperature range. The mixing drive mechanism 220 drives the reaction vessel 12 to reciprocate to achieve enzyme reaction.

[0285] After the enzyme reaction is completed, the second removal member 140 opens the insulation cover 213 and / or the lid of the reaction vessel 12. When opening the lid of the reaction vessel 12, the positioning component 244 can clamp the reaction vessel 12 to facilitate the second removal member 140 to remove the lid of the reaction vessel 12.

[0286] After the cover is removed, the tilting assembly 240 drives the reaction vessel 12 to tilt so that the solution can be taken out.

[0287] Example 2

[0288] When more reactants are needed according to process requirements, more reactants can be added according to process requirements through the second removal member 140 .

[0289] For example, the three reactants can be transferred to the reactant container of any one of the reactants through the second transfer member 140 for premixing.

[0290] For another example, after or before the first pipetting member 120 pipettes the premixed solution in the reactant container into the reaction vessel 12 , other reactants may be added to the reaction vessel 12 through the first pipetting member 120 .

[0291] Example 3

[0292] When performing the first purification operation, a preliminary preparation step is first performed.

[0293] In the preparatory step, pure water may be input through the first preparatory inlet port 540 . After passing through the first separation and purification device, the pure water flows to the second waste liquid collection port 541 , thereby achieving cleaning of the hollow fibers and the like.

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

[0295] Then, the balancing liquid can be input for rinsing through the first pre-prepared inlet port 540. After flowing through the first separation and purification device, the balancing liquid is divided into two paths and flows to the first waste liquid collection port 524 and the second waste liquid collection port 541 respectively.

[0296] During the balancing liquid flushing process, each first sensor component 542 in the pipeline can be calibrated. For example, the first sensor component 542 includes a pH sensor, which can be calibrated by comparing the value when the balancing liquid flows through with a reference value.

[0297] After the preparatory step is completed, the purification step is performed.

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

[0299] Then, the replacement fluid can be added to the first mixing container 525 through the first replacement fluid input port 526, and the replacement fluid and the aforementioned solution are circulated together 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, the solution output step is performed.

[0301] In the solution output step, a replacement fluid may be added to the first separation and purification device through the first replacement fluid input port 526 to fully push the purified solution out of the first separation and purification device. This step helps to reduce losses.

[0302] The replacement fluid has a preset flow rate, which is determined by prior calculation to prevent excessive addition of the replacement fluid and prevent it from flowing toward the first purification collection end 530 and the first filter assembly 531 .

[0303] Thereafter, the solution flows to the first filtering component 531 and flows to the first purification collection end 530 after being filtered.

[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-prepared inlet port 540. After the pure water passes through the first separation and purification device, it flows to the second waste liquid collection port 541, thereby achieving cleaning.

[0306] Furthermore, gas can be introduced through the first gas inlet port 550. The gas flows through the first filter assembly and then to the second waste liquid collection port 541, thereby facilitating the emptying of liquid from the pipeline. Furthermore, as the gas flows through the first filter assembly, a first detection sensor 551, such as a pressure sensor, can be used to detect whether the first filter assembly is damaged.

[0307] After completing the first extraction operation, the produced liquid is transported to the downstream lipid nanoparticle preparation process module through pipelines, etc., for use in preparing lipid nanoparticles.

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

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

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

[0311] Then, alkali solution is input through the second pre-prepared inlet port 740, and after the alkali solution flows through the second separation and purification device, it flows to the second waste liquid collection port 541. Then, pure water can be introduced again for cleaning, and the flow path is the same.

[0312] Then, the balancing liquid can be input for rinsing through the second pre-prepared inlet port 740. After flowing through the second separation and purification device, the balancing liquid is divided into two paths and flows to the third waste liquid collection port 724 and the fourth waste liquid collection port 741 respectively.

[0313] During the balancing liquid flushing process, each second sensor component 742 in the pipeline can be calibrated. For example, the second sensor component 742 includes a pH sensor, which can be calibrated by comparing the value when the balancing liquid flows through with a reference value.

[0314] After the preparatory step is completed, the purification step is performed.

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

[0316] Then, the replacement liquid, mother liquor, auxiliary material mother liquor, etc. can be added to the second mixing container 725 through the second replacement liquid input end, and the replacement liquid and the aforementioned solution can be circulated together in the second circulation loop, and then 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, the replacement fluid can be added to the second separation and purification device through the second replacement fluid input end to fully push the purified solution out of the second separation and purification device 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 the replacement fluid and prevent it from flowing into the second purification collection container and the second filter assembly 731 .

[0320] Thereafter, the solution flows to the second filter assembly 731 and flows to the second purification collection container after being filtered.

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

[0322] In the post-processing step, pure water can be input through the second pre-prepared inlet port 740. After the pure water passes through the second separation and purification device, it flows to the fourth waste liquid collection port 741, thereby achieving cleaning.

[0323] In addition, gas can be input through the second gas inlet port 750. After flowing through the second filter device, the gas flows to the fourth waste liquid collection port 741, thereby helping to empty the liquid in the pipeline. Furthermore, when the gas flows through the second filter device, a second detection sensor 751, such as a pressure sensor, can be used to detect whether the second filter device is damaged.

[0324] Example 4

[0325] Before performing the first purification operation, a magnetic bead purification operation may be performed using the magnetic bead purification process module 400 .

[0326] Magnetic beads are added to the solution from the upstream, such as the in vitro transcription device, and then introduced into the magnetic bead purification circulation loop through the magnetic bead purification inlet port 410 and circulated several times.

[0327] Then, the magnetic source 460 at the magnetic bead purification container 420 is started. During the flow of the solution, the magnetic beads are adsorbed by the magnetic source 460, thereby separating the magnetic beads and the solution. The magnetic beads are retained in the magnetic bead purification container 420, and the solution is discharged to the waste liquid outlet 440.

[0328] Next, a wash solution is introduced through the magnetic bead purification inlet 410. During this process, the magnetic source 460 is removed, allowing the magnetic beads to be released and come into contact with the wash solution. Simultaneously, an oscillation mechanism causes the wash solution and magnetic beads to vibrate, improving their contact. After washing is complete, the magnetic source 460 is returned to secure the magnetic beads, and the wash solution is discharged to the waste liquid outlet 440.

[0329] Next, the eluent is introduced through the magnetic bead purification inlet 410. During this process, the magnetic source 460 is removed, allowing the magnetic beads to be released and come into contact with the eluent. Simultaneously, the oscillation mechanism causes the eluent and magnetic beads to vibrate, enhancing their contact. After elution is complete, the magnetic source 460 is returned to immobilize the magnetic beads, and the eluent is then delivered through the magnetic bead purification outlet 450 to other downstream components, such as the first purification component.

[0330] Example 5

[0331] Before performing the first purification operation, a chromatography operation may be performed in the chromatography process module 300 .

[0332] During chromatography, a calibration solution is first introduced through chromatography inlet line 310. The calibration solution flows from first port 321 to fourth port 324, bypassing the chromatography column, before entering chromatography outlet line 330. During this process, the readings of various sensor components in the pipelines are calibrated to confirm that their readings are consistent with the expected parameters of the calibration solution, thereby confirming the status of the sensor components.

[0333] Then, the equilibration solution or other solutions are input through the chromatography inlet line 310 , and the solutions flow to the chromatography column through the first port 321 and the second port 322 , and then enter the chromatography outlet line 330 through the third port 323 and the fourth port 324 .

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

[0335] A solution from upstream, such as a solution from an in vitro transcription device, is introduced into the chromatography inlet line 310. The solution flows through the first port 321 and the second port 322 to the chromatography column, and then enters the chromatography outlet line 330 through the third port 323 and the fourth port 324. At this point, the desired substance is retained in the chromatography column, and the remaining solution is discharged.

[0336] Then, a washing solution is input into the chromatography column through the chromatography inlet line 310 for washing. The washing solution can be an alkaline solution to remove the remaining other solutions in the chromatography column. Here, in some examples, washing can be performed twice or more, each time using a washing solution of different concentrations to achieve gradient washing.

[0337] Next, eluent is introduced through the chromatography inlet line 310. The eluent flows through the first port 321 and the second port 322 to the chromatography column, and then enters the chromatography outlet line 330 through the third port 323 and the fourth port 324. The desired substance is thus eluted from the chromatography column and dissolved in the eluent. The eluent containing the desired substance is then introduced through the chromatography outlet line 330 to subsequent downstream components, such as the first purification process module 500.

[0338] It is understandable that when describing the embodiments of the present application, in order to illustrate their functions, in the steps of chromatography, magnetic bead purification, first purification, second purification, etc., some of the required solutions may be named similarly or identically, such as eluent, etc. However, in different components, when carrying out the actual process, the specific solution used will be determined according to the specific process requirements, and it does not mean that the components of the solutions used in different components 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. For the content that is not described in detail in a certain embodiment, the specific implementation details can refer to the descriptions in other embodiments. The example descriptions and technical effects shown in the aforementioned embodiments can all be implemented accordingly. For the repeated parts, this embodiment will not go into details.

[0340] The above is a detailed introduction to the equipment for preparing nucleic acid drugs and the method for preparing nucleic acid drugs provided by the present application. Specific examples are used herein to illustrate the principles and implementation methods of the present application. The description of the above embodiments is only used to help understand the method of the present application and its core idea. At the same time, for those skilled in the art, according to the ideas of the present application, there will be changes in the specific implementation methods and application scopes. In summary, the content of this specification should not be understood as limiting the present application.

Claims

1. A device for preparing nucleic acid drugs, characterized in that: include: In vitro transcription process module, used to provide stock solution; A first purification process module is provided downstream of the in vitro transcription process module and is used to purify the stock solution; a lipid nanoparticle preparation process module, disposed downstream of the first purification process module, to receive the purified stock solution and prepare it into lipid nanoparticles; a second purification process module, disposed downstream of the lipid nanoparticle preparation process module, to purify the solution containing the lipid nanoparticles; as well as The automatic control system is used to realize the 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.

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

3. The device for preparing nucleic acid drugs according to claim 2, characterized in that: The first purification process module also includes: a first purification collection end connected to the first mixing container; and The first filtering component is arranged between the first mixing container and the first purification and collecting end.

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

5. The device 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 port; and, a second waste liquid collection port; Wherein, the first separation and purification device is arranged between the first pre-prepared inlet end and the second waste liquid collection end through a pipeline.

6. The device for preparing nucleic acid drugs according to claim 2, characterized in that: The first mixing container is arranged on a mixing mechanism, and the mixing mechanism comprises: Mixing drive components; an eccentric connecting member, eccentrically connected to the mixing driving member; a supporting member rotatably connected to the eccentric connecting member; When the mixing driving member drives the eccentric connecting member to move, the supporting member and the first mixing container can be driven to rotate and shake, so as to mix the liquid medicine in the first mixing container.

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

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

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

10. The device for preparing nucleic acid drugs according to claim 9, characterized in that: The pre-purification component includes a chromatography process module, and the chromatography process module includes: a main chromatography circuit comprising a first port and a second port in fluidic connection, and a third port and a fourth port in fluidic connection; a chromatography inlet line 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 pipeline is connected to the fourth port.

11. The device for preparing nucleic acid drugs according to claim 10, characterized in that: The first port is selectively connectable to the third port, and the second port is selectively connectable to the fourth port.

12. The device for preparing nucleic acid drugs according to claim 10, characterized in that: The first port is selectively connectable to the fourth port.

13. The device for preparing nucleic acid drugs according to claim 10, characterized in that: A bubble sensor is provided in the chromatography inlet pipeline; The device for preparing nucleic acid drugs further comprises a bubble exclusion pipeline, which is connected to the chromatography inlet pipeline via a bubble trap.

14. The device for preparing nucleic acid drugs according to claim 10, characterized in that: In a state where two or more chromatography inlet pipelines are provided, the two or more chromatography inlet pipelines are connected to a static mixer and then to the chromatography main pipeline. The static mixer has a bent flow channel.

15. The device for preparing nucleic acid drugs according to claim 9, characterized in that: The pre-purification component includes a magnetic bead purification process module, and the magnetic bead purification process module includes: At least one magnetic bead purification inlet; 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 The magnetic source is located at the magnetic bead purification container and is used for selectively adsorbing the magnetic beads.

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

17. The device 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 an adsorption position and a de-adsorption position.

18. The device for preparing nucleic acid drugs according to claim 1, characterized in that: 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 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 according to any one of claims 1 to 18, characterized in that: The steps include: Performing an in vitro transcription process using an in vitro transcription process module to prepare a stock solution; Purifying the raw liquid through a first purification process module; The purified stock solution is transported to the lipid nanoparticle preparation process module, and lipid nanoparticles are prepared by the lipid nanoparticle preparation process module; as well as The solution containing lipid nanoparticles is purified by a second purification process module.

20. The method for preparing a nucleic acid drug according to claim 19, wherein: The purification of the stock solution by the first purification process module includes a purification step, and the purification step includes: The raw liquid is passed through the first separation and purification device multiple times through the first circulation loop; The replacement liquid is added to the first mixing container through the first replacement liquid input end, and the replacement liquid and the original liquid are circulated together in the first circulation loop and flow through the first separation and purification device multiple times.

21. The method for preparing a nucleic acid drug according to claim 20, wherein: After the purification step, a solution output step is further provided, and the solution output step includes: adding a replacement fluid to the first separation and purification device through the first replacement fluid input port to push the purified raw fluid out of the first separation and purification device; The purified raw liquid is made to flow to the first filtering component and then to the first purification collection end after being filtered.

22. The method for preparing a nucleic acid drug according to claim 20, wherein: Also included are post-processing steps, the post-processing steps comprising: Gas is input through the first gas inlet port, and the gas flows through the first filter component and then flows to the second waste liquid collection port; When the gas flows through the first filter assembly, the first detection sensor detects whether the first filter assembly is damaged.

23. The method for preparing a nucleic acid drug according to claim 19, wherein: The purification of the solution containing lipid nanoparticles by the second purification process module includes a preparatory step, wherein the preparatory step includes: Pure water is input through the second pre-prepared inlet end, and after passing through the second separation and purification device, it flows to the third waste liquid collection end; Alkali liquid is input through the second pre-prepared inlet end, and after the alkali liquid flows through the second separation and purification device, it flows to the third waste liquid collection end; Pure water is input again through the second pre-prepared inlet end, and the pure water flows through the second separation and purification device and then flows to the third waste liquid collection end; The balancing liquid is input through the second pre-prepared inlet port for rinsing.

24. The method for preparing a nucleic acid drug according to claim 19, wherein: Before the stock solution is purified by the first purification process module, a magnetic bead purification operation is performed by the magnetic bead purification process module, and the magnetic bead purification operation includes: The stock solution is passed into the magnetic bead purification circulation loop through the magnetic bead purification inlet and circulated several times; The magnetic beads are adsorbed by the magnetic source and retained in the magnetic bead purification container, and the stock solution is discharged to the waste liquid outlet; A washing solution is introduced through the magnetic bead purification inlet, and the magnetic source is removed, so that the magnetic beads are released and contacted with the washing solution. At the same time, the oscillation mechanism causes the washing solution and magnetic beads to vibrate. After washing for a first preset time, the magnetic source is moved back and fixes the magnetic beads, and then the washing solution is discharged to the waste liquid outlet; The eluent is introduced through the magnetic bead purification inlet, and the magnetic source is removed, so that the magnetic beads are released and come into contact with the eluent. The eluent and magnetic beads are vibrated by the oscillation mechanism. After the second preset elution time, the magnetic source is moved back and fixes the magnetic beads, and the eluent is transported to other downstream components through the magnetic bead purification outlet.

25. The method for preparing a nucleic acid drug according to claim 19, wherein: Before the stock solution is purified by the first purification process module, a chromatography operation is performed by the chromatography process module, and the chromatography operation includes: Input the stock solution into the chromatography column; The chromatography column is subjected to at least two gradient elutions using the eluent, wherein the concentration of the eluent used in each gradient elution is different; The chromatography column is eluted, and the eluted medicinal solution is collected.

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