Large-scale pharmaceutical production level nucleic acid synthesizer

Abstract

The utility model relates to a large-scale pharmaceutical production level nucleic acid synthesizer which comprises a monomer pipeline unit, a reagent pipeline unit and a solvent pipeline unit, each single pipeline unit comprises a first inlet valve group, a first flow cell, a first flow meter, a single pump, a first switching valve, a second switching valve, a second flow meter, a second flow cell, a column position valve and an outlet valve which are communicated in sequence, a first UV detector and a second UV detector are arranged at the two ends of the column position valve, and a third flow cell is arranged between the second UV detector and the outlet valve; the reagent pipeline unit comprises a second inlet valve group, a reagent pump, a fourth flow cell, a third flow meter and a T-shaped valve which are communicated in sequence, and the T-shaped valve is communicated with the first switching valve; the solvent pipeline comprises a third inlet valve group, a circulating pump and a fifth flow cell, and the output end of the fifth flow cell is communicated with the second switching valve. The device is simple in overall structure, small in size and short in synthesis pipeline, and the reaction speed and the detection efficiency of each detector are improved.

Description

Technical Field

[0001] The utility model relates to the technical field of nucleic acid synthesizers, in particular to a large-scale pharmaceutical production-level nucleic acid synthesizer. Background Art

[0002] With the rapid development of oligonucleotide chain synthesis technology, the synthesis cost has been continuously reduced, and the synthesis length and precision have been continuously improved, making large-scale DNA and RNA synthesis starting from oligonucleotide chains possible. Therefore, nucleic acid synthesizers have emerged. They are used in the biopharmaceutical field and traditional and biopharmaceutical companies engaged in nucleic acid-related research and development.

[0003] The large-scale pharmaceutical production-level driven nucleic acid synthesizer in the existing technology has a complex overall structure and a large overall structure volume. The distance between the synthesis pipelines is long. On the one hand, more reagents are retained inside the pipelines during the synthesis process, resulting in higher production costs; on the other hand, the longer pipelines will cause the reaction speed of each detector to be slow, affecting the synthesis efficiency. Utility Model Content

[0004] Therefore, the technical problem to be solved by the utility model is to overcome the defects of the prior art that the production-level nucleic acid synthesizer is large in size and has a long synthesis pipeline, resulting in low synthesis efficiency.

[0005] In order to solve the above technical problems, the utility model provides a large-scale pharmaceutical production-level nucleic acid synthesizer, comprising:

[0006] A monomer piping unit, the monomer piping unit comprising a first inlet valve group, a monomer pump, a first switching valve, a second switching valve, a column valve and an outlet valve connected in sequence, a first circulation pool and a first flow meter are connected in series between the first switching valve and the monomer pump, a second flow meter and a second circulation pool are connected in series between the second switching valve and the column valve, a first UV detector and a second UV detector are respectively provided at an input port of the column valve and an output port of the column valve, and a third circulation pool is provided between the second UV detector and the outlet valve;

[0007] A reagent piping unit, wherein the reagent piping unit comprises a second inlet valve group, a reagent pump and a T-type valve connected in sequence, a fourth circulation pool and a third flow meter are connected in series between the reagent pump and the T-type valve in sequence, and an output end of the T-type valve is connected to the first switching valve;

[0008] A solvent pipeline unit, wherein the solvent pipeline comprises a third inlet valve group, a circulation pump and a fifth circulation pool which are connected in sequence, and an output end of the fifth circulation pool is connected to the second switching valve.

[0009] In one embodiment of the present invention, at least two first inlet valve groups are provided, and a third switching valve is provided between at least two first inlet valve groups and the monomer pump.

[0010] In one embodiment of the present invention, an expansion valve is further provided between the second switching valve and the monomer pump.

[0011] In one embodiment of the present invention, the first flow cell, the fourth flow cell and the fifth flow cell are all two-in-one flow cells, and the two-in-one flow cell includes two first pressure sensors connected in series.

[0012] In one embodiment of the present invention, both the second flow cell and the third flow cell are three-in-one flow cells, and the three-in-one flow cell includes a temperature sensor, a second pressure sensor and a conductivity detector integrated inside.

[0013] In one embodiment of the present invention, a heat exchanger valve group is connected in series between the second flow meter and the second circulation pool.

[0014] In one embodiment of the present invention, a fourth switching valve is further provided at the output end of the T-type valve.

[0015] In one embodiment of the present utility model, a fifth switching valve is provided between the third inlet valve group and the circulation pump, and the output end of the fifth switching valve is also connected to the outlet valve.

[0016] In one embodiment of the utility model, it also includes a support frame and an electric control cabinet, the monomer pipeline unit, the reagent pipeline unit and the solvent pipeline unit are arranged in the support frame, the electric control cabinet is arranged on the top of the support frame, and the electric control cabinet is electrically connected to the monomer pipeline unit, the reagent pipeline unit and the solvent pipeline unit.

[0017] In one embodiment of the utility model, a plurality of rollers and adjustable feet are provided at the bottom of the support frame.

[0018] The above technical solution of the utility model has the following advantages compared with the prior art:

[0019] The utility model discloses a large-scale pharmaceutical production-level nucleic acid synthesizer with a simple overall structure and a small size. The entire synthesis pipeline is short, and less buffer solution is contained in the pipeline during the synthesis process, thereby reducing production costs. Secondly, the reaction speed of each detector is increased, thereby improving the detection speed and detection efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to make the content of the utility model easier to understand, the utility model is further described in detail according to the specific embodiments of the utility model in combination with the accompanying drawings, wherein

[0021] Figure 1 It is a schematic diagram of the overall structure of the utility model;

[0022] Figure 2 It is the overall piping diagram of the utility model;

[0023] Figure 3 for Figure 2 Partial piping diagram of the monomer piping unit and reagent piping unit;

[0024] Figure 4 for Figure 2 Partial piping diagram of the solvent piping unit;

[0025] Figure 5 It is an operation flow chart of the utility model;

[0026] Description of the accompanying drawings: 100, monomer pipeline unit; 200, reagent pipeline unit; 300, solvent pipeline unit; 400, support frame; 500, electric control cabinet; 101, first inlet valve group; 102, monomer pump; 103, first switching valve; 104, second switching valve; 105, column valve; 106, outlet valve; 107, first circulation pool; 108, first flow meter; 109, second flow meter; 110, second circulation pool; 111, first UV detector device; 112, second UV detector; 113, third circulation cell; 114, third switching valve; 115, expansion valve; 116, heat exchanger valve group; 201, second inlet valve group; 202, reagent pump; 203, T-valve; 204, fourth circulation cell; 205, third flow meter; 206, fourth switching valve; 301, third inlet valve group; 302, circulation pump; 303, fifth circulation cell; 304, fifth switching valve; 401, roller; 402, adjustment foot. DETAILED DESCRIPTION

[0027] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

[0028] Reference Figure 1-Figure 5 As shown, the utility model discloses a large-scale pharmaceutical production-level nucleic acid synthesizer, comprising:

[0029] A monomer piping unit 100, the monomer piping unit 100 comprises a first inlet valve group 101, a monomer pump 102, a first switching valve 103, a second switching valve 104, a column valve 105 and an outlet valve 106 which are connected in sequence, a first circulation pool 107 and a first flow meter 108 are connected in series between the first switching valve 103 and the monomer pump 102, a second flow meter 109 and a second circulation pool 110 are connected in series between the second switching valve 104 and the column valve 105, a first UV detector 111 and a second UV detector 112 are respectively provided at an input port of the column valve 105 and an output port of the column valve 105, and a third circulation pool 113 is provided between the second UV detector and the outlet valve 106;

[0030] A reagent piping unit 200, wherein the reagent piping unit 200 includes a second inlet valve group 201, a reagent pump 202 and a T-valve 203 which are connected in sequence, a fourth circulation pool 204 and a third flow meter 205 are connected in series between the reagent pump 202 and the T-valve 203, and an output end of the T-valve 203 is connected to the first switching valve 103;

[0031] The solvent pipeline unit 300 includes a third inlet valve group 301 , a circulation pump 302 and a fifth circulation pool 303 which are connected in sequence, and the output end of the fifth circulation pool 303 is connected to the second switching valve 104 .

[0032] It can be imagined that the large-scale pharmaceutical production-level nucleic acid synthesizer in the utility model includes three groups of feeding units during use, wherein the monomer solution enters from the first inlet valve, enters the monomer pipeline through the monomer pump 102, and passes through the first circulation pool 107, the first flow meter 108, the first switching valve 103 and the second switching valve 104 in sequence. Here, the first switching valve 103 and the second switching valve 104 can switch the monomer pipeline and the circulation pipeline online at any time according to process requirements; after passing through the second switching valve 104, it passes through the second flow meter 109, the second circulation pool 110, the first UV detector 111, the column position valve 105, the second UV detector 112 and the third circulation pool 113 once, and is finally discharged from the outlet valve 106. The first circulation pool 107 is used as a detection module to detect the pressure at the output end of the monomer pump 102, which plays an explosion-proof role. The first flow meter 108 and the second flow meter 109 detect the flow rate inside the pipeline. The second circulation pool 110 and the third circulation pool 113 are integrated with multiple detection modules to detect multiple data in the pipeline and feedback (temperature, pressure, conductivity and other data); the first UV detector 111 monitors the content of nucleic acid pre-column substances, the column position valve 105 is used to achieve dual selection of forward column entry and reverse column entry during nucleic acid synthesis, and the second UV detector 112 is used to monitor the content of nucleic acid post-column substances.

[0033] The reagent solution enters from the second inlet valve group 201, is pumped into the fourth circulation pool 204 through the reagent pump 202 to detect various data, enters the T-valve 203, flows into the first switching valve 103, passes through the second switching valve 104, passes through the second flowmeter 109, the second circulation pool 110, the first UV detector 111, the column position valve 105, the second UV detector 112 and the third circulation pool 113, and is finally discharged from the outlet valve 106.

[0034] The solvent solution enters from the third inlet valve group 301 and is pumped into the fifth circulation pool 303 through the circulation pump 302. The detection module integrated in the fifth circulation pool 303 detects the pressure of the pipeline. After passing through the fifth circulation pool 303, the solvent solution enters the second switching valve 104. After passing through the second switching valve 104, it passes through the second flowmeter 109, the second circulation pool 110, the first UV detector 111, the column position valve 105, the second UV detector 112 and the third circulation pool 113, and is finally discharged from the outlet valve 106.

[0035] As a preferred embodiment of the utility model, the first inlet valve group 101, the second inlet valve group 201 and the third inlet valve group 301 all adopt a structure of assembling multiple valve blocks, which can reduce the residual liquid inside the valve block while reducing the installation space, thereby enhancing the performance of the entire system. The remaining valve groups combine multiple valves into a multi-channel valve block, which greatly saves the use space, reduces a large amount of medium residue, and facilitates cleaning and maintenance. Multiple sensors are assembled on a circulation pool, which can realize centralized monitoring of temperature and pressure, realize flexible expansion of the nucleic acid synthesizer, shorten the length of the flow path pipeline, reduce the volume inside the circulation pool, and minimize the flow path volume of the entire system.

[0036] The utility model has a simple overall structure and a small volume, the entire synthesis pipeline is short, and less buffer solution is in the pipeline during the synthesis process, thereby reducing production costs and secondly increasing the reaction speed of each detector, thereby increasing the detection speed and detection efficiency.

[0037] Further, at least two first inlet valve groups 101 are provided, and a third switching valve 114 is provided between at least two first inlet valve groups 101 and the monomer pump 102. An expansion valve 115 is also provided between the second switching valve 104 and the monomer pump 102.

[0038] Specifically, multiple groups of first inlet valve groups 101 are set according to the process requirements to select the inlet of the monomer pipeline, and then the third switching valve 114 is set to switch different first inlet valve groups 101. The expansion valve 115 can add multiple monomer inlets according to the process requirements. Secondly, after the monomer solution enters the first inlet valve, the expansion valve 115 plays a role in controlling and regulating the fluid passage. It is necessary to accurately control the flow and mixing of various reagents to ensure the efficiency, safety and reliability of the nucleic acid synthesis process.

[0039] Furthermore, the first circulation cell 107, the fourth circulation cell 204 and the fifth circulation cell 303 are all two-in-one circulation cells, and the two-in-one circulation cells include two first pressure sensors connected in series; the second circulation cell 110 and the third circulation cell 113 are both three-in-one circulation cells, and the three-in-one circulation cells include an internally integrated temperature sensor, a second pressure sensor and a conductivity detector.

[0040] Specifically, the two-in-one flow cells in the utility model are both arranged at the output port of the pump in each pipeline, and the two pressure sensors in the flow cells are integrated together as a double backup setting, which is also to protect the pump from overpressure and stop. Two three-in-one flow cells are arranged at the input port and output port of the column valve 105, and the three-in-one flow cells integrate a pressure sensor, a temperature sensor and a conductivity detector, which are used to measure the pressure value, temperature value and conductivity value of the target substance before the nucleic acid column.

[0041] Furthermore, a heat exchanger valve group 116 is connected in series between the second flow meter 109 and the second circulation pool 110. Specifically, the temperature in the pipeline is regulated by the heat exchanger valve group 116 according to process requirements.

[0042] Furthermore, a fourth switching valve 206 is also provided at the output end of the T-shaped valve 203 .

[0043] Specifically, the fourth switching valve 206 is set at an outlet of the T-type valve 203. During normal use, the fourth switching valve 206 is in a closed state, and the liquid enters the first switching valve 103 after passing through the T-type valve 203. When other processes are required, they can be expanded and met according to demand through the fourth switching valve 206.

[0044] Furthermore, a fifth switching valve 304 is provided between the third inlet valve group 301 and the circulation pump 302 , and an output end of the fifth switching valve 304 is also connected to the outlet valve 106 .

[0045] Furthermore, it also includes a support frame 400 and an electric control cabinet 500, the monomer pipeline unit 100, the reagent pipeline unit 200 and the solvent pipeline unit 300 are arranged in the support frame 400, the electric control cabinet 500 is arranged on the top of the support frame 400, and the electric control cabinet 500 is electrically connected to the monomer pipeline unit 100, the reagent pipeline unit 200 and the solvent pipeline unit 300.

[0046] Specifically, the support frame 400 supports the installation of various components, facilitates the layout of the entire pipeline and the integration of valve group parts, and reduces the overall installation size. Specifically, the electric control cabinet 500 is electrically connected to the monomer pipeline unit 100, the reagent pipeline unit 200 and the various parts in the solvent pipeline. On the one hand, it is used to feedback the real-time data of the monitoring of each detection part, and on the other hand, the electric control of each valve group is coordinated with the automation system to achieve automatic control.

[0047] Furthermore, a plurality of rollers 401 and adjustable feet 402 are provided at the bottom of the support frame 400; specifically, the rollers 401 are installed at the bottom of the support frame 400 to facilitate the transportation of the entire device, and the adjustable feet 402 can ensure the stability of the device after it is fixed, avoiding shaking during the synthesis process that affects the synthesis effect.

[0048] It should be noted that in the actual operation process, the reagents required for synthesis in each pipeline are all organic solutions, which are volatile and produce toxic gases. Therefore, as a preferred solution of the utility model, each valve is equipped with position feedback of explosion-proof function, and the explosion-proof type is intrinsically safe, which improves the safety of the entire equipment.

[0049] Similarly, in order to ensure the safety of the entire equipment, the electric control cabinet 500 in the utility model has a single-sided double door and has an explosion-proof function, and the explosion-proof type is a positive pressure type. Secondly, the system is also equipped with a remote control box and a mobile control platform. The remote control box can be placed in a safe area to remotely control the system. When the system needs repair or maintenance, the mobile control platform can be pushed into the explosion-proof room for operation, and then pushed back to the safe area for operation.

[0050] In summary, the utility model introduces a large-scale pharmaceutical production-level nucleic acid synthesizer, in which a monomer solution enters from a first inlet valve, enters a monomer pipeline through a monomer pump 102, and passes through a first circulation pool 107, a first flow meter 108, a first switching valve 103, and a second switching valve 104 in sequence. Here, the first switching valve 103 and the second switching valve 104 can switch the monomer pipeline and the circulation pipeline online at any time according to process requirements; after passing through the second switching valve 104, it passes through the second flow meter 109, the second circulation pool 110, the first UV detector 111, the column position valve 105, the second UV detector 112 and the third circulation pool 113 once, and is finally discharged from the outlet valve 106. The reagent solution enters from the second inlet valve group 201, is pumped into the fourth circulation pool 204 through the reagent pump 202 to detect various data, enters the T-valve 203, flows into the first switching valve 103, passes through the second switching valve 104, passes through the second flow meter 109, the second circulation pool 110, the first UV detector 111, the column valve 105, the second UV detector 112 and the third circulation pool 113, and finally is discharged from the outlet valve 106. The solvent solution enters from the third inlet valve group 301, is pumped into the fifth circulation pool 303 through the circulation pump 302, and the detection module integrated in the fifth circulation pool 303 detects the pressure of the pipeline. The solvent solution enters the second switching valve 104 after passing through the fifth circulation pool 303, passes through the second switching valve 104, passes through the second flow meter 109, the second circulation pool 110, the first UV detector 111, the column valve 105, the second UV detector 112 and the third circulation pool 113, and finally is discharged from the outlet valve 106. The utility model has a simple overall structure and a small volume, the entire synthesis pipeline is short, and less buffer solution is in the pipeline during the synthesis process, thereby reducing production costs and secondly increasing the reaction speed of each detector, thereby increasing the detection speed and detection efficiency.

[0051] Obviously, the above embodiments are merely examples for the purpose of clear explanation and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention of the utility model.

Claims

1. A large-scale pharmaceutical production-grade nucleic acid synthesizer, characterized in that: include: A monomer piping unit, the monomer piping unit comprising a first inlet valve group, a monomer pump, a first switching valve, a second switching valve, a column valve and an outlet valve connected in sequence, a first circulation pool and a first flow meter are connected in series between the first switching valve and the monomer pump, a second flow meter and a second circulation pool are connected in series between the second switching valve and the column valve, a first UV detector and a second UV detector are respectively provided at an input port of the column valve and an output port of the column valve, and a third circulation pool is provided between the second UV detector and the outlet valve; A reagent piping unit, the reagent piping unit comprising a second inlet valve group, a reagent pump and a T-type valve connected in sequence, a fourth circulation pool and a third flow meter are connected in series between the reagent pump and the T-type valve in sequence, and an output end of the T-type valve is connected to the first switching valve; A solvent pipeline unit, wherein the solvent pipeline comprises a third inlet valve group, a circulation pump and a fifth circulation pool which are connected in sequence, and an output end of the fifth circulation pool is connected to the second switching valve.

2. The large-scale pharmaceutical production-level nucleic acid synthesizer according to claim 1, characterized in that: At least two first inlet valve groups are provided, and a third switching valve is provided between at least two first inlet valve groups and the monomer pump.

3. The large-scale pharmaceutical production-level nucleic acid synthesizer according to claim 2, characterized in that: An expansion valve is further provided between the second switching valve and the monomer pump.

4. The large-scale pharmaceutical production-level nucleic acid synthesizer according to claim 1, characterized in that: The first flow cell, the fourth flow cell and the fifth flow cell are all two-in-one flow cells, and the two-in-one flow cell includes two first pressure sensors connected in series.

5. The large-scale pharmaceutical production-level nucleic acid synthesizer according to claim 1, characterized in that: The second flow cell and the third flow cell are both three-in-one flow cells, and the three-in-one flow cell includes a temperature sensor, a second pressure sensor and a conductivity detector integrated inside.

6. The large-scale pharmaceutical production-level nucleic acid synthesizer according to claim 1, characterized in that: A heat exchanger valve group is connected in series between the second flow meter and the second circulation cell.

7. The large-scale pharmaceutical production-grade nucleic acid synthesizer according to claim 1, characterized in that: A fourth switching valve is also provided at the output end of the T-type valve.

8. The large-scale pharmaceutical production-grade nucleic acid synthesizer according to claim 1, characterized in that: A fifth switching valve is provided between the third inlet valve group and the circulation pump, and an output end of the fifth switching valve is also connected to the outlet valve.

9. The large-scale pharmaceutical production-grade nucleic acid synthesizer according to claim 1, characterized in that: It also includes a support frame and an electric control cabinet, the monomer pipeline unit, the reagent pipeline unit and the solvent pipeline unit are arranged in the support frame, the electric control cabinet is arranged on the top of the support frame, and the electric control cabinet is electrically connected to the monomer pipeline unit, the reagent pipeline unit and the solvent pipeline unit.

10. The large-scale pharmaceutical production-level nucleic acid synthesizer according to claim 9, characterized in that: The bottom of the support frame is provided with a plurality of rollers and adjustable feet.

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