Cell factory automation device and control method thereof

Abstract

The invention provides a cell factory automation device and a control method thereof, and relates to the technical field of cell factory automation, the cell factory automation device comprises an operation device, a tube sealing machine, a sterile tube receiving machine and a control monitoring module; the pipe sealing machine and the sterile pipe connecting machine are used for sterile connection of pipelines; the operation device is used for cleaning and digesting cells after sterile connection is completed, resuspending the cells with a culture medium, and sub-packaging the cells into a 10-layer cell factory, a 40-layer cell factory and a disposable liquid storage bag; the sterile pipe receiving machine comprises a main machine, a pipe support and a power supply, the operation device comprises a mechanical arm, a cell culture frame, an operation platform and a system operation panel, and the cell factory is automatically controlled and monitored, so that sterile automatic treatment and abnormality recognition are realized, the treatment efficiency is improved, and the abnormal loss is reduced.

Description

Technical Field

[0001] The present invention provides a cell factory automation device and a control method thereof, relating to an automation device, and specifically to the technical field of cell factory automation. Background Art

[0002] The current operation of cell factories adopts a manual operation mode. In the traditional Vero cell passage operation process, manual cleaning and digestion of cell factories are carried out manually, and operations such as cell factory passage and cell suspension collection are completed. When adding or changing the liquid in the cell factory, it needs to be opened, which requires a very high environmental level and needs to be carried out in a sterile environment, generally under the protection of a Class A laminar flow. The cell factory is relatively heavy, especially the cell factory after adding cell culture medium is more difficult to handle and is prone to collision. After collision, the factory cannot be used for production, resulting in a reduction in product yield. In the digestion and oscillation operation of the cell factory, the shaking effect is uneven, the number of cells and the cell viability decrease, resulting in certain batch-to-batch differences. The traditional method is extremely likely to cause biological product contamination or quality non-uniformity. It is difficult for traditional cell engineering automation devices to conduct separate control anomaly analysis for each control stage and adjacent continuous anomaly analysis for multiple control stages, resulting in difficulty in accurately identifying control anomalies, and thus a low yield rate and large losses. Summary of the Invention

[0003] The present invention provides a cell factory automation device and a control method thereof to solve the above problems: A cell factory automation device and a control method thereof proposed by the present invention, the cell factory automation device includes an operation device, a tube sealer, a sterile tube connecting machine, and a control and monitoring module; The tube sealer and the sterile tube connecting machine are used for aseptic connection of pipelines; The operation device is used to wash, digest cells and resuspend them with a culture medium after aseptic connection, and dispense them into 10-layer cell factories, 40-layer cell factories, and disposable liquid storage bags; The control and monitoring module is used to conduct control analysis on multiple control stages of a preset operation process, obtain determination information of the control stages, and then conduct stage determination early warning and marking; The sterile tube connecting machine includes a main machine, a tube support, and a power supply; The operation device includes a robotic arm, a cell culture rack, an operation platform, and a system operation panel.

[0004] Further, the control method includes: Connect the connection pipeline of the cell factory to the cell factory through the sterile tube connecting machine to obtain a completed connection pipeline; The manipulator is controlled by an operating device to grasp the cell factory with the connected pipeline and the cell culture rack to a designated station and perform preset operations, completing the cell passage operation; Obtain a preset operation process, divide it to obtain multiple control stages, obtain control acquisition data for each control stage, and perform control state analysis and scoring on each control stage according to the control acquisition data to obtain control scoring data; Obtain the control scoring data of adjacent control stages and the next adjacent control stages, perform comparative analysis of the control scoring data, and then obtain the stage determination information of the adjacent control stages and the next adjacent control stages; Perform stage determination early warning and marking according to the stage determination information.

[0005] Advantages of the present invention: The present invention provides an automated process method used in a biological product production workshop. The tube connecting machine and the tube sealing machine are used for docking and sealing, and aseptic operation can be carried out in a low-level aseptic environment. The operation mode of the cell factory automated operating system for transporting the cell factory and preparing Vero cells in the cell factory has been upgraded from traditional manual operation to robot operation. Utilizing the advantages of high action consistency, good stability, high precision, and high efficiency of the robot reduces the labor intensity, realizes an efficient and safe biological product preparation scheme, saves materials, improves product quality, greatly reduces the human input, and improves the operation efficiency. The present invention is a simple and feasible operation scheme to realize the operation of the cell factory, thereby saving materials, reducing costs, and ensuring the consistency of operations.

[0006] This method uses the cell factory automated operating system to complete the handling and oscillation of the cell factory, which can effectively reduce labor costs, improve culture efficiency, improve product quality, and reduce the occupied space.

[0007] During the process operation, it is completely sealed without open operation. During the cell passage process, the pipeline is aseptically connected through a tube sealing machine and a tube connecting machine. The culture medium in the culture bottle is pumped out using a peristaltic pump. The cells are washed and digested through the cell factory automated operating system, and the digested cells are resuspended with the culture medium and subpackaged into 10-layer cell factories, 40-layer cell factories, and disposable liquid storage bags. There is no opening throughout the process, reducing the requirements for the operation environment level and reducing the pollution risk.

[0008] The fully automated operating system of the cell factory transfers the cell factory placed in the constant temperature room to the operating table for operation, avoiding handling, reducing the risk of breakage, and improving the cell production quality.

[0009] The present invention also realizes independent abnormal monitoring and continuous abnormal monitoring of multiple control stages, thereby improving the product yield rate and reducing the losses caused by the difficulty of detecting abnormal control. Description of the Drawings

[0010] Figure 1 It is a schematic diagram of an automated control method for a cell factory. Specific implementation manners

[0011] The preferred embodiments of the present invention will be described below with reference to the accompanying drawings. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0012] An embodiment of the present invention is an automated device for a cell factory. The automated device for the cell factory includes an operating device, a tube sealer, a sterile tube connecting machine, and a control and monitoring module; The tube sealer and the sterile tube connecting machine are used for aseptic connection of pipelines; The operating device is used to wash, digest cells and resuspend them with a culture medium after aseptic connection, and dispense them into 10-layer cell factories, 40-layer cell factories, and disposable liquid storage bags; The control and monitoring module is used to perform control analysis on multiple control stages of a preset operation process, obtain determination information of the control stages, and then perform stage determination early warning and marking; The sterile tube connecting machine includes a main machine, a tube holder, and a power supply; The operating device includes a robotic arm, a cell culture rack, an operating platform, and a system operation panel.

[0013] The working principle of the above technical solution is as follows: In the present invention, a tube sealer and a tube connecting machine are used for docking and sealing. Aseptic operations are carried out in a bacterium-containing environment with a lower environmental level. The operation modes of the automated operating system of the cell factory for transporting and oscillating and for preparing Vero cells in the cell factory are robotic operations. The automated operating system of the cell factory is used to complete the transportation and oscillation of the cell factory. During cell passage, the pipelines are aseptically connected through a tube sealer and a tube connecting machine. The culture medium in the culture bottle is pumped out by a peristaltic pump. The cells are washed and digested through the automated operating system of the cell factory, and the digested cells are resuspended with a culture medium and dispensed into 10-layer cell factories, 40-layer cell factories, and disposable liquid storage bags.

[0014] The technical effects of the above technical solution are as follows: In this device, a tube connecting machine and a tube sealer are used for docking and sealing, and aseptic operations can also be carried out in a bacterium-containing environment with a lower environmental level. The operation modes of the automated operating system of the cell factory for transporting and oscillating and for preparing Vero cells in the cell factory are upgraded from traditional manual operations to robotic operations. By taking advantage of the high action consistency, good stability, high precision, and high efficiency of the robot, the labor intensity is reduced, an efficient and safe biological product preparation scheme is realized, materials are saved, the product quality is improved, the manpower input is greatly reduced, and the operation efficiency is enhanced. The present invention provides a simple and feasible operation scheme to realize the operation of the cell factory, thereby saving materials, reducing costs, and ensuring the consistency of operations.

[0015] The use of an automated operating system for cell factories to complete the handling and oscillation of cell factories can effectively reduce labor costs, improve culture efficiency, enhance product quality, and reduce occupied space.

[0016] During the process operation, it is completely airtight without any open operation. During the cell passage process, the pipelines are aseptically connected through a tube sealing machine and a tube connecting machine. The culture medium in the culture bottle is pumped out using a peristaltic pump. The cells are washed and digested through the automated operating system of the cell factory, and the digested cells are resuspended with the culture medium and then subpackaged into 10-layer cell factories, 40-layer cell factories, and disposable liquid storage bags. There is no opening throughout the process, reducing the risk of bacterial contamination.

[0017] The fully automated operating system of the cell factory transfers the cell factory placed in the constant temperature room to the operating table for operation, avoiding handling, reducing the risk of breakage, and improving the quality of cell production.

[0018] In one embodiment of the present invention, the control method includes: S1. Connect the connection pipeline of the cell factory to the cell factory through a sterile tube connecting machine to obtain a completed pipeline connection; S2. Control the robotic arm through an operating device to grab the cell factory with the completed pipeline connection and the cell culture rack to a designated station and perform preset operations to complete the cell passage operation; S3. Obtain a preset operation process, divide it to obtain multiple control stages, obtain the control acquisition data for each control stage, and perform control state analysis and scoring on each control stage according to the control acquisition data to obtain control scoring data; Collect image data for each control stage through a sensor, and obtain control stage analysis and determination data by analyzing the image data; S4. Obtain the control scoring data of adjacent control stages and further adjacent control stages, perform comparative analysis of the control scoring data, and then obtain the stage determination information of adjacent control stages and further adjacent control stages; the further adjacent control stages are two adjacent control stages. For example, 1 and 2 are an adjacent control stage, 3 and 4 are a control stage, and 1, 2 and 3, 4 are further adjacent control stages.

[0019] S5. Perform stage determination warning and marking according to the stage determination information.

[0020] The working principle of the above technical solution is as follows: The sterile tube connecting machine aseptically connects the connection pipeline of the cell factory to the cell factory main body through an automated cutting and welding method. The main machine controls the cutting tool to form a smooth cut at the pipeline contact part, and then the welding module realizes the seamless connection between the pipeline and the cell factory through hot melting to form a complete pipeline system.

[0021] The operating device grabs the cell factory and the cell culture rack with the connected pipeline through a robotic arm, transfers them to the designated workstations, and performs cell processing; In the preset operation process, the system collects parameters (such as images) of each control stage in real time. Based on the collected control data, it evaluates the status of each control stage and generates control scoring data.

[0022] Obtain the control scoring data of adjacent control stages (such as stage 1 and stage 2) and further adjacent control stages (such as stage 1-2 and stage 3-4).

[0023] Compare the scoring differences between adjacent stages and analyze the operation stability or the changing trend of cell status.

[0024] Determine whether there are abnormalities (such as operation deviation, cell contamination risk) in adjacent stages and further adjacent stages.

[0025] According to the comparison result, generate stage determination information (such as "normal", "abnormal", "attention required"), and mark the specific abnormal type or risk level.

[0026] The technical effects of the above technical solution are as follows: The automated operation of the aseptic pipe connection machine eliminates the risk of manual contamination, ensures the aseptic connection between the pipeline and the cell factory, and reduces the cell culture failure rate.

[0027] The robotic arm performs the subculture operation according to the preset process, reduces human error, and improves the operation consistency and cell survival rate.

[0028] The collected control data reflects the operation status in real time, supports dynamic adjustment of parameters (such as flow rate, temperature), and ensures the stability of cell culture conditions.

[0029] By comparing the scores of adjacent and further adjacent control stages, identify operation deviations or cell status abnormalities in advance, and reduce the risks of contamination or culture failure.

[0030] Through automated connection, standardized operation, real-time data collection and intelligent analysis, achieve precise control and risk warning in the cell factory culture process, and significantly improve the cell culture efficiency and reliability.

[0031] In an embodiment of the present invention, connecting the connecting pipeline of the cell factory to the cell factory through an aseptic pipe connection machine to obtain a pipeline with completed connection includes: Turn on the power supply and press the switch button to start and self-check the aseptic pipe connection machine; After the self-check is completed, insert the pipe support into the inner pipe support base of the machine through the top cover of the aseptic pipe connection machine, and install the blade on the blade socket; Install the two connecting pipelines to be installed in the grooves in the pipe support; Heat the blade and then cool it to the welding temperature, and perform cutting and welding of the connecting pipe; After welding, cool down the blade; Obtain the connected pipeline and close the aseptic pipe connecting machine.

[0032] The working principle of the above technical solution is: The main structure of the BioWelderTC aseptic pipe connecting machine consists of a main unit, a pipe support and a power supply. It mainly cuts and welds pipes by heating the blade.

[0033] The operation steps include: 60. Connect the power supply and turn on the switch button.

[0034] 61. The device enters the login interface and the machine top cover automatically pops open. Press "▼" on the touch screen, select "Example" in the box under User name, and the box under Password is blank.

[0035] 62. Press "√" on the touch screen to enter the waiting self-check state. Cover the machine top cover, and at this time the machine starts routine self-check.

[0036] 63. Installation After the self-check is completed, the machine top cover will pop open automatically, and "Insert blade, tubes (C-Flex374) and close cover" will be displayed in the middle box of the screen.

[0037] Insert the pipe support on the pipe support base inside the machine, noting that the side of the pipe support with the pipe diameter marking faces outward to make the pipe support fit with the base.

[0038] Forcefully install the blade on the blade socket, noting that the side with the identification point should face downwards and the identification point should face to the right for installation.

[0039] 64. Aseptic pipe connection Install the two pipelines to be docked in the grooves inside the pipe support, noting that the pipelines should be installed firmly and locked.

[0040] Cover the machine top cover and press "►" on the screen to start aseptic pipe connection.

[0041] Heat the blade to 410 degrees to remove all heat sources, then cool it to the welding temperature, and perform cutting and welding.

[0042] After welding is completed, the machine will cool down the blade inside, and the top cover will pop open automatically after the automatic operation ends.

[0043] Take out the already docked pipelines, use the blade clip to take out the blade, remove the pipe support, cover the machine top cover, and the operation ends.

[0044] The technical effects of the above technical solution are as follows: Through a series of designs such as takeover startup, installation, and aseptic takeover, the full-process automated operation from starting the aseptic takeover machine to obtaining the connected and completed pipeline and shutting down the machine is realized, reducing manual intervention, improving the accuracy and consistency of operations, and reducing the risk of operation errors caused by human factors.

[0045] The entire connection process is completed inside the aseptic takeover machine. By utilizing the closed structure and specific design of the machine itself, the entry of external pollutants is effectively avoided, ensuring the aseptic conditions during the connection process of the cell factory connection pipeline, maintaining the purity of the cell culture environment, and improving the quality and success rate of cell culture.

[0046] The aseptic takeover module first heats the blade and then cools it to the welding temperature, and then cuts and welds the connection pipeline. This precise temperature control can achieve precise cutting and high-quality welding, ensuring the sealing performance and connection strength of the connection pipeline, and reducing problems such as leakage of cell culture medium caused by loose connection or poor sealing.

[0047] After turning on the power and pressing the switch button, the aseptic takeover machine starts and self-checks, and can promptly detect potential faults or problems of the equipment, ensuring that the equipment performs pipeline connection operations under normal operating conditions, and improving the reliability and stability of the equipment operation.

[0048] In an embodiment of the present invention, the cell factory and the cell culture rack with the connected and completed pipeline are grabbed by the robotic arm through the operating device and placed at the designated station for preset operations to complete the cell passage operation, including: Install the robotic arm on the operating platform and place the cell culture rack on the operating platform; Turn on the power of the robotic arm, and control the robotic arm through the system operation panel to grab the cell culture rack and the cell factory with the connected and completed pipeline at the corresponding station according to the preset operation process for operation; After the operation is completed, turn off the power of the robotic arm to complete the cell passage operation.

[0049] The operations include: sequentially performing cell confirmation, pipeline connection, cell cleaning, cell digestion, cell resuspension, cell inoculation, and cell culture.

[0050] The working principle of the above technical solution is: The equipment consists of a robotic arm, a cell culture rack, an operating platform, and a system operation panel. Operation instructions are sent to the robotic arm through the system operation panel, and the robotic arm operates according to the operation instructions in accordance with the technological steps to complete cell passage.

[0051] The specific operation steps include 70. The system is powered on and enters the login interface. After the operator enters the username and password, enter the main interface; 71. New Recipe Click on "Recipe Management" to create a passage batch number; After selecting the newly created batch in the batch list, click "Batch Confirmation" to confirm the passage batch of this operation.

[0052] Click to return to the main page, click the "Power" button to turn on the power of the robotic arm.

[0053] According to the batch required for passage, click on "CF10 / CF40 Process Selection" at the lower left corner of the selection interface, click the "Start" button to perform cell passage, and according to the operation process, grasp the cell culture rack on the corresponding work station for operation.

[0054] 72. After the operation is completed, turn off the power switch on the main interface, and this cell passage operation is completed.

[0055] Specific implementation example: In the process of preparing the cell suspension of freeze-dried human rabies vaccine (Vero cells), the cell factory automated operating system is used in the passage and cell suspension collection processes of 10-layer cell factories and 40-layer cell factories. The specific process is as follows: 1. Cell Passage (Passage of 10-Layer Cell Factory) 1.1 Pipeline Connection (1) Start the cell factory automated operating system, enter the user name and password, log in to the program, connect the pipeline of the cell factory to the 10-layer cell factory through the aseptic pipe connecting machine, use the cell factory automated operating system to grasp the 10-layer cell factory with the pipeline connection completed to the designated work station, and use the aseptic pipe connecting machine to connect the 10-layer cell factory to the cell factory connecting pipeline and grasp it to the designated work station.

[0056] (2) Use the aseptic pipe connecting machine to connect the digestion and liquid separation pipeline to the hot melt pipe, disposable liquid storage bag on the three-way valves of the cell factory connecting pipeline, washing liquid supply pipeline, cell growth liquid supply pipeline, and digestion liquid supply pipeline respectively, and place the 113L disposable liquid storage bag on the weighing and oscillating cart.

[0057] 1.2 Cell Cleaning and Digestion (1) Cell Cleaning a. Click to enter the passage program of the cell factory automated operating system, click "Drainage" on the screen, open the pipeline valve of the disposable liquid storage bag connected to the cell factory pipeline, use the peristaltic pump to drain the culture solution in the cell factory, and close the pipeline valve of the disposable liquid storage bag after all the liquid is drained.

[0058] b. Open the valve of the washing liquid supply pipeline, click the "Next" button on the screen of the cell factory automated operating system, use the peristaltic pump to add washing liquid to each cell factory, and close the valve of the washing liquid supply pipeline.

[0059] c. Wash the cells. After washing, open the pipeline valve of the disposable liquid storage bag, click the "Next" button on the screen of the cell factory automated operating system, and use a peristaltic pump to drain the washing liquid in the cell factory. After all the liquid is drained, close the pipeline valve of the disposable liquid storage bag, and click the screen of the cell factory automated operating system to enter the digestion procedure.

[0060] (2)Cell Digestion a. Open the valve of the digestion solution supply pipeline, click the "Next" button on the screen of the cell factory automated operating system, add the digestion solution through a peristaltic pump, close the valve of the digestion solution supply pipeline, digest the cells, and after standing and digesting the cells, open the pipeline valve of the disposable liquid storage bag, click the "Next" button on the screen of the cell factory automated operating system, and use a peristaltic pump to drain the digestion solution in the cell factory. After all the liquid is drained, close the pipeline valve of the disposable liquid storage bag.

[0061] b. Stop digestion when obvious cell gaps appear in the cells.

[0062] 1.3 Cell Resuspension (1)Open the valve of the cell growth solution supply pipeline, add the cell growth solution to the disposable liquid storage bag through a peristaltic pump, and close the valve of the cell growth solution supply pipeline.

[0063] (2)Click the "Next" button on the screen of the cell factory automated operating system, use a peristaltic pump to add the cell growth solution to the digested 10-layer cell factory, click the "Next" button on the screen of the cell factory automated operating system, and perform cell oscillation.

[0064] (3)After the oscillation is completed, use a peristaltic pump to add the cell suspension in the 10-layer cell factory to the disposable liquid storage bag, disconnect the connection between the cell factory pipeline and the digestion liquid separation pipeline through a sterile tube sealer, and remove the 10-layer cell factory that has completed cell resuspension from the cell culture room.

[0065] (4)Start the weighing and oscillating vehicle.

[0066] 1.4 Cell Inoculation (1)Use the cell factory automated operating system to grab a set of 10-layer cell factories with pipeline connections completed to the designated work station.

[0067] (2)Connect the cell factory connection pipeline to the digestion liquid separation pipeline through a sterile tube connector.

[0068] (3)Click the "Next" button on the screen of the cell factory automated operating system, and inoculate the cell suspension into the 10-layer cell factory through a peristaltic pump, and perform subculture according to the corresponding ratio.

[0069] (4) After the passage is completed, disconnect the connection between the cell factory connection pipeline and the digestion and liquid separation pipeline through a sterile pipe capping machine. Click the operation button on the screen of the cell factory automation operating system and place the 10-layer cell factory after passage at the designated station.

[0070] (5) Perform passage of the 10-layer cell factory.

[0071] 1.5 Cell culture The 10-layer cell factory is statically cultured in a 37°C cell culture room.

[0072] 2 Cell suspension preparation 2.1 Pipeline connection 2.1.1 Start the cell factory automation operating system, enter the username and password, log in to the program, and use the cell factory automation operating system to grab a set of 40-layer cell factories to the designated station. Connect the cell suspension pipeline to the hot melt pipes on the three-way valves of the washing liquid supply pipeline, cell growth liquid supply pipeline, and digestive solution supply pipeline respectively.

[0073] 2.1.2 Connect the cell suspension pipeline to the disposable liquid storage bag respectively, and place the 50L disposable liquid storage bag on the weighing and oscillating vehicle.

[0074] 2.1.3 Connect the cell suspension pipeline to the cell factory connection pipeline.

[0075] 2.2 Cell washing and digestion 2.2.1 Cell washing (1) Click to enter the cell suspension preparation program of the cell factory automation operating system, click "Drain" on the screen, open the pipeline valve of the disposable liquid storage bag and the cell factory connection pipeline, and use a peristaltic pump to drain the culture solution in the cell factory. After all the liquid is drained, close the pipeline valve of the disposable liquid storage bag.

[0076] (2) Open the valve of the washing liquid supply pipeline, click the "Next" button on the screen of the cell factory automation operating system, and use a peristaltic pump to add washing liquid to each cell factory. Then close the valve of the washing liquid supply pipeline.

[0077] (3) Wash the cells. After washing, open the pipeline valve of the disposable liquid storage bag, click the "Next" button on the screen of the cell factory automation operating system, and use a peristaltic pump to drain the washing liquid in the cell factory. After all the liquid is drained, close the pipeline valve of the disposable liquid storage bag, and click the screen of the cell factory automation operating system to enter the digestion program.

[0078] 2.2.2 Cell digestion (1) Open the valve of the digestive solution supply pipeline, click the "Next" button on the screen of the cell factory automation operating system, and add digestive solution through a peristaltic pump. Then close the valve of the digestive solution supply pipeline.

[0079] (2) Digest the cells. After allowing the cells to be digested and settle, open the pipeline valve of the 208L disposable liquid storage bag, click the "Next" button on the screen of the cell factory automated operating system, and use a peristaltic pump to drain the digestive fluid in the cell factory. After all the liquid has been drained, close the pipeline valve of the disposable liquid storage bag.

[0080] 2.2.3 Cell resuspension (1) Open the valve of the cell growth medium supply pipeline, click the "Next" button on the screen of the cell factory automated operating system, and use a peristaltic pump to add cell growth medium to each 40-layer cell factory, then close the valve of the cell growth medium supply pipeline.

[0081] (2) Click the "Next" button on the screen of the cell factory automated operating system to perform cell oscillation.

[0082] 2.3 Cell suspension collection 2.3.1 Cell suspension collection (1) Open the pipeline valve of the disposable liquid storage bag.

[0083] (2) Click the "Next" button on the screen of the cell factory automated operating system, and use a peristaltic pump to collect the cell suspension in the cell factory into the disposable liquid storage bag, and at the same time start the weighing and oscillating cart.

[0084] 2.3.2 Use a sterile tube sealer to disconnect the connection between the cell suspension pipeline and the cell factory connection pipeline, and use a sterile tube connector to reconnect another set of cell factory connection pipelines. Collect 40-layer cell factories according to this operation process;

[0085] The technical effects of the above technical solutions are as follows: By presetting the operation process on the system operation panel, the robotic arm can accurately grasp the cell culture rack and the connected cell factory, and execute the entire process of cell passage (cell confirmation, pipeline connection, cleaning, digestion, resuspension, inoculation, culture), reducing human error and improving the consistency and repeatability of operations.

[0086] The preset operation process ensures that each passage operation follows the same parameters (such as time, temperature, flow rate, etc.), improving the stability of cell culture quality.

[0087] After the robotic arm is installed on the operation platform, it can quickly connect to the power supply and start the preset process, shortening the operation preparation time.

[0088] The full process automation from cell confirmation to cell culture reduces manual intervention, and the single-batch processing time can be shortened by 30%-50%.

[0089] Adjust the digestive enzyme concentration and action time according to the preset parameters to avoid over-digestion; evenly mix the cell suspension during the resuspension stage to ensure the consistency of cell density.

[0090] The robotic arm completes pipeline connection and cell operations under sterile conditions, reducing the risk of external contamination and lowering the cell culture failure rate.

[0091] The automated process reduces the direct contact between operators and cell samples, further reducing the possibility of contamination.

[0092] The system operation panel records the full-process control and generates an electronic batch record.

[0093] In one embodiment of the present invention, the method for obtaining a preset operation process, dividing it into multiple control stages, obtaining control acquisition data for each control stage, and analyzing and scoring the control status of each control stage based on the control acquisition data to obtain control scoring data includes: Divide the operation process into multiple control stages according to the preset operation process to obtain multiple control stages of the operation process; The multiple control stages include a cell confirmation stage, a pipeline connection stage, a cell washing stage, a cell digestion stage, a cell resuspension stage, a cell seeding stage, and a cell culture stage; The cell confirmation process is to transfer the cell factory to a designated position using an automated device and confirm the cell status using other equipment; Collect control data for each control stage by setting a sensor group to obtain control acquisition data; the control acquisition data includes images, etc.

[0094] Preprocess the control acquisition data to obtain control processed data; Perform image feature comparison and analysis on the control processed data for each control stage to obtain control status determination information for each control stage.

[0095] Each control stage includes multiple feature analysis categories. Compare the image feature data of each feature analysis category with the target feature data to obtain control status determination information for the image feature data of each feature analysis category; When the image feature data meets the target feature data, set the control status score of the feature analysis category to 1; When the image feature data does not meet the target feature data, set the control status score of the feature analysis category to 2; When the product of the control status scores of all feature analysis categories is 1, determine that the control status score of the control stage is 1; When the product of the control status scores of all feature analysis categories is greater than 1, determine that the control status score of the control stage is 2.

[0096] The working principle of the above technical solution is as follows: Deploy multiple types of sensors (such as image sensors) in each control stage to collect key parameters (such as image data) in real time: perform normalization processing and missing value filling processing on the control-acquired data, etc.; Extract key features from the image data (such as cell density, pipeline connection integrity, cell morphology uniformity). Compare the real-time image features with the preset standard template to identify abnormalities (such as cell clumps, pipeline offsets).

[0097] Based on the feature comparison results, generate control status determination information (such as "normal", "pipeline leakage", "abnormal cell density").

[0098] According to the control-acquired data (feature data of the image) and the status determination information, score each control stage (1 or 2).

[0099] The technical effect of the above technical solution is as follows: Through multi-stage data collection, realize the control analysis and monitoring of multiple stages in the whole process of cell passage. Quickly locate the problem stage (such as "low score in the cell digestion stage"), and reduce the troubleshooting time.

[0100] Generate control score data in real time, quantify the operation quality, and give early warnings of potential risks.

[0101] Through image feature comparison, automatically identify abnormal cell states (such as excessive cell clumps), and avoid manual subjective judgment errors. Through stage score comparison, ensure that each operation meets the qualified requirements. Through the status determination information, quickly locate stage faults and reduce downtime. Support parameter adjustment for different cell types (such as adherent cells, suspension cells), and adapt to 10-layer / 40-layer cell factories and disposable culture bags.

[0102] In one embodiment of the present invention, the image feature comparison and analysis of each control stage for the control-processed data to obtain the control status determination information of each control stage includes: Sequentially obtain the image data of the control-processed data of each control stage, perform feature extraction on the image data of the control stage to obtain image feature data; Obtain the target feature data of the control stage, compare the image feature data with the target feature data in terms of data of multiple feature types to obtain the types of feature deviations and their feature deviation data of the control stage; Conduct control status analysis on the control stage according to the types of feature deviations combined with the feature deviation data to obtain control status analysis data; when the control status analysis data is normal control status, determine its control status score as 1, and when the control status analysis data is abnormal control status, determine its control status score as 2.

[0103] Based on the control status analysis data, perform control status scoring to obtain the control scoring data for the control phase.

[0104] The working principle of the above technical solution is as follows: For each control phase (such as cell confirmation, pipeline connection, etc.), extract the corresponding image data from the control processing data.

[0105] Extract key image features through image processing algorithms (such as edge detection, texture analysis, morphological operations), for example: Cell morphology, density, and distribution uniformity in the cell confirmation phase. Pipeline interface integrity and liquid flow state in the pipeline connection phase. Cell clump size and dispersion degree in the cell digestion phase.

[0106] Preset the target feature data for each control phase (such as the ideal cell morphology, image template for leak - free pipeline connection).

[0107] Perform multi - dimensional comparison between the real - time image feature data and the target feature data to identify the deviation type (such as morphological deviation, density deviation) and the deviation value (such as cell density deviation ±10%).

[0108] According to the deviation type and threshold, divide the control status into "normal" or "abnormal": The deviation value is within the preset tolerance range (such as cell density deviation <5%). The deviation value exceeds the threshold (such as liquid leakage occurs in pipeline connection). Scoring = 1 (indicating that the operation meets the standard). Scoring = 2 (indicating that manual intervention or equipment adjustment is required).

[0109] Summarize the scoring data for each control phase to form the full - process control scoring data.

[0110] Feed the real - time scoring result back to the control system to trigger corresponding actions (such as pausing the operation and alarming in case of abnormality).

[0111] The technical effect of the above technical solution is as follows: Through image feature comparison, quickly identify operation abnormalities (such as too large cell clumps, pipeline connection deviation), reducing the dependence on manual inspection.

[0112] Preset standard image feature data to ensure that each operation meets the unified standard and reduce human operation differences.

[0113] Enforce operation compliance through the scoring mechanism (normal = 1, abnormal = 2) to improve batch - to - batch consistency.

[0114] When scoring = 2, automatically trigger an alarm to prompt the operator to intervene (such as reconnecting the pipeline).

[0115] Based on the statistics of abnormal types (such as frequent "pipeline connection abnormalities"), maintain the equipment in advance (such as replacing seals).

[0116] Long-term accumulated characteristic deviation data (such as cell digestion time deviation) can reveal abnormal stage operations and prompt parameter adjustment.

[0117] Through the correlation analysis of stage score data (such as "abnormal cell digestion" leading to "low cell seeding score"), the analysis of the impact of control anomalies in adjacent control stages before and after is realized, and the parameters of the whole process are optimized.

[0118] In an embodiment of the present invention, the control score data of adjacent control stages and re-adjacent control stages are obtained, and a comparative analysis of the control score data is performed, and then the stage determination information of the adjacent control stages and the re-adjacent control stages is obtained, including: Obtain the control score data of adjacent control stages, which are set as the first control score data and the second control score data; the first control score data is the control score data of the control stage that is carried out first in the adjacent control stages, and the second control score data is the control score data of the control stage that is carried out later in the adjacent control stages.

[0119] When the first control score data is greater than the second control score data, it is determined that the control stage corresponding to the first control score data is an abnormal stage; When the second control score data is greater than the first control score data, it is determined that the control stage corresponding to the second control score data is an abnormal stage; When the first control score data is equal to the second control score data and greater than 1, it is determined that the control stages corresponding to the first control score data and the second control score data are both abnormal stages; When the first control score data is equal to the second control score data and equal to 1, it is determined that the control stages corresponding to the first control score data and the second control score data are both normal stages.

[0120] The working principle of the above technical solution is: obtain the control score data of adjacent control stages, which are specifically divided into the first control score data and the second control score data. The first control score data represents the score of the control stage that is carried out first in the adjacent control stages, while the second control score data represents the score of the control stage that is carried out later.

[0121] Compare the first control score data and the second control score data to judge the states of the two control stages.

[0122] According to the comparison result, stage determination is carried out: If the first control score data is greater than the second control score data, it is determined that the control stage corresponding to the first control score data is an abnormal stage. For example, the first control score data is 2 and the second control score data is 1; If the second control score data is greater than the first control score data, it is determined that the control phase corresponding to the second control score data is an abnormal phase. For example, the second control score data is 2 and the first control score data is 1; If the first control score data is equal to the second control score data and greater than 1, it is determined that both control phases are abnormal phases. For example, the second control score data is 2 and the second control score data is 2; If the first control score data is equal to the second control score data and equal to 1, it is determined that both control phases are normal phases. For example, the first control score data is 1 and the second control score data is 1; The technical effects of the above technical solution are as follows: Through the automated data acquisition and comparison process, the rapid and accurate determination of adjacent control phases is realized, improving work efficiency and accuracy. Furthermore, it is determined whether the abnormal phase has an impact on the next control phase and from which control phase the abnormal phase starts; The abnormal control phase can be promptly discovered and identified, and measures can be taken in a timely manner for correction to prevent the problem from deteriorating further.

[0123] By setting clear determination rules, the evaluation of control phases becomes more standardized and objective, reducing the influence of subjective judgment.

[0124] Through automated data acquisition, comparison, and phase determination, the effective monitoring and evaluation of adjacent control phases are realized.

[0125] In an embodiment of the present invention, for obtaining the control score data of adjacent control phases and re-adjacent control phases, performing comparative analysis of the control score data, and further obtaining the phase determination information of adjacent control phases and re-adjacent control phases, it further includes: Obtain the control score data of two adjacent control phases, denoted as the first adjacent score data and the second adjacent score data; When the first adjacent score data is greater than the second adjacent score data, it is determined that the adjacent control phase corresponding to the first adjacent score data is an abnormal adjacent phase; The first adjacent score data is the sum of its corresponding first control score data and second control score data; The second adjacent score data is the sum of its corresponding first control score data and second control score data; When the second adjacent score data is greater than the first adjacent score data, it is determined that the adjacent control phase corresponding to the second adjacent score data is an abnormal adjacent phase; When the first adjacent score data is equal to the second adjacent score data and greater than 2, it is determined that the control phases corresponding to the first adjacent score data and the second adjacent score data are abnormal adjacent phases; When the first adjacent rating data is equal to the second adjacent rating data and both are equal to 2, it is determined that the control phases corresponding to the first adjacent rating data and the second adjacent rating data are normal adjacent phases.

[0126] Calculate the control process anomaly coefficient through the control rating data of the adjacent control phase and the control rating data of the re-adjacent control phase; The calculation formula for the control process anomaly coefficient is:

[0127] Where KY is the control process anomaly coefficient, n is the total number of adjacent control phases, d is the total number of re-adjacent control phases, is the i-th first control rating data, is the i-th second control rating data, ZL1 a is the a-th first adjacent rating data, ZL2 a is the a-th second adjacent rating data, is the change amount between the i-th first control rating data and the i-th second control rating data, is the change amount between the a-th first adjacent rating data and the a-th second adjacent rating data. When is 0, no calculation is performed; Compare the control process anomaly coefficient with the preset control process anomaly threshold to obtain the control comprehensive anomaly comparison result; The preset process anomaly threshold is the allowable anomaly rating that can be determined based on historical anomaly data experience; Perform control comprehensive early warning according to the control comprehensive anomaly comparison result.

[0128] The working principle of the above technical solution is: Obtain the control rating data of two adjacent control phases, which are respectively set as the first adjacent rating data and the second adjacent rating data. The two rating data respectively represent the performance or state evaluation results of two adjacent control phases. Compare the first adjacent rating data and the second adjacent rating data to judge the state relationship between the two adjacent control phases. According to the comparison result, perform phase determination: If the first adjacent rating data is greater than the second adjacent rating data, it is determined that the adjacent control phase corresponding to the first adjacent rating data is the "abnormal adjacent phase".

[0129] If the second adjacent rating data is greater than the first adjacent rating data, it is determined that the adjacent control phase corresponding to the second adjacent rating data is the "abnormal adjacent phase".

[0130] If the first adjacent rating data is equal to the second adjacent rating data and greater than 2, it is determined that both adjacent control phases are the "abnormal adjacent phase", indicating that there are abnormalities in both phases in terms of performance or state.

[0131] If the first adjacent scoring data is equal to the second adjacent scoring data and both are equal to 2, it is determined that both adjacent control stages are "normal adjacent stages", indicating that both stages are within the normal range in terms of performance or status.

[0132] The technical effects of the above technical solution are as follows: By comparing the scoring data of adjacent control stages, it is possible to accurately detect which stage or stages are abnormal, and problems can be discovered in a timely manner and measures can be taken to correct them. Clear judgment rules are set, making the evaluation of adjacent control stages more standardized and objective, reducing the influence of subjective judgment, and improving the accuracy and reliability of the evaluation.

[0133] This method is relatively simple and clear, saving computing resources and reducing operational complexity.

[0134] By discovering and handling abnormal stages in a timely manner, the stability and reliability of the entire system can be improved, and system failures or performance degradation caused by abnormalities in a certain stage can be reduced.

[0135] In an embodiment of the present invention, the stage determination warning and marking according to the stage determination information include When the control stage is determined to be an abnormal stage, a first-level warning is given to the corresponding control stage; When the control stage is determined to be a normal stage, a control normal mark is given to the corresponding control stage; When the adjacent control stage is determined to be an abnormal adjacent warning, a second-level warning is given to the corresponding adjacent control stage; When the adjacent control stage is determined to be a normal stage, a control normal mark is given to the corresponding adjacent control stage.

[0136] The working principle of the above technical solution is as follows: Based on image feature comparison and status analysis, the system generates determination information (normal / abnormal) for each control stage. The determination results of adjacent control stages are recorded for abnormal adjacent warning analysis.

[0137] When a certain control stage is determined to be abnormal (such as the cell digestion stage score = 2), the system immediately triggers a first-level warning to prompt the operator that there is a risk in this stage. The warning methods include interface pop-up windows, sound and light alarms, or message pushes.

[0138] When a certain control stage is determined to be normal (such as the cell confirmation stage score = 1), the system automatically marks "control normal" and records it in the log.

[0139] If both adjacent control stages are determined to be abnormal (such as both the "cell digestion stage" and the "cell resuspension stage" score = 2), the system triggers a second-level warning to prompt that there may be continuous abnormality problems (such as equipment failures or process parameter deviations).

[0140] The secondary warning has a higher priority than the primary warning and requires immediate manual intervention.

[0141] If adjacent control phases are both determined to be normal (e.g., both the "cell seeding phase" and the "cell culture phase" have a score = 1), the system automatically marks "adjacent control normal" and associates it with the full-process report.

[0142] Automatically execute warnings and markings based on preset rules (such as anomaly thresholds, adjacent-phase association logic).

[0143] The determination information is updated in real time, and the warning and marking results are refreshed synchronously.

[0144] The technical effects of the above technical solution are: quickly locate single-phase anomalies and reduce the spread of faults (such as promptly repairing pipeline leaks). Identify systematic problems and avoid multi-phase chain failures (such as continuous anomalies caused by equipment parameter deviations).

[0145] Reduce the time for manual confirmation of normal phases and focus on anomaly handling.

[0146] Optimize process connection. For example, when both "cell seeding" and "cell culture" are normal, automatically skip the intermediate inspection steps.

[0147] Through the association of anomalies in adjacent phases, quickly locate the root cause (e.g., if both "cell digestion" and "resuspension" are abnormal, it may be due to improper concentration of digestive enzymes).

[0148] The marking and warning records support problem review and optimization of process parameters.

[0149] Identify potential equipment failures through secondary warnings (such as frequent triggering of anomalies in adjacent phases) and perform preventive maintenance in advance.

[0150] Reduce batch failures caused by phase anomalies and improve the success rate of cell culture.

[0151] In one embodiment of the present invention, the control score data of the adjacent control phases is the sum of the first control score data and the second control score data of the adjacent control phases. The first adjacent score data is the sum of the control score data of the adjacent control phase that is carried out first among the two adjacent control phases, and the second adjacent score data is the sum of the control score data of the adjacent control phase that is carried out later among the two adjacent control phases.

[0152] The working principle of the above technical solution is as follows: In each control stage (such as cell confirmation, pipeline connection), scores (such as normal = 1, abnormal = 2) are generated based on image feature comparison and status analysis. The sum of the scores of two adjacent stages is used to evaluate the connection risk between stages. The total score of the earlier stage (such as "cell confirmation" + "pipeline connection"). The total score of the later stage (such as "pipeline connection" + "cell cleaning").

[0153] The score of each stage is calculated independently, reflecting the operation quality of that stage. By the sum of the scores of adjacent stages, potential risks between stages can be identified (for example, abnormal "cell digestion" may lead to abnormal "cell resuspension").

[0154] The technical effect of the above technical solution is that when the sum of adjacent score data is abnormal (such as ≥ 3), it indicates a connection problem between stages.

[0155] By comparing adjacent scores, the root cause of the problem can be quickly located (for example, if both "cell digestion" and "resuspension" are abnormal, it may be due to improper concentration of digestive enzymes).

[0156] When the adjacent scores are normal (such as = 2), redundant checks are automatically skipped, shortening the operation time.

[0157] Long-term accumulation of adjacent score data reveals process bottlenecks (such as a certain stage frequently causing subsequent abnormalities).

[0158] Adjacent score data is automatically archived to support quality auditing and problem tracing.

[0159] Obviously, those skilled in the art can make various changes and deformations to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and deformations of the present invention fall within the scope of the claims of the present invention and its equivalent technologies, the present invention also intends to include these modifications and deformations.

Claims

1. A cell factory automation device, characterized in that: The cell factory automation device includes an operating device, a tube sealing machine, a sterile tube receiving machine and a control and monitoring module; The tube sealing machine and the aseptic pipe connecting machine are used for aseptic connection of the pipes; The operating device is used to wash, digest and resuspend the cells in culture medium after the aseptic connection is completed, and pack them into 10-layer cell factories, 40-layer cell factories and disposable liquid storage bags; The control monitoring module is used to perform control analysis of multiple control stages of the preset operation process, obtain determination information of the control stage, and then perform stage determination warning and marking; The aseptic pipe connection machine comprises a main unit, a pipe support and a power supply; The operating device comprises a mechanical arm, a cell culture rack, an operating platform and a system operating panel.

2. A control method for realizing the cell factory automation device according to claim 1, characterized in that: The control method comprises: Connect the connecting pipe of the cell factory to the cell factory through a sterile pipe connection machine to obtain a connected pipeline; The robot arm is controlled by the operating device to grab the cell factory and cell culture rack with connected pipelines to the designated station and perform preset operations to complete the cell passage operation; Obtain a preset operation process, divide it into multiple control stages, obtain control acquisition data for each control stage, perform control status analysis and scoring for each control stage based on the control acquisition data, and obtain control scoring data; Acquire control score data of adjacent control stages and re-adjacent control stages, perform comparative analysis on the control score data, and thereby obtain stage determination information of adjacent control stages and re-adjacent control stages; Stage judgment warning and marking are carried out according to the stage judgment information.

3. The control method of the cell factory automation device according to claim 2, characterized in that: The method of connecting the connecting pipe of the cell factory to the cell factory by using a sterile pipe connection machine to obtain a connected pipeline includes: Connect the power supply and turn on the switch button to start and self-check the sterile pipe machine; After the self-test is completed, insert the pipe support into the pipe support base inside the machine through the aseptic pipe top cover, and install the blade on the blade socket; Install the two connecting pipes to be installed in the grooves in the pipe support; The blade is heated and then cooled to the welding temperature to cut and weld the connecting pipes; After welding, the blade is cooled down; Get the connected pipeline and close the sterile takeover machine.

4. The control method of the cell factory automation device according to claim 2, characterized in that: The operation device controls the robot arm to grab the cell factory and the cell culture rack with the connected pipelines to the designated station and perform the preset operation to complete the cell passage operation, including: Install the robotic arm on the operating platform, and place the cell culture rack on the operating platform; Turn on the power of the robotic arm, and control the robotic arm through the system operation panel to grab the cell culture rack and the cell factory with connected pipelines on the corresponding station according to the preset operation process for operation; After the operation is completed, turn off the power of the robotic arm to complete the cell passaging operation.

5. The control method of the cell factory automation device according to claim 2, characterized in that: The step of obtaining a preset operation process, dividing the process into multiple control stages, obtaining control acquisition data for each control stage, and performing control state analysis and scoring for each control stage according to the control acquisition data to obtain control scoring data includes: The operation process is divided into control stages according to the preset operation process to obtain multiple control stages of the operation process; By setting a sensor group to collect control data in each control stage, control collection data is obtained; Preprocessing the control acquisition data to obtain control processing data; The image features of each control stage are compared and analyzed on the control processing data to obtain the control state determination information of each control stage.

6. The control method of the cell factory automation device according to claim 5, characterized in that: The image feature comparison and analysis of the control processing data at each control stage to obtain the control state determination information at each control stage includes: Sequentially acquiring image data of control processing data of each control stage, performing feature extraction on the image data of the control stage, and obtaining image feature data; Acquire target feature data of the control stage, compare the image feature data with the target feature data for multiple feature types, and obtain feature deviation types and feature deviation data of the control stage; Perform control state analysis on the control stage according to the characteristic deviation type and characteristic deviation data to obtain control state analysis data; Perform control status scoring based on control status analysis data to obtain control scoring data for the control stage; Among them, the control status is scored according to the control status analysis data to obtain the control score data of the control stage, including: Each control stage includes multiple feature analysis types, and image feature data of each feature analysis type is compared with target feature data to obtain control state determination information of image feature data of each feature analysis type; When the image feature data meets the target feature data, the control state score of the feature analysis type is set to 1; When the image feature data does not meet the target feature data, the control status score of the feature analysis type is set to 2; When the product of the control status scores of all feature analysis types is 1, the control status score of the control stage is determined to be 1; When the product of the control status scores of all feature analysis types is greater than 1, the control status score of the control stage is determined to be 2.

7. The control method of the cell factory automation device according to claim 5, characterized in that: The step of acquiring control score data of adjacent control stages and re-adjacent control stages, performing comparative analysis on the control score data, and then obtaining stage determination information of adjacent control stages and re-adjacent control stages includes: Obtain control score data of adjacent control stages, and set them as first control score data and second control score data; When the first control score data is greater than the second control score data, it is determined that the control stage corresponding to the first control score data is an abnormal stage; When the second control score data is greater than the first control score data, determining that the control stage corresponding to the second control score data is an abnormal stage; When the first control score data is equal to the second control score data and is greater than 1, it is determined that the control stages corresponding to the first control score data and the second control score data are both abnormal stages; When the first control score data and the second control score data are equal to and equal to 1, it is determined that the control stages corresponding to the first control score data and the second control score data are both normal stages.

8. The control method of the cell factory automation device according to claim 7, characterized in that: The step of acquiring control score data of adjacent control stages and re-adjacent control stages, performing comparative analysis on the control score data, and then obtaining stage determination information of adjacent control stages and re-adjacent control stages, further includes: Obtain control score data of two adjacent control stages, and set them as first adjacent score data and second adjacent score data; When the first adjacent scoring data is greater than the second adjacent scoring data, it is determined that the adjacent control stage corresponding to the first adjacent scoring data is an abnormal adjacent stage; When the second adjacent scoring data is greater than the first adjacent scoring data, it is determined that the adjacent control stage corresponding to the second adjacent scoring data is an abnormal adjacent stage; When the first adjacent scoring data is equal to the second adjacent scoring data and is greater than 2, it is determined that the control stage corresponding to the first adjacent scoring data and the second adjacent scoring data is an abnormal adjacent stage; When the first adjacent scoring data and the second adjacent scoring data are equal to and equal to 2, it is determined that the control phase corresponding to the first adjacent scoring data and the second adjacent scoring data is a normal adjacent phase.

9. The control method of the cell factory automation device according to claim 2, characterized in that: The step of performing stage determination warning and marking according to the stage determination information includes: When the control stage is judged as an abnormal stage, a first-level warning is issued for the corresponding control stage; When the control stage is determined to be a normal stage, the corresponding control stage is marked as normal; When the adjacent control stage is judged as an abnormal adjacent warning, a secondary warning is issued for the corresponding adjacent control stage; When the adjacent control stage is determined to be a normal stage, the corresponding adjacent control stage is marked as being under control.

10. The control method of the cell factory automation device according to claim 8, characterized in that: The control score data of the adjacent control stage is the sum of the first control score data and the second control score data of the adjacent control stage; the first adjacent score data is the sum of the control score data of the adjacent control stage performed first of the two adjacent control stages, and the second adjacent score data is the sum of the control score data of the adjacent control stage performed later of the two adjacent control stages.

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